Pharmacology

UNIT -1Sources of drugs

Drugs are obtained from different sources

Most of the drugs that are currently used are manufactured synthetically

Recently drugs are synthesized by genetic technologies like human recombinant gene technologyEx Erythropoietin

Source Specific source and drugs Category

Plants

Belladonna- Atropine

Digitalis- Digitoxin

Opium - Morphine

Ant cholinergic

Cardio tonic

Narcotic analgesics

Animals

Pork, Beef – Insulin

Horse – Tetanus anti toxin

Various animals - Heparin

Anti-diabetic

Ant tetanus

Anti- coagulant

Minerals

Charcoal

Magnesium sulfate

Aluminum hydroxide

Antidote

Purgative

Antacid

Microbes

Penicillium Notatum – Penicillin

Actinomycetes – Streptomycin

E. Coli - L- asparaginase

Antibiotic

Antibiotic

Anti-cancer

Synthetic

Aspirin

Cimetidine

Paracetamol

Phenitoin

Phenobarbitone

Analgesics

Antacid

Anti-pyretic

Anti-epileptic

Hypnotic

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Dosage forms

Pharmaceutical companies dispense a drug in a variety of formulations suitable for a single or multiple routes of administration

Some antibiotics are available in tablet, capsules or suspension form for oral administration

So doctor can choose the formulation suitable for the patient

It is important because it influences the bioavailability of drug

For ex

Digoxin when injected intravenously, the bioavailability of that drug is 1.00

But when the same amount of the drug is administered into the body by oral route in tablet form, the bioavailability is about is 0.62

On the other hand, the bioavailability of digoxin elixir administered orally is 0.80

When a tablet form of drug is swallowed, it is necessary to disintegrate as well as to dissolve before absorption

But in case of capsule, there is no question of disintegration , only dissolution is necessary

In case of suspension, there is no disintegration or dissolution

So, the rate of absorption is greater in suspension than capsule or tablet

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Route of administration

To produce a pharmacological effect it is very important for the drug to reach the site of action

This depends on the transfer of drugs across one or more membrane barriers

Drugs after reaching the blood circulation builds up a therapeutic concentration

The concentration depends on the volume of distribution, biotransformation and excretion

There are some drugs which are not absorbable from one site but get into the circulation from another

Benzyl penicillin is inactivated in the stomach at gastric PH and is not administered orally

Some drugs absorbed from the gastrointestinal tract pass the intestinal mucosa and the small intestine but metabolized by the gut wall (such as chlorpromazine , dopamine) orby the liver ( such as lignocaine, pethidine, propranolol) In order to select the route for administration this first-pass biotransformation is considered and on occasions is avoided

Slowly absorbed drug may have delayed onset of effect and may even fail to achieve effective concentration

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Mechanism of drug action

Many drugs produce their effects by binding to specific target proteins like receptors, enzymes and ion channels .

Drugs may act on the cell membrane, inside or outside the cell to produce their effect

Drugs may act by one or more complex mechanisms of action

The fundamental mechanism of drug action may be

1.Through receptor

2. Through enzymes and pumps

3. Through ion channels

4. By physical action

5. By chemical interaction

6. By altering metabolic process

1. Through the receptors

Drugs may act by interacting with specific receptors in the body

Receptor

It is a macromolecular site on the cell with which an agonist binds to bring about a change

Affinity

Its the ability of a drug to bind to a receptor

Efficacy

Its the ability of a dung to elicit a response after binding to the receptor

Agonist

An agonist is a substance that binds to the receptor and produces a responseIt has affinity and intrinsic activity

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Antagonist An antagonist is a substance that binds to the receptor and prevents the Action of agonist on the receptorIt has affinity but no intrinsic activity

Partial agonist It binds to the receptor but has low intrinsic activity

Inverse agonist

Some drugs , after binding to the receptors produce opposite to those produced by a pure agonist

Eg

Diazepam acting on benzodiazepine receptors produces sedation, anxiolyses, muscle relaxation and controls convulsions, while beta – carbolines bind to the same receptors to cause arousal , anxiety, increased muscle tone and convulsions

Ligand is a molecule which binds selectively to a specific receptor

Various receptor are have been identified, isolated and extensively studiedSite

The receptors may be present in the cell membrane, in the cytoplasm or on the nucleusNature receptors

Receptor are proteins

Synthesis and life – span

Receptor proteins are synthesized by the cellsThey have a definite life span after which the receptors are degraded by the cell and new receptors are synthesized

Function of Receptors

Recognition and binding o the ligand

Propagation of the message

For the above e function , the receptor has two functional domains (areas)

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A ligand binding domain - The site to bind the drug molecule

An effecter domain – which undergoes a change to propagate the message

The drug – receptor interaction has been considered to be similar to lock and key relationship where the drug specifically fits into the particular receptor ( lock) like a key.

Interaction of the agonist with the receptor brings about changes in the receptor which in turn conveys the signal to the effectors system

The final response is brought about by the effecter system through second messengers.The agonist itself is the first messenger

The entire process involves a chain of events triggered by drug receptor interaction

2. Through enzymes and pumps

Drugs may act by inhibition of various enzymes, thus altering the enzyme- mediated reactions

Ex

Allopurinol inhibits the enzyme xanthene oxidizes ,Acetazolamide inhibits carbonic anhydrase

Membrane pumps like H-K ATPase may be inhibited by drugs

Ex

Omeprazole, digoxin

3. Through ion channels

Drugs may interfere with the movement of ions across specific channels ExCalcium channel blockers and potassium channel blockers

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4. Physical action. The action of a drug could result from its physical properties like

Adsorption - Activated charcoal in poisoning

Mass of the drug - Bulk laxatives like psyllium, branOsmotic property - Osmotic diuretics- Mannitol ,

Osmotic purgatives – Magnesium sulphate

Radioactivity - I 131

Radio- opacity - Barium sulphate contrast media

5. Chemical interaction

Drugs may act by chemical reaction

Antacids - Neutralize Gastric Acids

Oxidizing agents - Like potassium permanganate – germicidal

Chelating agents - Bind heavy metals making them nontoxic

6. Altering metabolic processes

Drugs like antimicrobials alter the metabolic pathway in the micro- organisms resulting in destruction of the micro-organisms Ex

Sulfonamides interfere with bacterial folic acid synthesis

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ANERGIC RECEPTOR

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Cholinergic receptor

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GABA Receptor

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Opium receptor

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Receptor effectors coupling

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Neurotransmitter

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Secondary messengers

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Ligand gated ion channels

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G protein coupled receptor

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TRK RECEPTOR

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Nuclear receptor

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Regulation of receptor

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NEUROTRANSMITTERS

Def The chemical substance that acts as the mediator for the transmission of nerve impulse from one neuron to another neuron through a synapse is called the neurotransmitter Presynaptic neuron Dendrite ---- axon----- break down into minute branches that terminate in small swellings called synaptic knobs or terminal boutons These are in close proximity to the dendrite & the cell body of the post- synaptic neuron The space between them is the synaptic clept In the end of the synaptic knobs are spherical synaptic vesicles The synaptic vesicles containing a chemical known as neurotransmitter The transmitter is released into the synaptic clept the gap between two neurons The neurotransmitter are synthesized by nerve cells & transported along the axons & stored in the synaptic vesicles They are released in response to the action potential & diffuse across the synaptic clepts They act on specific receptor sites on the post-synaptic membranes Their action is short lived Neurotransmitter are either inactivated by enzymes or taken back into the synaptic knobs PROPERTIES The substance must be found in a neuron It must be produced by a neuron It must be released by a neuron After release it must act on a target area & produce some biological effect After the action it must be inactivated

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CLASSIFICATION

1. Depending on chemical nature

A. Amino acids

The neurotransmitters of this group are involved in fast synaptic transmission & are inhibitory and excitatory in actionExGABA, Glycine, glutamate (glutamic acid) and aspirate(aspartic acid)

B. Amines

These are modified amino acidsThese have slow synaptic transmissionThese have inhibitory or excitatory in action

Ex

Adrenaline , nor-adrenaline, dopamine, serotonin and histamine

C. Others

Some neurotransmitters do not fit into any of there categories

2. Depending on function

A. Expiatory neurotransmitter

B. Inhibitory neurotransmitter

A .Expiatory neurotransmitter

It is responsible for the conduction of impulse from the presynaptic neuron to the post-

Neurotransmitter + Receptor--- Opening of Na channels – influx of sodium

ExAcetyl choline, adrenaline

B. Inhibitory neurotransmitters

The inhibitory neurotransmitter inhibits the conduction of impulse from the presynaptic neuron to the post-synaptic neuron

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Inhibitory neurotransmitter is released from the presynaptic axon terminal due to the arrival of action potential

It causes opening of K channels in post-synaptic membrane and efflux of potassium ions

This leads to hyper-polarization which is called inhibitory post-synaptic potential ( IPSP)

When IPSP is developed, the action potential is not generated in the post-synaptic neuron

Ex

GABA , Glycine and Dopamine

Important neurotransmitter are

Acetyl choline

Nor-adrenaline

Dopamine

Serotonin

GABA

Histamine

Glycine

Glutamate

Substance P

Nitric acid

1 . ACETYLE CHOLINE

It is a cholinergic transmitter

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Site of secretion

Preganglionic parasympathetic nerve endings

Postganglionic parasympathetic nerve endings

Preganglionic sympathetic nerve ending

Neuromuscular junction

Cerebral cortex

Basal ganglia

Thalamus

Amacrine cells of retina

Synthesis Acetate activating reaction Acetate + Co-Enzyme-A + ATP ------------------------------------- Acetyl CoEn-A

Choline acetylaseAcetyl CoEn-A + CHOLINE -- --------------------------------- ACETYLCHOLINE

Receptor

Nicotinic receptor and Muscarinic receptor

1. Nicotinic receptor

These are of two subtypes N1 & N2 also referred to as Nm and Nn receptors

The nicotinic receptors are located on postganglionic cell bodies in the autonomic ganglia at neuromuscular junctions of skeletal muscle and on neurons of CNS

2. Muscarinic receptors These are of five types M1, M2, M3, M4 and M5 of which the first three are well definedThe muscarinic receptors are located on smooth h muscle, cardiac muscle, gland cell and some neurons of CNS

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FunctionExcitatory function It is synthesized in axon terminals and stored inside the vesicles

Excitatory functionOpening of legand gated Na channelsAch has very quick and potent action It also destroyed immediately after executing the actionIt is destroyed by the enzyme acetyl-cholinesteraseThis enzyme is present in basal lamina of the synaptic cleft

2. Nor-adrenaline

It is the neurotransmitter in adrenergic nerve fibers

Site of secretion

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Post gang ionic sympathetic nerve endingsCerebral cortexHypothalamusBasal gangliaBrainstemSpinal cord

In many places, it is the excitatory chemical mediator and in very few places, it causesInhibitionIt is believed to be involved in dreams, arousal and elevation of moods

Synthesis

It is synthesized from the amino acid tyrosine in the chromaffin cells of adrenal medulla

These hormones are formed from phenylalanine, but phenylalanine has to be converted into tyrosine

Formation of tyrosine from phenylalanine in the presence of enzyme phenylalanine Hydroxylase

Uptake of tyrosine from blood into the chromaffin cells of adrenal medulla by active Transport

Conversion of tyrosine into dihydroxyphenylalanine (DOPA) by hydroxylation in thepresence of tyrosine hydroxylase

Decarboxylation of DOPA into dopamine by DOPA decarboxylase

Entry of dopamine into granules of chromaffin cells

Hydroxylation of dopamine into nor-adrenaline by the enzyme dopamine betaHydroxylase

Release of nor-adrenaline from granules into the cytoplasm

RECEPTOR

The action of nor-adrenaline are executed by binding with receptors called adrenergicReceptors

They are two types of receptors

A. Alpha- adrenergic receptor

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B. Beta – adrenergic receptor

A. Alpha- adrenergic receptor

It is subdivided into Alpha1 and Alpha2Alpha-adrenergic receptors mediate more of nor-adrenaline action than the adrenalineAction

1. Alpha1 receptor

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Mode of action

It exert their actions by activating the secondary messenger IP3 through phospholipase C

2.Alpha 2 receptor

It exert their effects by inhibiting adenyl cyclase and reducing intracellular CAMP

B. Beta- adrenergic receptor

1. Beta1- receptor

These mediate the actions of both adrenaline and nor-adrenaline almost equally

2. Beta2 receptor

These receptors are larger than B2

These receptors mediate more of adrenaline actions than nor-adrenaline actions

Both B1 and B2 receptors produced their actions by activating adenyl cyclase through G protein and increasing intracellular cyclic AMP

3. SEROTONINE

It also known as 5- hydroxyl-tryptamine

It is synthesized from tryptophan by hydroxylation and decarboxylation

Large amount of serotonin (90%) is found in intero-chromatin cells of GIT

Small amount is found in platelets and nervous system

It is also called Enteramine as GIT contains 80-90% of all the 5 HT in the body

Platelets contain 5HT while passing through the GIT

It is secreted in the following areas

HypothalamusCerebellum

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Limbic systemMidbrainSpinal cordGIT Lungs PlateletsRetina

Synthesis

It is produced from tryptophan ,essential amino acid and is metabolized by mono-amine 0xidase

Tryptophan hydroxylase Tryptophan --------------------------------------------- 5-Hydroxy-tryptophan (5 HTP)

O2 decarboxylase

5- Hydroxy- tryptamine (5 HT) --------------------------- 5HT MAO

5-HT -------------------------------------------5- Hydroxy- indole acetic acid (5HIAA)

Serotonin receptor

There are 4 families of 5 HT receptors—5HT1 – 5HT4

It comprising of 14 receptors subtypes

It is contained mainly in the brainstem neurons that innervate practically all other areas of the CNSIn general 5 HT hasAn excitatory effect on motor pathways

An inhibitory effect on the sensory pathways

It plays important role in the neural pathways controlling moods

The presence of descending serotonergic neurons in the brainstem and spinal cord is essential for the analgesic action of morphine

4. GABA

It is an inhibitory neurotransmitter in synapses particularly in CNS

It is responsible for presynaptic inhibition

It is secreted by nerve endings in the following structuresCerebral cortexCerebellumBasal gangliaSpinal cord

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Retina

Mechanism of actionPresynaptic inhibition

It is also known as indirect inhibition and it occurs because of the failure of presynapticaxon terminal to release the excitatory neurotransmitter substance

Post synaptic inhibition

It also called direct inhibition

It occurs due to the release of an inhibitory neurotransmitter from presynaptic terminalinstead of excitatory neurotransmitter substance

The most important inhibitory neurotransmitter is gamma amino butyric acid (GABA) and Glycine

The GABA acts on post-synaptic membrane by binding with receptor

The transmitter receptor complex opens the ligand gated potassium channels instead of sodium channels

The K channels which are more in the cell body of post-synaptic neurons more to ECF

Simultaneously Cl channels also open and Cl ions which are more in ECF move inside the cell body of post-synaptic neurons

The exit of K ions and influx of Cl ions cause more negativity inside, leading to hyperpolarization

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Receptors

1. GABA A ( Intrinsic ion channel receptor)

Opening of ion channels known as chloride channels and conduction of chlorine influx of Cl ions2. GABA B ( G- protein coupled receptor)

Hyper polarization

K conduction

Altering of Ca influx3. GABA C

5. DOPAMINE

It is secreted by nerve endings in the following areas

Basal ganglia

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Hypothalamus

Limbic system

Retina

Sympathetic ganglia

Receptor

Dopamine acts on 5 types of dopamine receptors (D1-D5) - G proteins mediated

The brain contains more of D2 receptors

Synthesis

Dopamine is secreted by adrenal cortex

Dopamine also secreted by dopaminergic neurons in some areas of brain particularly , basal ganglia

In brain this acts as a neurotransmitter

The other physiological functions of circulating dopamine are not understood clearly

Functions

Vaso-constriction by releasing nor-adrenaline

Vasodilatation in mesentery

Increases in heart rate via beta receptorIncreasing in systolic blood pressure

Dopamine dies not affect diastolic blood pressure

Deficiency of dopamine in basal ganglia produces nervous dies-order called Parkinsonism

6. HISTAMINE

It is formed by decarboxylation of the amino acid known as Histidine

It is exciter neurotransmitter

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It is secreted by nerve endings of

Hypothalamus

Limbic cortex

Other parts of cerebral cortex

Gastric mucosa

Mast cells

Spinal cord

Mechanism of action

It is believed to play an important role in arousal mechanism

Functions

Intra-cerebroventricular administration produces

Rise in BP

Cardiac stimulation

Behavioral arousal

Hypothermia

Vomiting

ADH release

Sensation of itching

7. GLUTAMATE (ASPARATE)

It is the most abundant amino acid in the brain and is concentrated in dorsal sensory nerve terminals

It is an important excitatory neurotransmitter in dorsal root afferent and at other sits in CNS

It depolarizes spinal motor neurons and cortical neurons by increasing Na permeability of the membrane

Receptor

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1. Metabotropic receptor

Protein coupled receptor

Mainly involved in production of synaptic plasticity

2. Inotropic receptorLegend gated ion channels

There are 3 subtypes of receptors

In this NMDA ( N- methyl-d-aspirate) are important

This receptors play important role in memory and learning

3. m – GLU8. GLYCINE

It is inhibitory neurotransmitter

It is formed and released by inhibitory inter-neurons which act on motor neurons in the brain and spinal cord

In the spinal cord it is responsible for direct inhibition

It acts by increasing Cl permeability

Site of secretion

Fore brain, brain stem, spinal cord and retina

Gyycine concentration in the ventral grey matter of the spinal cord is higher than any other amino acids

9. SUBSTANCE – P

It is a neuropeptide that acts as a neurotransmitter

It is a polypeptide with 11 amino acid residues

It belongs to a family called neurokinins

The substance p is secreted by the nerve endings of pain pathway in spinal cord

It also found in hypothalamus retina and intestine

It mediates pain sensation

It is a potent vasodilator in CNS

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It is also responsible for regulations of anxiety, stress, mood disorders, neurotexicity, nausea and vomiting

10. NO

It is a neurotransmitter in the CNS

It is produced by non- neuronal cells like the endothelial cells of blood vessels

From the site of production it diffuses into the neuronal and non-neuronal cells where itexerts its action

It also produced in the brain and is responsible for long term protestation LTP and long term depression (opposite of LTP)

NO is synthesized from arginine by action of enzyme NO synthetics

It activates guanyl cyclase in cells, producing c GMP which brings about relaxation of vascular smooth muscle

NO acts as a mediator for the dilator effect Ach on small arteries

It indirectly causes dilatation of arterioles

NO is inactivated by haemoglobulin

NO is released by variety of agents such as Ach, sudden increase in tissue blood flow and products of platelet aggregation

NO deficiency produces hypertension , atherosclerosis and impotency

Drug dependence

Drug dependence means a state of physical or psychic or some times both , characterized by a compulsion to take the drug continuously or periodically in order to experience the psychic effects of well being or to avoid the discomfort of its absence.

A person may be dependent on one or more drugs

Drug dependence is of two types namely

1. Physical dependence

2. Psychic dependence

1. Physical dependence

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It is an adoptive state which causes intense physical disturbance when the administration of the drug is stopped

These disturbances , that is withdrawal produce specific symptoms characteristic for each drug type

It may produce tolerance

2. Psychic dependence

Here there is a feeling of satisfaction and a psychic drive that requires periodic or continuous use of the drug to produce a sense of well being or to avoid discomfort

Psychic dependence is specific and it varies with the individuals and with the drug

The following drugs are produce drug dependence

1. Opium drugs

2. Morphine , Heroin , codeine, synthetic drugs like pethidine and methadone

3. Coca leaves and cocaine

4. Cannabis—Ganja, chars and hashish

5. Alcohols , barbiturates, chlorolhydrates, chlor- diazapoxide, diazepam, methaqualone and meprobamide

6. Volatile solvents like toluene, acetone and carbon tetrachloride

7. Caffeine, tobacco, betel leaves and nutmegs

Problems of drug dependence

Mere dependence on drugs itself is a problem as it necessitates the use of drugs continuously even though they are not required therapeutically

Dependence on caffeine is condonable.

Dependence on tobacco is avoidable dependence

Where as dependence on alcohol has to be condemned and legally prevented

The problems associated with drug dependence are of three types

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1. The individual problems are that the drugs may adversely affect the physical and mental health of the addict

2. Socio-cultural problems are that the drug dependence may cause loss of earning capacity of the drug user

3. Socio-legal problem is prohibiting and controlling the traffic in such dangerous drugs. Further the smuggling of dangerous drugs is to be considered as criminal activity

Tolerance

Def

Tolerance is the requirement of more amount of drug to produce specific response

Concept of can be explained in easiest possible way with the example of effect of alcohol

Specific quantity of alcohol produces a certain effect in CNS

After periodic consumption of alcohol the same quantity of alcohol the same can not produce the same effect, this effect is reduced

To get the same effect, one has to consume more amount of alcohol.

This is development tolerance for alcohol

Drugs also follow the same rules

Some times tolerance is observed even when drug is administered for the first time

Tolerance can be classified into

1. Natural tolerance2. Acquired tolerance

1. Natural tolerance

It is the presence of tolerance without prior exposure to the drugThe effect of drug in a few individuals or few species are less in magnitude from the very first exposure to drug

Ex

Some individuals require more amount of anticoagulants as compared to normal therapeutic doses. The reasons are usually genetic

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2. Acquired tolerance

It is the development of tolerance after a prolonged or rapid or excessive use of drugs

Mechanism for development of acquired tolerance

1.Down regulation of receptors

It is the decrease in number and sensitivity of receptors for an agonist after prolonged exposure to it

2. Internalization of receptor

After prolonged exposure to agonists some receptors are taken inside the cell and they remain unavailable for action

3. Enzyme induction

Alcohol induces hepatic microsomal enzymes that are required for its own metabolism

So long term use of alcohol results in faster metabolism and elimination and reduced action of alcohol. Tachyphylaxis

It is the development of tolerance after repeated administrations of a drug

Ex

Ephedrine stimulates release of stored nor adrenaline from the nerve endings

After repeated administrations of ephedrine, the store of nor adrenaline is exhausted and effect of ephedrine is reduced

Clinical implications of tolerance

Previous prolonged exposure to drug can produce clinical effects that are less than what are expected

Development of tolerance when demands increase in doses, decision is not very easy. Because tolerance for effect may not be associated with tolerance for side effects

Cross tolerance

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If prolonged use of one drug results in development of tolerance for another drug, it is cross tolerance for another drug

Such two drugs are usually similar in either structure or in function

Ex

Prolonged exposure to barbiturates results in development of tolerance for hypnotic agents

Pseudo tolerance

From the prehistoric period, poisons are consumed regularly and in small quantities to develop tolerance against them . This type of logic is not scientifically proved

DISTRIBUTION

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METABOLISM

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UNIT – 2

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NEURO-HUMARAL TRANSMISSION

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Synaptic transmission involves many steps

Synapse

It is a region including the axon terminal of a presynaptic neuron, the plasma membrane of the postsynaptic cell

In presynaptic neurons

Ex

Neurotransmitter synthesis and storage in vesicles

Synaptic cleft

physical space between the cells is known as synaptic cleft

Postsynaptic cells can be neurons or other cells( effecter cell in the muscle) At synapse, electrical transmissions –action potentials along presynaptic neurons are translated into chemical signals which lead to postsynaptic cell responses, increases or excitation , decrease or inhibition or modulation of neuron activity or biochemistry

On postsynaptic membranes

Ex

Binding to receptors, change in ion channel function

In postsynaptic neurons

Ex

Effect on second messenger transduction

Stimulations of enzymes

Physiological action

Communication (transmission of information) across synapses occurs via chemical

messengers – neurotransmitters- stored in vesicles in presynaptic neurons

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Action potentials at presynaptic axon terminals initiate steps that release neurotransmitter

molecules into a synapse which cross the synaptic cleft and bind reversibly to

postsynaptic receptors

Receptor activators (ex drugs) are agonists and antagonists are drugs that combine with

but do but activate receptors

Transmitters are removed form synapses by enzymatic destruction m diffusion, and

active reuptake into presynaptic neurons

Major peripheral neurotransmitters are acetylcholine ,catecholamine(ephedrine and

dopamine)

In brain and spinal cord , major excitatory neurotransmitters are glutamate and aspirate

Major inhibitory neurotransmitters are GABA and glycine

5 –HT, or serotonin and neuropeptides are other neurotransmitters

Neurohumoral transmission implies that nerves transmit their message across synapses

and neuroeffector junctions by the release of humeral messengers

Neurohumoral transmitters substance must fulfill the following criteria

1. It should be present in the presynaptic neurons ( usually along with enzymes

synthesizing it)

2. It should be released in the medium following nerve stimulation

3. Its application should produce response identical to those produced by nerve

stimulation

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4. Its effects should be antagonized or potentated by other substances which

similarly alter effects of nerve stimulation

Steps in Neurohumoral transmission

1. Impulse conduction

2. Transmitter release

3. Transmitter action on postjunctional membrane

4. Postjuctional activity

5. Termination of transmitter act ion

1. Impulse conduction

The resting Tran membrane potential (70 mV negative inside) is established by high K

permeability of axonal membrane and high axoplasmic concentration of this ion coupled

with low Na permeability and its active extrusion

Stimulation or arrival of an electrical impulse causes a sudden increase in Na

conductance—depolarization and overshoot ( reverse polarization – 20 mV positive)

K ions then move ort in the direction of their concentration gradient and repolarization

occurs

Ionic distribution is normalized during the refractory period by the activation of Na-K

pump

The action potential generated sets up local circuit currents which activate ionic channel

at the next excitable part of the membrane ( next node of Ranvier in myelinated fiber )

and the AP is propagated without decrement

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Transmitter release

The transmitter (excitatory or inhibitory) is stored in prejunctional nerve endings within

synaptic vesicles

Nerve impulse promotes fusion of vesicular and axonal membranes, through Ca entry

which fluidizes membranes

All contents of the vesicle ( transmitter, enzymes and other proteins)are extruded in the

functional cleft

3. Transmitter action on postjunctional membrane

The released transmitter combines with specific receptors on the postjunctional

membrane and depending on its mature induces an excitatory postsynaptic potential

(EPSP) or (IPSP) an inhibitory postsynaptic potential

EPSP

It increase in permeability to all cations –Na or Ca influx ( through fast or slow channels)

causes depolarization followed by K efflux

These ionic movements are passive as the flow is down the concentration gradients

IPSP

It increase in permeability to smaller ions

That is K and Cl ( hydrated K ion is smaller than hydrated Na ion) only, so that K

moves out and CL moves in (in the direction of their concentration gradients ) resulting

in hyper polarization

4. Postjunctional activity

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A suprathreshold EPSP generates a propagated postjunctional AP which results in nerve

impulse ( in neuron), contraction ( in muscle ) or secretion ( in gland)

IPSP stabilizes the postjunctional membrane and resists depolarizing stimuli

5. Termination of transmitter action

Following its combination with the receptor ,the transmitter is either locally degraded (ex

Ach) or is taken back into the prejunctional neuron by active uptake or diffuses away (ex

NA, GABA)

Rate of termination of transmitter action governs the rate at which responded can bet

transmitted across a junction (1 to1000 /sec)

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Parasympathomimetic drugs

1. Choline esters

Acetyl cholineMethacholine - 10-30 mg , s/cCarbachol- 0.2 – 0.5mg s/c , or 1-4mg , orallyBethanechol- 2.5 mg s/c, 5 -30 mg orally

2. Naturally occurring alkaloids

PolocarpineMuscarineArecholine

3. A . Cholinesterase inhibitors

PhysostigmineNeostigminePyrodostigmineBenzpyriniumAmbenoniumEdrophoniumDemecarium

3. B Cholinesterase inhibitors (irreversible ) or organ phosphorus compounds

DFP –(Di-iso-propyl fluorophosphate)HETP- (Hexa ethyl tetra phosphate)TEPP – (Tetra ethyl pyrophosphate)OMPA – Octa methyl pyrophosphoramide)

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Cholinergic receptor

PNS

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Cholinergic system

Acetyl choline (Ach) an ester of choline, is an important neurotransmitter of the ANSThe nerves that synthesize, store and release Ach are called cholinergic

The site of release of Ach is

Cholinergic receptors

There are two classes of cholinergic receptors

They are nicotinic and muscarinic receptors

Muscarinic receptors are present in the heart, smooth muscles, glands , eyes and CNS

Five subtypes of muscarinic receptors – M1 to M5 are recognized

Nicotinic receptors are present in the neuromuscular junction, autonomic ganglia and adrenal medulla

Two subtypes of nicotinic receptors are identified

Nm receptors are present at the skeletal muscle end plate and Nn receptors at the autonomic ganglia and adrenal medulla

1. Ganglia - All the preganglionce fibers of ANS I.e. both the sympathetic and parasympathetic ganglia

2. The postganglionic nerve fibers of parasympathetic nerve endings

3. Sweet glands – The sympathetic postganglionic nerve endings supplying the sweet Glands

4. Skeletal muscles – Somatic nerve endings supplying skeletal muscles

5. Adrenal medulla

6. CNS - Brain and spinal core

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Synthesis of Ach

Acetyl choline synthesized from acetyl coA and choline , catalyzed by the enzyme choline acetyltransferase

This Ach is stored in small oval vesicles known as synaptic vesicles in the cholinergic nerve terminals

Transmission of an impulse

When as action potential reaches the presymaptic membrane, Ach is released into the synaptic cleft

This Ach binds to and activates the cholinergic receptor on the postsynaptic membrane leading to the depolarization of this membrane

Thus the impulse is transmitted across the synapse

The Ach released into the synaptic cleft is rapidly destroyed by the acetyl cholinesterase enzyme

Then the postsynaptic membrane is repolarised

Cholinesterase

Acetylcholine is hydrolyzed to choline and acetic acid by the enzymes cholinesterase Two types of Ach enzymes are present

True cholinesterase - at neurons, ganglia and neuromuscular junction

Pseudo cholinesterase - In plasma, liver and other organs

Receptor Subtype LocationM1 Autonomic ganglia , gastric glands, CNS

Muscarinic M2 Heart, nerves, smooth musclesM3 Glands , smooth musclesM4 CNSM5 CNS

Receptor Subtypes LocationNicotinic Nm Neuromuscular junction

Nn Autonomic gangliaAdrenal medulla, CNS

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Cholinergic receptor

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Parasympatholytic drugs

1. Belladonna alkaloids

AtropineScopolamine

2. Semi-synthetic substitutes of belladonna alkaloids

HomatropineAtropine methyl nitrateScopolamine methyl bromideHomatropine methyl bromide

3. Synthetic substitutes of belladonna alkaloids

MethamthelinePropanthelineOxyphenoniumDibutolineCyclopentolate

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Sympathomimetic drugs

Classification as per their site and mode of action

1.Alpha receptors

NoradrenalinMephentermineMetarminolMethoxaminePhenylephrine

2. Beta receptor IsoprenalineIsoxsuprineNylidrine

3. Acting on both alpha and beta receptor

Adrenaline EphedrineAmphetamine

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ANERGIC RECEPTOR

58

59

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Sympathetic blocking agents

1. Alpha adrenergic blocking agents

A. Alpha -1 blockers

Prazosine

B. Alpha – 2 blockers

Yohimbine

C. Both alpha1 and alpha-2 blockers

PhenoxybenzamineDibenamineTolazolinePhentolamineErgot alkaloids

11. Beta adrenergic blocking agents

A. Beta -1 blockers

AtenololAcebutololMetaprolol

B. Beta-2 blockers

Butoxamine

C. Both beta-1 and beta-2 blockers

PropranololSotololNodololTimolol

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UNIT - 3

Adrenergic neuron blocking agents

GuanethidineGuanoxonGuanachlorBethanidineDebrisoquine sulphate

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Ganglionic stimulating agents

Drugs can act on sympathetic and parasympathetic ganglia producing either stimulation or blockade

Ganglionic stimulants have extremely limited therapeutic application

But ganglion blocking agents are effective in the treatment of hypertension

Though the ganglionic stimulating agents have no therapeutic use, they find use as experimental tools

Classification

1. Natural alkaloids

NicotineLobeline

2. Synthetic compounds

Tetra-methyl- ammonium (TMA)Di-methyl-phenyl- piperasinium (DMPP)

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Ganglionic blocking agents

1. Selective blocking agents

NicotineLobelineDim ethyl phenyl piperazinium iodide (DMPP)Tetra methyl ammonium (TMA)

2. Non selective muscarinic agonists

AcetylcholineCarbacholPilocarpineAnticholinesterases

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Neuromuscular blocking agents

1. Competitive agents

D- TunocurarineGallaminePancuroniumAlcuroniumAtracuriumVecuronium

2. Depolarizing agents

Succinylcholine

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Local anestheticsDef

Local anesthetics are drugs that block nerve conduction when applied locally nerve tissue in appropriate concentrations

1. Injectable

A. Low Potency, Short Duration Of Action

ProcaineChlo-procaine

B. Intermediate potency and duration

Lignocaine (Lidocaine)Prilocaine

C. High potency, long duration

Tetracaine (Amethocaine)CinchocaineBupivacaineRopivacaine

11. Surface anesthetics

A. Soluble

CocaineLignocaineTetracaine

B. Insoluble

BenzocaineButamben

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Oxethazaine

The action is completely reversible

They act on every type of nerve fiber and can cause both sensory and motor paralysis in the innervated area

They act on axons, cell body , dendrites, synapse and other excitable membranes that utilize sodium channels as the primary means of action potential generation

Cocaine was the first agent to be isolated by Niemann in 1860 and used for 30 years

Procaine was synthesized in 1905 and it rules the field for the next 50 years

In 1943 , Lignocaine was synthesized and it continues to dominate the field till today

Chemistry

Local anesthetics are bases and consist of a hydrophilic amino groups on one side and a lopophilic aromatic residue on the other side , joined by an intermediate chain through an ester or amide linkage

Local anesthetics are weak bases and the infected tissues have a low extra cellular PH

Local anesthetics ionize in such medium bases and the infected tissues have a low extra cellular PH

Local anesthetics ionize in such medium and a very low fraction of non-ionized LAs available for diffusion into the cell

So LA are much less effective in infected tissues

Action potential

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If enough Na channels are opened, then the rate of Na entry into the axon exceeds the rate of K exit

Threshold potential

At the point where the rate of Na entry into the axon exceeds the rate of K exit that point is called threshold point or threshold point

At the this point, the entry of Na ions further depolarizes the membrane

This opens more Na channels, resulting in further depolarization that opens more Na channels and so on.

The fast inward Na current quickly depolarizes the membrane towards the Na equilibrium potential around + 70 m V

Then, Inactivation of the Na channels and the continuing efflux of K ion cause the repolarization of the membrane

Finally, the Na channels regain their normal excitable state and the Na pump restores the lost K and removes the gained Na ions

Mechanism of action

Local anesthetics prevent the generation and the conduction of nerve impulses

The primary mechanism of action is blockade of voltage – gated sodium channels

Local anesthetics directly interact with specific site or receptor on voltage – sensitive Na channels and gradually raise the threshold for excitation

With increasing concentration, impulse conduction slows, rate of rise of AP declines, AP amplitude decreases and finally the ability to generate an AP is abolished

These result from binding of LA to more and more Na channels

So it prevents the generation of an AP and its conduction

The small fibers are blocked first

That is autonomic fibers are blocked first followed by sensory fibers conducting pain, temperature sense, then touch, pressure and vibration sensations in the same order

Sensory and motor fibers are equally sensitive

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Non – myelinated fibers are blocked more readily than the myelinated

Pharmacological actions

1. Effect on sensation

They cause the reversible loss of sensory perception

The order of blockade is pain- temperature- touch

They produce blockade of smaller nerve fibers initially followed by large nerve fibersRecovery occurs in the reverse order

Applied to the tongue, bitter taste is lost firs followed by sweet and sour and salty taste

If it is given with adrenaline through injection route, the adrenaline reduces the systemic toxicity of local anesthetics because it reduces the rate of absorption and metabolismkeeps the plasma concentration lower and increase the activity when exactly the action is required

2. CNS

They produce sequence of stimulation followed by depression cocaine is a powerful CNS stimulant causing in sequence

Euphoria – excitement - mental confusion - restlessness - tremor and twitching of muscles - convulsions - unconsciousness - respiratory depression - death in a dose dependent manner

Procaine and lignocaine are synthetic compounds and much less potent in this regard

3. CVS

All local anesthetic except cocaine produce vasodilatation and hypotension

But cocaine produces vasoconstriction and so a hypertensive effect

All LA produces depressant effect on the myocardium, they increase the effective refractory periods similar effect of the quinidine so used in the arrhythmias 4. Other effects

They produce relaxant effect on smooth muscles and neuromuscular blockade

They relax the vascular and brachial smooth muscles

Pharmacokinetics

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These are rapidly absorbed from the mucous membranes and abraded skin

Rate of absorption is dependent on the vascularity of the area

The vasoconstriction decreases the absorption

Toxicity depends on the balance between absorption and metabolism That is if it gets metabolized as it gets absorbed, then toxicity is less

They are usually administered through the subcutaneous route

They are metabolized in the liver and excreted in the kidney

Adverse effects

Hypersensitive reactions like skin rashes, dermatitis , angioedema, asthma and rarely anaphylaxis

CVS Effects

Like light headedness, dizziness, auditory and visual disturbances , mental confusion, disorientation, shivering, twitching, tremors, finally convulsions and reparatory arrest

CVS Effects

The effects like bradycardia, hypotension, cardiac arrhythmias and vascular collapseRarely cardiac arrest is seen

USES

Surface anesthesia or pain due to burns, fissures and ulcers

Infiltration anesthesia to anaesthetize nerve endings by subcutaneous infiltration

Nerve block anesthesia where I t is injected close to specific nerve

Spinal anesthesia where it is injected close to specific nerve

Systemic use for anti- arrhythmic affect

Some of the important drugs which possess this action are cocaine, procaine.lignocaine, benzocaine and amethocaine

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Cocaine

It is an alkaloid obtained from the leaves of coca plant

It is insoluble in water but its salts are soluble in water

It is poorly absorbed in the intestines but well absorbed by the mucous membrane and it can be given as surface anesthetic

Actions

Local anesthetic action

CNS stimulants

Dilates pupil

Raise the body temperature

Rise the BP

Produces euphoria

Toxic effects

Mental excitement

Confusion

Tremors

Convulsions

Respiratory paralysis

Dose

8 – 16 mg by injection

Adrenaline has to be given along with cocaine which produces local vasoconstriction and prolong the local anesthetic effect

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Procaine

It is synthetic product having local anesthetic effect

Administration – It I snot absorbed by mucous membrane and hence has to be given by injection

It rapidly diffuses from the site of injection and vasoconstrictors like adrenaline as to given , to prolong the effect of procaine

Dose0.25 - 2% solution is injected subcutaneously

For spinal anesthesia it is still popular

It is injected into the spinal theca to block spinal nerves and to produce spinal anesthesia

Lignocaine ( Lidocaine or xylocaine)

It is an active surface anesthetic and also efficient on injection

This is more powerful and more stable and longer acting than procaine

ToxicityToxicity is very low

It is injected as a 0.5% to 2% solution

Duration of action is about 15- 45 min

I fit is combined with adrenaline the effect will last for about two hours

It can also be used in the treatment of status epilepticus and acute ventricular arrhythmia

BenzocaineThis is a local apathetic employed as an application to various mucous surfaces

It is incorporated in throat lozenges to relieve the local soreness and is used in rectal suppositories

Amethocaine

This is a more powerful anesthetic than procaineIt is well absorbed form mucous membrane and is often used in t he form of spray or lozenges to anaesthetize the throat before various manipulationsBut toxic effects are same as procaine

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UNIT - 4

General anesthetics

DefGeneral anesthetics are drugs which produce reversible loss of all sensation and consciousness

Conditional feature of General anesthetics are

Loss of all sensation. Specially pain

Sleep ( unconsciousness) and amnesia

Immobility and muscle relaxation

Abolition of reflexes

1. Inhalation anesthetics

A. Gas

Nitrous oxideCyclopropaneEthylene

B. Liquids

EtherChloroformHalothaneEthyl chlorideVinyl ether

11. Intravenous anesthetics

ThiopentoneMethohexitoneKetamineParaldehyde

Ether ( Di-ethyl ether )

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Properties

It is one of the oldest anesthetic agents in use It is a colorless and volatile liquid with a pungent odorIt is highly inflammable and explosiveIt is quickly absorbed and eliminated through lungs

Actions

5-10% of ether is required in the inspired air to induce anesthetic and at least 3-5% to maintain it

It irritates respiratory tract leading to efflux secretion of saliva and mucous from the mouth and respiratory tract

So atropine should be given at least half an hour before to paralyses secretion

The initial stages are more prolonged with ether in the absence of premeditation

Other actions

Ether does little damage to the heart

It increases cardiac output and coronary blood flow

The rate and depth of respiration may be increased

It does not cause any damage to liver

Advantages

It is safest agent . It can be used even by a nurseIt produces analgesiaIt produces skeletal muscle relaxationIt produces less inhibition of respiratory centre than other unaesthetic agents It does not effect the blood pressureIt dies not interfere with liver or kidney functionsIt can be given by all techniques

Dis-advantages

It catches fireInduction of anesthesia as well as Recovery are slowVomiting is likely to occur postoperativelyGeneralized convulsions are produced specially in children

Chloroform

It is a volatile liquid having a powerful anesthetic property

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It is a colorless non-inflammable volatile liquid with a sweetish smell

It produces server toxic effects on the liver and heart

It is not used at present

Actions

Anesthesia is induced by the open drop method or by closed circuit method 2% of chloroform is required in the inspired air to induce anesthesia and about 0.5% for maintenance of anesthesia

Other action

In addition to general an aesthesia, externally it is used as a rubefacint

Internally it is used as a carminative

It is used as a vehicle in mixtures

Advantages

It does not irritate respiratory tractMuscular relaxation is goodRecovery is accompanied by less nausea and vomiting than with etherIt is non inflammableInduction is rapid and pleasant

Disadvantages

Chloroform depresses myocardium resulting in slowing down of the heart and even cardiac arrest

It depresses the respiratory centre

Liver function is affected leading to necrosis and hepatic failure and deathIntestinal motility is diminished

Margin of safety is very less

Blood concentration of about 15 mg% is required to maintain anesthesia but about 20-25 mg% is fatal

Halothane

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Physical properties

It is heavy, colorless liquid, anesthetic agent

It is non inflammable, non toxic fluorinated hydrocarbon

It has sweet , fruity odor and boils

It affects most of metals including stainless steel ,,copper, rubber

Advantages

Induction is very smooth as it has sweet , fruity odor

Recovery is also fast , smooth with low incidences of nausea and vomiting It is not inflammable and hence does not irritate respiratory passage inhibits salivary secretion hence endotracheal intunotion is much easier

It does not produce bronchospasm, and can be used in patients with bronchial asthma

Dis advantages

Muscular relaxation is inadequate

It causes respiratory, cardiovascular depression

Mental recovery is delayed

Shivering during recovery is very common

It is poor analgesic

It is expensive, needs special apparatus for administration

Nitrous oxide

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Properties

It is also called as laughing gas

It induces laughing in the patient under the anesthesia

It is colorless gas with sweet odor and taste

It is non inflammable

Advantages

Induction and recovery are quick

Irritation is less

Does not produce vomiting and cardiovascular collapse

It is not toxic to liver and kidney

Disadvantages

It dies not produce muscular relaxation

It is not potent, means it requires 90% concentration to produce complete anesthesiaCauses cyanosis

It produces excitation and euphoria

Uses

It is used for short duration operations such as tooth extraction or setting right a fracture

It is used along with the oxygen for producing partial anesthesia following basal anesthetics

Halothane

Physical properties

I t is heavy , colorless liquid, anesthetic agent

It is non inflammable , non toxic fluorinated hydrocarbon

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It has sweet, fruity odor and boils at 50 C

It effects most of metals including stainless steel, brass, cupper and rubber

Advantages

Induction is very smooth as it has sweet ,fruity odor

Recovery is also fast, smooth with low incidences of nausea , vomiting

It is not inflammable and hence does irritate respiratory passage inhibits salivary secretion hence end tracheal intubations is much easier

It does not produce branch spasm, larygospasm, hence can be used in patients with bronchial asthma

Disadvantage

Muscular relaxation is inadequate

It causes respiratory, cardiovascular depression

Mental recovery is delayed

Shivering during recovery is very common

It is poor analgesic

It is expensive ,needs, special apparatus for administration

Intravenous anesthetics

Barbiturates are generally used as intravenous general anesthetics for short term operations

Of these Thiopentone and hex baritone are the drugs of choice being given by the slow route to avoid respiratory arrest

Advantages

Easy to administer

Induction is rapid and smooth

Past anesthetic complications are rare

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Recovery is very fast

Respiratory and myocardial functions remains unaffected

No irritation of respiratory passage

Less excitement and vomiting

Non-expensive

Pre-medication is not needed

Disadvantages

Usual stages of anesthesia are not clear

Muscular relaxation is very poor

Poor analgesia

Short duration of action

Coughing apnea is common during induction

PreparationsThiopental sodium --- 2.5% solution Methohexitone --- 1% solution Propanidid --- 4mg/KgKetamine --- 1.2mg/Kg

General anesthetics

General anesthetics are the drugs which are used to produce complete loss of sensation to allow the surgical operations to be performed without the sensation of pain to the patient

General anesthetics depress the sensory as well as motor nerves and produce loss of sensation which is reversible

The common method of inducing anesthesia is by inhalation, intravenous , spinal and rectal anesthesia are also used

Requirement of an ideal anesthetic

Administration should be easy without requiring complicated apparatus

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Anesthesia must be induced rapidly, smoothly and easily controllable

BP should remain normal

When discontinued the anesthetic should be eliminated quickly without harming the tissues

It should produce adequate muscular relaxation with complete motor and sensory paralysis

Stages of anesthesia

Induction of general anesthesia is divided into four stages according to the deapth of CNS depression

All these stages are continuous but described separately for the sake of clarity

Four stage of anesthesia are

1. Stage of induction

2. Stage of excitement

3. Stage of surgical anesthesia

4. Stage of modularly depression or respiratory paralysis

1. Stages of induction

There is a sensation of warmth and suffocation , reflex secretion of mucous and saliva with coughing and sneezing are noticed

Muscle are stiff, pupils are dialate and pulse rate is quick

2. Stage of excitement

Blunting of consciousness occurs

There will be loss of self control and motor excitement

Pulse rate is rapid

Respiration becomes irregular and fast

Pupils are dilated and active

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Sensory nerves cells are paralyzed first but motor reflexes are still present

There is a gradual unconsciousness

3. Stages of surgical anesthesia

Here complete paralysis of the enters of cerebral cortex and Spinal reflexes commencesThis is reversible

Muscles are relaxed , pulse is slow and regular, respiration becomes slow

Pupils are contracted

Eye balls are fixed, there will be a fall in body temperature

This stage is suitable for surgical operations to be performed as all the motor reflexes are abolished and the muscles are relaxed fully 4. Stage of modularly depression

The modularly centers are gradually depressed

There is deep unconsciousness

Respiration becomes slower and slower

Pupil are dilated and inactive , pulse becomes weak and blood pressure falls.

Finally respiration stops leading to the arrest of the heart and death

Recovery from the anesthesia

Soon after the removal of the anesthetic the respiration becomes quieter and less strenuous

The eye lid and deglutition movements reappear

Pupils dilate, coughing, acute vomiting may occur just before returning to consciousness

This is commonly succeed by natural sleep lasting for several hours

Mechanism of action

Reticular activating system

This is a complex polysynaptic pathway in the brainstem reticular formation that projects diffusely to the cortex

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Activity in the RAS is concerned with maintaining consciousness and because it is sensitive to the depressant action of anesthetics, it is thought to be their primary site of action

The general anesthetics increase the sensitivity of the gamma- amonobutyric acid (GABA A) receptors to the neurotransmitter, GABA, at clinically effective concentration of the drug

This causes a prolongation of the inhibitory chloride ion current after a pulse of GABA release.

Postsynaptic neuronal excitability is thus diminished

Others receptors are also affected by volatile anesthetics

Ex

The activity of the inhibitory glycine receptors in the spinal motor neurons is increased

The inhalation anesthetics block the excitatory postsynaptic current of the nicotinic receptors

Pre-unaesthetic medication

The pharmacological agent when administered externally with an important objective to make anesthetic more smooth and agreeable for patient , the phenomenon is termed as preanaesthetic medication

Aim

To induce sedationTo decrease gastric secretion

To minimize pre and post operative complications

To facilitate smooth and rapid induction

To overcome secretary effects of general anesthetics

To decrease vagal stimulation and secretions

Supplement analgesic actions to potentate anesthetics so less anesthetic is needed

Drugs used in preanaesthetic medication are

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1.Opiods

Ex

Morphine

To produce analgesia

2. Sedatives

Ex

Diazepam or lorazepam

Ant anxiety drugs –for smooth induction

3. Anti-cholinergic

ExAtropine

To reduce salivary and bronchial secretions

4. Neuroleptics

ExChlorpromazine

To smooth induction and anti-emetic action

5. H2 Blockers

ExRanitidine

To prevent the ulcer formation

6. Anti-emeticsExMetaclopramideTo reduce post operative vomiting

S No Type Drug Dose

1 Opoid analgesic Morphine, pethidine 15,30 mg

2 Barbiturates Phenobarbitone, secobarbitone 30mg

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3 Anxiolytic Diazepam 5mg

4 Anti- emetic Promethazine 30mg

5 Anti-secretary Atropine 0.6mg

6 Skeletal muscle relaxants D-tuocurarine 10mg

Alcohols

Alcohols are aliphatic hydrocarbons

They contain one or more hydroxyl groups

Classification

1. Mono-hydroxy alcohols

Methyl, ethyl and propyl alcohols

2. Dihydroxy alcohols

Ethylene glycols, propylene glycol

3. Tri-hydroxy alcohols

Glycerol or glycerine

4. Poly-hydroxy alcohols

Mannitol, sorbitol

Ethyl alcohol

Ethyl alcohol is commonly used alcohol

It is the main constituent of all kinds of alcoholic beverages

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It is generally obtained by fermentation of sugars by yeast

The alcohol is separated by simple distillation

It is a colorless, volatile and inflammable liquid

The alcohol content of various beverages varies between 4-55% by volume

Wines containing more than 16% of alcohol

Beer contains 4-6 % (v/v) of alcohol

Stronger preparation are called Spirit

Mechanism of action

Alcohol produce CNS depression by a generalized membrane action by altering the state of membrane lipids

Alcohol promotes GABAA receptor mediated synaptic inhibition (through chloride channel opening ) as well as inhibits NMDA and type of excitatory amino acid receptors (operating thorough captions channels)

Alcohol can indirectly reduce neurotransmitter release by inhibiting voltage sensitive neuronal calcium channels

Blockade of adenosine uptake by alcohol could also contribute to synaptic depressionThe activity of membrane bound enzymes like Na – K ATPase and adenyl cyclase is also altered

The activity and translocation of channel or enzyme proteins in the membrane could be affected by alcohol through protein kinase C and protein kinase A mediated alteration in the state of their phosphorlation

Pharmacological actions

1. Externally

It evaporates quickly and producing cooling effect and is used for reducing the temperature in fevers

It is used in shaving lotion for producing cooling effect on the skin

In concentration of 40- 50, it act as rubifacient and mild irritant action

In concentration of 70% , it acts as antiseptic , the action is seen only against vegetative forms of organism and spores are resistant

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Concentrated alcohol , if injected , produces tissue destruction

Higher concentration denature proteins by partial precipitation and dehydration In such concentration , it acts as an astringent, a germicidal and an irritant 2. GIT

If taken orally , it increases salivary secretion by reflex action

It has an irritant action on the gastric mucous membrane and act as appetizer50 ml of 7-10% alcohol increases the gastric secretion ,by releasing histamine and gasstrin from the antrum of the stomach Concentration above 15% inhibit both motility and secretion and effect may persist for many hours

Concentration above 20% reduce the enzymatic activity of the gastric and the intestinal juices

Concentration above 40% and over have a direct toxic effect on gastric mucosa and may precipitate gastritis, giving rise to pain, nausea, vomiting and other symptoms

Many alcoholics suffer from gastritis and chronic achlorhydria

Many alcoholics suffer from chronic diarrhea as a result of malabsorption from chronic mucosal damage

3. CNS

It is primarily a CNS depressant and acts by enhancing the inhibitory GABA receptor activity or inhibiting NMDA receptors

Proteins are the primary site of its actions

It produces initial excitation due to depression of higher inhibitory centers

This is followed by progressive depression, drowsiness, sleep and unconsciousness as the dose is increased

Sudden withdrawal of alcohol causes excitation and hyperactivity of the CNS

4. CVS

Small dose produce only cutaneous and gastric vasodilatation B.P is not affected

Moderate doses cause tachycardia and a mild rise in BP due to increased muscular activity and sympathetic stimulation

Large doses cause direct myocardial as well as vasomotor centre depression and there is fall in BPChronic alcoholism may contribute to hypertension and lead to cardiomyopathy

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Atrial fibrillation and other cardiac arrhythmias may occur due to conduction defects and Q-T prolongation

5. On respiration

Moderate doses produce slight stimulation whereas large doses produce respiratory depression which may be fatal

6. Kidney

Diuresis is often notified after alcohol intake

It is due to depression of ADH production

It does not impair renal function

7. Sax

Alcohol is reputed as an aphrodisiac.

Aggressive sexual behavior is due to loss of inhibitory control

It also provokes the sensation but takes away the performance

Chronic alcoholism can produce impotence, gynaecomastia and infertility

8. Body temperature

Alcohol produces a sense of warmth due to cutaneous and gastric vasodilatation , but heat loss is increased in cold surroundings

High intake of alcohol produces depress temperature regulating centre

9. Liver

It produces fatty liver on chronic administration

It mobilize peripheral fat and increases fat synthesis in liver

Proteins may also accumulate in liver because their secretion is decreased

Acetaldehyde produced during metabolism of alcohol appears to damage the hepatocytes on chronic ingestion of large amounts

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Increased lipid peroxidation and glutathione depletion occurs

Regular alcohol intake induces microtonal enzymes

10. Skeletal muscle

Alcohol produces little direct effect. Fatigue is produced by small doses, but muscle work is increases or decreased

Weakness and myopathy occurs in chronic alcoholism

11. Blood

Regular intake of small to moderate amounts has been found to raise HDL levels and decrease LDL oxidation Megaloblastic anemia has been seen in chronic alcoholism due to interference with folate metabolism

Absorption , fate and excretion

Alcohol is absorbed in the stomach (25%) and 75% in small intestine

It is metabolized in the liver as follows

Alcohol dehydrogenaseEthyl alcohol -------------------------------------------------------Acetaldehyde

Aldehyde dehydrogenaseAcetaldehyde-------------------------------------------------------------Acetyl CoA

Acetyl CoA is further metabolized to carbon dioxide and water

Alcohol is eliminated mostly through kidneys and lungs

Toxicity

Side effects of moderate drinking

Nausea, vomiting , flushing, hangover, traffic accidents

Acute alcoholic intoxication

Fall in body temperature

Hypotension gastritis

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hypoglycemiaCollapse, respiratory depression Coma and death

Treatment

Gastric lavage maintain patent airway and take steps to prevent aspiration of vomit us

Positive pressure respiration may be needed if it is markedly depressed

Most patients will recover with supportive treatment, maintenance of fluid and electrolyte balance and correction of hypoglycemia by glucose infusion till alcohol is metabolized

Recovery can be hastened by haemodialysis

Insulin + fructose drip has been found to accelerate alcohol metabolism

Chronic alcoholism

On chronic intake, tolerance develops to subjective and behavioral effects of alcohol

It is both pharmacokinetic and cellular tolerance

Psychic dependence often occurs even with moderate drinking

Physical dependence occurs only on heavy and round the clock drinking

Heavy drinking is often associated with nutritional deficiencies, because food is neglected and malabsorption may occur

Alcoholic cirrhosis of liver, hypertension, cardiomyopathy , CHF, arrhythmias, stroke and skeletal myopathy are complications

Treatment

Psychological and medical supportive measures are needed during withdrawal

Many CNS depressants like barbiturates , phenothiazines, chloral hydrate have been used as substitution therapy in the past to suppress withdrawal syndrome but benzodiazepines like chordiazepoxide, diazepam are the preferred drugs now

These have a long duration of action and can be gradually withdrawn later

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Disulfiram

It is a drug for the treatment of chronic alcoholism

It is a inhibits the enzyme aldehyde dehydrogenaase

So acetaldehyde is not converted into Acetyl CoA

This leads to accumulation of acetaldehyde which produces nausea and vomiting

It is administered at a dose of 500 mg once daily for a week and alter 250 mg daily as maintenance dose

When alcohol is ingested after taking disulfiram, the concentration of acetaldehyde in tissues and blood rises and a number of distressing symptoms (aldehyde syndrome ) are produced These are

Flushing Burning sensation Throbbing headache PerspirationUneasinessTightness in chest Dizziness Vomiting Visual disturbances Mental confusion and circulatory collapse

Duration of the syndrome (1-4 hours ) depends on the amount of alcohol consumed

Disulfiram is used in chronic alcoholics who are motivated and sincerely desire to leave the habit

Sensitization to alcohol develops after 2-3 hours of first dose and lasts for 7-14 days after stopping it ,because inhibition of aldehyde dehydrogenase with disulfiram is irreversibleSynthesis of fresh enzyme is required for return of activity

It should not be used in patients who are physically dependent on alcoholSide effect of disulfiram are DrowsinessHeadacheCramps RashesMetallic tasteNervousnessAbdominal upset

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Unit - 5Hypnotics and sedatives

Hypnotics are drugs which produce sleep resembling natural sleep

Sedatives are drugs which reduce excitement without producing sleep

Qualitatively hypnotics and sedatives produce depression of CNS and the difference between them is mainly quantitative

1. Barbiturate derivatives2. Non – barbiturate derivatives

1 .Barbiturate derivatives

A. Long acting barbiturates (8 -12 hours )

Phenobarbitone Mephobarbitone Methylphenobarbitone Barbitone

B. Intermediate acting barbiturates

AmylobarbitoneButobarbitoneAllobarbitoneVinbarbitone

C. Short acting barbiturates

PentobarbitoneSecobarbitoneCyclobarbitoneHepatobarbitone

D. Ultra short acting barbiturates

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ThiobarbitoneHexabarbitoneMethobarbitone

11. Non –barbiturate derivatives

A. Benzodiazepines

Diazepam

Oxazepam

B. Aldehydes

Chloral hydrate

Chloral formamide

Paraldehyde

C. Bromides

Potassium bromide

Sodium bromide

Ammonium bromide

D. Alcohols

Ethyl alcohol

Tribromo-ehamol

Amylene hydrate

E. Piperidine derivatives

Glutethimide

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Methyprylon

Barbiturates

Barbiturates o derivatives of barbituric acid which is obtained by condensation of urea and malonic acid

Barbituric acid itself does not possess hypnotic activity but hypnotic activity is produced, if the hydrogen atoms at position 5 are replaced by alkyl or aryl groups

The barbiturates were formerly the mainstay of treatment used to sedate the patient or to induce and maintain sleep

Today , they have been largely replaced by the benzodiazepines, primarily because barbiturates induce tolerance, drug metabolizing enzymes, physical dependence and severe withdrawal symptoms

The barbiturates in severe doses produces coma

Mechanism action of barbiturates

The sedative – hypnotic action of the barbiturates is due to their interaction with GABA A

receptors which enhances GABA nergic transmission

The binding site of distinct from that of the benzodiazepines

Barbiturates potentate GABA Acton on chloride entry into the neuron by prolonging the duration of the chloride channel openings

In addition , barbiturates can block excitatory glutamate receptors

Anesthetic concentration of pentobarbital also block high frequency sodium channels

All of these molecular action lead to decreased neuronal activity

Pharmacological actions

On CNS

Barbiturates produce all degrees of CNS depression like mild sedation, hypnosis and general anesthesia

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Sleep

Barbiturate induced sleep resembles natural sleep

But it decreases the time spent on rapid-eye movement sleep, also there is hangover effect after awakening

Analgesic effect

Barbiturates do not relieve pain without producing unconsciousness

They enhance the analgesic effect of salicylates and para-amino phenol derivatives

Anesthetic effect

Thionarbiturates and some ultra short acting oxybarbriturates produce anesthesia on intravenous administration

Anti- consultant effect

Barbiturates like phenobarbitone which have a phenyl group at the 5 th carbon atom have anticonvulsant effect

Respiration

Respiration is not affected at sedative or hypnotic dose

Large dose administered intravenously may produce death due to central respiratory paralysis

GIT

Intestinal motility is not affected at a normal dose, but gastric secretion may be depressed

Uterus

Force and frequency of uterine contractions are depressed at toxic dose

Kidney

No effect at normal dose but anesthetic dose decreases urinary output due to decrease in glomerular filtration and release of Ach

Liver

No effect at normal dose but anesthetic dose may produce hepatic dysfunction

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Enzyme induction

Barbiturates induce P450 microsomal enzymes in the liver

Chronic barbiturate administration diminishes the action of many drugs that a re dependent on P450 metabolism to reduce their concentration

ADME

Barbiturates can be administered by oral and parenteral routes

They are distributed in all tissues and body fluids

They cross placental barrier and also are excreted in milk They are chiefly metabolized in the liver and to a small extent in kidney and brain

Excretion is through urine both in free form and as glucuronic acid conjugate

Adverse reaction

Intolerance like nausea, headache and diarrhea

Fetal respiratory depression if administered during labor

Drug automatism due to repeatedly taking the drug owing to forgetfulness

Tolerance because of increased inactivation in the liver

Dependence and withdrawal symptoms

Therapeutic uses

Sedation in case of anxiety or tension

Hypnosis to relieve insomnia

Anticonvulsant effect in case of tetanus or status epilepticus

Pre anesthetic medication and to produce basal anesthesia

Potentiation of analgesics like salicylates

In psychiatric practice and in neonatal jaundice

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Benzodiazepines

These are very important class of hypnotics and sedatives because of their high therapeutic index

The important Benzodiazepines are

DiazepamFlurazepamNitrazepamLorazepamOxazepam

Mechanism of action

The GABA (Gamma amino butyric acid ) is acts as an inhibitory neurotransmitter in the body

It acts on GABA receptors

But the benzodiazepine receptor are associated with GABA receptors

These benzodiazepines acts on GABA and stimulate the GABA receptors , leading to increase in the GABA activity

GABA activating the chloride channels leading to increase in the Cl conductance and hence decrease firing of the regions

Benzodiazepines produce increase in pre-synaptic inhibition , decrease in turnover of 5HT, nor adrenaline and dopamine

These also posses GABA agonistic activity Therapeutic uses

In anxiety and insomnia

As a pre-anesthetic medication

Treatment of epilepsy and seizure states or muscular relaxation in spastic conditions

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In control of ethanol and sedative- hypnotic withdrawal symptoms

As diagnostic aid for treatment in psychiatry

Adverse effectsDrowsiness, confusion, impaired motor in co-ordination, tolerance and dependence to the less extent and reparatory depression

Chloral hydrate

Chloral hydrate is a trichlorinated derivative of acetaldehyde .

It is converted to the active metabolite , trichloroethanol, in the body

The drug is an effective sedative and hypnotic that induces sleep in about thirty minutes and lasts about six hours

Chloral hydrate is irritating to the gastrointestinal tract and causes epigastric distress

It also produces an unusual, unpleasant taste sensation

It synergizes with ethanol

It does not have the analgesic activity but may produce excitement and delirium in presence of pain

Adverse effectsNausea, vomiting, gastric irritation, respiratory and vasomotor depression , myocardial depression and arrhythmia

Paraldehyde

It is nauseating and volatile, liquid hypnotic which is harmless and quick in Acton

It is more potent than the chloral hydrate and polymer of acetaldehyde

During labor it causes analgesic effect but it can cross placenta and may delay respiration in new born

Higher doses may cause hypotension, respiratory depression and coma

It can be used as anticonvulsant , hypnotic and basal anesthetic

It is absorbed thorough the oral and parental administration

It is excreted through the lungs with offensive smell

It reacts with plastic materials so cannot administer with the plastic syringes

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Rectal administration cause irritation to mucosa of rectum an may cause ulceration

Ethyl alcohol

It has antianxiety and sedative effects , but its toxic potential outweighs its benfits

Alcoholism is a serious medical and social problem

Ethanol is a CNS depressant producing sedation and ultimately hypnosis with increasing dosage

It is readily absorbed orally and has a volume of distrinution close to that of total body water

It is metabolized primarily in the liver, first to acetaldehyde by alcohol dehydrogenate and then to acetate by aldehyde dehydrogenate

Elimination is mostly through the kidney, but a fraction is excreted through the lungs

Ethanol synergizes wit h many other sedative agents and can produce severe CNS depression with antihistamines or barbiturates

Chronic consumption can lead to severe liver disease, gastritis and nutritional deficiencies

Cardiomyopathy is also a consequence of heavy drinking

The treatment of choice for alcohol withdrawal are the benzodiazepines

Carbamzepine is effective in treating convulsive episodes during withdrawal

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Antianxiety drugs

DefAntianxiety drugs (anxiolytics) are CNS depressants which control symptom of anxietyThey produce a calming effect in anxiety states

1. BenzodiazepinesDiazepam

Oxazepam

Lorazepam

Alprazolam

2. Azapirones

Buspirone

Gipirone

Benzodiazepines

These are the commonly used antianxiety drugs

They have anxiolytic, hypnotic, muscle relaxant and anticonvulsant actions

They are less toxic and addiction liability is very low

Mechanism of action

It is believed that these agents facilitate the effects of GABA receptor activation in the CNS

It potentates GABA ergic inhibition

Side effects

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SedationLethargyAtaxiaWeight gainConfusionTolerance Dependence

Diazepam

It is an important benzodiazepine compound L

Like all other benzodiazepines, it has a hypnotic, anxiolytic, muscle relaxant and anticonvulsant actions

It is quickly absorbed on oral administration

Uses

Acute panic states

Anxiety associated with organic disease

Status epileptic us

Dose 2- 5 mg twice a day Oxazepam

It is active metabolites of diazepam

This benzodiazepine is slowly absorbed on oral administration also

It also penetration slow

It has a short duration of action

So it is used mainly in short lasting anxiety states

Dis-advantages

It is short acting

It is not well absorbed

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Dose

10 mg

Lorazepam

This benzodiazepine is slowly absorbed on oral administration

It also penetration in brain is slow

It has a short duration of action

So it is used mainly in short lasting anxiety states

Dose

1-4mg

Alprazolam

It is a recently introduce antianxiety drug

In addition to anxiolytic effect

It has a mood elevating action

It also produces less drowsiness

USE

Anxiety states associated with depression

Dose

0.25-1 mg three times daily

Meprobamate

The drug produces calmness In as individual

It reduces tension and hostility

Reactions of the patient to his environment become – congenial

Unlike phenothiazines it dies not abolish conditioned reflexes

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Adverse reaction

DrowsinessAngioneurotic edema and other r allergic manifestationsBlood dyscrasias

Disadvantages

Tolerance develops

IT produces drug

Dependence

USES

Anxiety

Neurosis

Chlordiazapoxide

Though it is a benzodiazepine, its actions resemble barbiturates

It produces calmness

It also produces sedation

It produces skeletal muscle relaxation

It stimulates appetite

Adverse reaction

Drowsiness, lethargy and ataxia

Hypotension is produce in few

Disadvantages

Tolerance develops

It induces physical dependence , withdrawal symptoms are produced on its stoppage

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Use

Anxiety and neurosis

It is used to suppress withdrawal symptoms of alcohol

As preanaesthestic medication

Buspirones

It is new antianxiety drug

It does not have sedative, hypnotic, muscle relaxant and anticonvulsant effects as produced by benzodiazepines

It has a slow action and the effect is delayed for even two weeks

Mechanism of action

It acts by stimulating presynaptic 5-HT 1A auto receptors

USE

Mild to moderate anxiety

Dose

10-30 mg daily is divided doses

Flumazinil

It is a benzodiazepine antagonist

It binds competitively with benzodiazepine receptors and blocks many of the pharmacological actions of benzodiazepines

USE

To reverse benzodiazepine anesthesia

In Benzodiazepine overdose

Hepatic coma and alcohol intoxication

Centrally acting muscle relaxants

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Skeletal muscle relaxation without altering consciousness or normal voluntary movement is necessary during unwanted muscular spasms and rigidity and during operative procedures

The classes of drugs which can be used fro skeletal muscle relaxation are centrally acting drugs and drugs acting peripherally at neuromuscular junction

1. Mephenesin group

Mephenesin Carisoprodol Chlorzoxazone Chlormezamone Methocarbamol

2 .Benzodiazepines

Diazepam and others

3. GABA derivative Baclofen

4. Central alpha 2 agonists

Tizanidine

Mepaenesin

It is the first centrally acting muscle relaxant which was introduced in 1946 still being widely used today

It relaxes normal and spastic skeletal muscles without interfering within neuro-muscular transmission

In moderate dose it reduces muscle tone and motor activities

But large doses produce hypotension, respiratory paralyses and death

The drug is will absorbed orally and parent rally ,but duration of action is short

It is used to treat acute spasm of skeletal muscle in tetanus and status epileptic us

It is used to produce muscular relaxation during operative procedures

Use to reduce agitation in chronic alcoholism an to relieve muscular rigidity and tremors in parkinsonism

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Dose

orally 1 gram to 3 grams

Parentally 100mg to 1 gram

Mephenesin carbamate an ester of mephanesin has a longer duration of action and hence is preferred

Dose – 1 to 1.2 gram per day orally

Methocarbamol

This chemically elated to mephenesin carbamate

It acts both as muscle relaxant and sedative

It is orally active with a longer duration of action and milder side effects

Uses - Same as mephenesin

Dose – 0.5 grams per day orally

It can also be given by I.M or I.V route

Carisoprodol

It is chemically related to meprobamate

It produces muscle relaxation and sedative effects

It is used in cerebral palsy to produce muscular relaxation

Unwanted side effects are drowsiness, vertigo, weakness and allergic reactions on skin

Dose - 350 mg oral

Metaxalone

Dose - 0 3.2 rams per day in divided doses

Serious side effects are leucopenia and jaundice

Muscle relaxants are contra-indicated in pregnant women , in the presence of renal damage and myasthenia gravis

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Muscle relaxants acting at neuromuscular junction

The contraction of skeletal muscle is initiated by acetyl choline at the neuromuscular junction

Acetyl choline acts on the receptor of the muscle producing contraction

But there are drugs which block the action f acetyl choline on skeletal muscle receptors thereby producing muscle relaxation

They are of two types namely

1. Competitive blockers

2. Depolarization blockers

1. Competitive Blockers

The drugs which act by this mechanism are d-tubocurarine and gallamine

They compete with the acetylcholine to reach the muscle receptors

D-TubocurarineThis is the dextro rotatory alkaloid obtained from the strychnos species

Curare was mainly used as an arrow poison in South America

It competes with acetyl choline to reach the receptors and thus blocks the action of acetylcholine at the neuromuscular junction and produces muscle relaxation

It is inactive orally, but is active parent rally

The drug is given intravenously for muscle relaxation during operative procedures

Dose -- 6 to 10 mg given with general anesthetic

Disadvantage - It is that it causes release of histamines from the tissues

Gallamine

It is a synthetics quaternary ammonium compound with curare like action

It also acts as a skeletal muscle relaxant by competitive blockade of acetylcholine

But is less potent than d – tubocurarine It does not release histamineIt is not active orallyHence given parent rally

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It is also used to produce muscular relaxation during operative procedures

Dose - 100 mg by I.V injection

Depolarization blockers

Here the drugs act by depolarizing the receptor motor end plate of the muscle which becomes resistance to further stimulation

The drug which stimulation

The drug which acts by this process and relaxing skeletal muscles is succinyl chloride

It has very short duration of action

Its action can be enhanced by anti-choline esterasis like neostigmine

It does not release histamine

It is used in anesthesiology to produce muscle relaxation by continuous I. V infusion

Other drugs which act this process is decamethonoum

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Unit - 6

Anti-psychotic drugs

These are the drugs which used in treatment of major psychosis

They are also called a major tranquilizers, since they reduce agitation and disturbed behavior seen in schizophrenia

1. Phenothiazines

ChlorpromazineTriflupromazineFluphenazineThioridazine

2. Butyrophenones

HaloperidolTrifluperidol

3. Rauwolfia alkaloids

Reserpine

4. Thioxanthines

ChlorprothixeneThiothixene

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5. Indolic derivatives

Molindine

6. Miscellaneous

OxypertineTetrabenazinePimozide

CHLOPROMAZINE (CPZ)

These are the most widely used compounds in the treatment of major psychosesPhenothiazines are three ringed structures

In which two benzene rings are linked by a sulphur and a nitrogen atom

Chlorpromazine is the important phenothiazine and was synthesized in 1950

According to the chemical structure , phenothiazines could be predominantly antipsychotic c, ant cholinergic or antihistaminic

Mechanism of actionPhenothiazines and other antipsychotic drugs produce beneficial effects probably by affecting three of the major integrating systems in the brain

Mesolimbic system

Mesocortical system

Hypothalamus

Cause blockage mainly of postsynaptic dopaminergic (D2) receptors and to smaller extent 5-HT receptors

Modify the function of the mesolimbic system Reduce the incoming sensory stimuli by acting on the brainstem reticular formation

Pharmacological actionsOn CNSWhen chlorpromazine is given to patients with psychosis , it produces

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Psychomotor slowing

Emotional quietening

Decreased initiative

Decreased anxiety

Phenothiazines do not have as analgesic effect

But they potentate the analgesic effect of morphine

They dontot have anticonvulsant effect

Behavioral effects

In normal subjects CPZ reduces motor activity, produces drowsiness and indifference to surroundings

In psychotic agitated patients, it reduce aggression , initiative and motor activity, relieves anxiety and brings about emotional quietening and drowsiness

It normalizes the sleep disturbances characteristic of psychoses

Other CNS actions

Cortex

CPZ lowers seizure threshold and can precipitate convulsions in untreated epileptics

Hypothalamus

CPZ decreases gonadotrophin secretion and may result in amenorrhea in women It increases the secretion of prolactin resulting ins galactorrhiea and gynaecomastia

Basal ganglia

CPZ acts as a dopamine antagonist and therefore results in extra-pyramidal motor symptoms ( drug induced parkinsonism)

Brainstem

Vasomotor reflexes are depressed leading to a fall in BP

Anti-emetic action

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CPZ has a powerful anti emetic effect

These block the dopamine (DA) receptors in the CTZ

This effect is produced by depress the chemoreceptor trigger zone

On ANS

The actions on the ANS are complexCPZ is an alpha adrenergic blocker

The alpha blocking potency varies with each neuroleptic

CPZ also has ant cholinergic properties which leads to side effects like dryness of mouth, blurred vision, reduced sweating, decreased gastric motility, constipation and urinary retention

The degree of anti cholinergic activity also varies with each drug

CVS

CPZ produce hypotension due to alpha blockade action and reflex tachycardia

It also has a direct myocardiac depressant effect like guanidine

It also has anti- fibrillatory effect

Local anesthetic effect

These has local anesthetic properties but is not used for the purpose since in is an irritant

Kidney

CPZ depresses ADH secretion and has weak diuretic effects

Tolerance develops to the sedative and hypertensive actions while no tolerance is seen to the anti psychotic actions

On endocrine glands

These produces inhibition of ovulation, amamenorrhea and lactation in females

In males, it produces loss of libido

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These effect are produced by blocking the action of dopamine on hypothalamus and pituitary

Other actions

Inhibition of hiccough

Skeletal muscle relaxant effectPharmacokinetics

It is well absorbed after oral and parenteral administration

It is highly protein bound

High concentration is found in the lungs, liver and adrenal glands

It is subjected to enterohepatic circulation

This increases its duration of action

The half life period is 20 to 24 hours and is therefore given once a day

It is metabolized in the liver and the metabolic products are excreted in urine s

Adverse reaction

CNS effects

Drowsiness, excitement, psychotic reactions, confusion and parkinsonism

ANS effects

Blurred vision, constipation, nasal stuffiness and urinary retentionThese occur due to the ant cholinergic effects

CVS effects

Hypotension, palpitation and tachycardia

Hemopoietic effects

Agranulocytosis, thrombocytopenia and aplastic anemia

Endocrine effects

Gymaecomastia, lactation and menstrual disturbances

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Hypersensinitivity reactions

Jaundice, agranulocytosis and skin rashes

Drug interactions

CPZ enhance the sedative effects of CNS depressants, alpha blockers and of ant cholinergic drugs

When combined with these groups of drugs , the effects may be additive

These inhibit the actions of dopamine agonists and Levo dopa

Dose

Chlorpromazine tablets and syrup- 25 to 1000mg by mouth

Chlorpromazine injection-25 to 50 mg by intramuscular injection

Uses

These are given orally ( chlorpromazine 100 – 800mg)

In acute psychosis they may be given intramuscularly and response is seen in 24 hrs

While in chronic psychosis it takes 2-3 weeks of treatment to demonstrate the beginning of obvious response

It is used in the treatment of major psychosis

It is used to control aggressiveness in children

It is used as ant emetic

CPZ can control intractable hic- cough

It is used in pre- anesthetic medication

It used in neuropsychiatry disorders such as Huntington’s disease

Drug dependence

They are useful in the management of psychosis associated with chronic alcoholism tbu are contraindicated in acute withdrawal syndromes for fear of precipitating seizures

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Haloperidol

This is a very potent drug, belonging go the class of butyrophenones but with similar clinical effects as piperzine phenothiazines

It is more effective in highly agitated or manic patients and has less prominent sedative and autonomic effects than chlorpromazine

It is given orally in the dose of 1.5 to 7.5mg , there times day

It can also be given IM in the dose of 2-10 mg, repeated every hour up to a total of 30 mg, in agitated and violent patients

Depot injection preparation of haloperidol are also available

The incidence of EPS with this drug is high and it dies not seem to be superior to phenothiazines in the routine treatment of schizophrenia

The irreversible toxic encephalopathy has been reported in patients on lithium if they are given high doses of haloperidol

The other drugs of this series are trifluperidol and droperidol which are used in combination with fentamyl for neuroleptanalgesia

Rauwolfia alkaloids

It is alkaloid obtained from a plant called Rauwolfia serpentine

In ancient Ayurvedic medicine, the extract of this plant has been claimed to be useful in cases of insomnia , insanity and snake bite

It is called serpentine because of the resemblances of the root to a snake

Mechanism of action

Reserpine is of great pharmacological interest because it produces depletion of endogenous catecholamine and 5-HTfron the brain and peripheral sites by interfering with amine storage

Such depletion can last for day or weeks

A single dose of 5 mg / kg body weight is sufficient to cause 90% reduction in brain nor adrenaline and 5-HT over a period of 10 days

This depletion of cerebral monoamines is believed to be responsible for its central actionsPharmacological actions of reserpine

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CNSIt has central antipsychotic action resembling those of phenothiazines

It differs from the latter compounds in that it has no antihistaminic, cholinergic blocking or direct adrenergic blocking effects

In man , it produces a similar calming effect as well as extra pyramidal action as those observed flowing chlorpromazine

It does not produce clouding of consciousness

Reserpine is less effective than phenothiazines in t he treatment of schizophrenia

It may cause mental depression precipitating suicidal tendencies , hence it is no more used as an antipsychotic drug

CVSIt is used as antihypertensive drug

Reserpine is less effective tam phenothiazines in the treatment of schizophrenia But is commonly used as an antihypertensive drug

Clozapine

This antipsychotic drug, related to heterotricyclic compounds like imipramine , was synthesized in 1960

It was found to cause agranulocytosis and its use was abandonedIt has selective effects in the limbic, dopaminergic systems, its other actions include antiadrenergic , anti5-HT and ant cholinergic actionsIt differs from phemothiazines in that it causes fewer EPRs and does not cause hyperprolactinemia

It given orally, it produces antipsychotic effects similar to other standard neuroleptics

Its major advantage is that the drug improves not only the positive symptoms but also the negative symptoms such as emotional withdrawal, bunted affect, retardation and social withdrawal

It is started in the dose of 12.5 mg once daily and gradually increased to 200- 450 mg / day in divided doses

Adverse reactionsThese includes nausea, vomiting , sedation , hypotension , severe tachycardia , and confusion

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Anti-depressant drugs

These are the drugs used for the treatment of mental depression

They are also called as psycho analeptics or mood elevators

Classification of Anti-depressant drugs

1. Monoamine oxidase inhibitors

Meclobemide

Phenelzine

Isocarboxazid

Nialamide

11. Try cyclic compounds

Imipramine

Desipramine

Amitriptyline

Nortriptyline

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111. Selective Serotonin reuptake inhibitorsFluoxetine

Citalopram

Escitalopram

Paroxetine

Sertaline

IV. Serotonin or nor epinephrine re-uptake inhibitors

Phenelzine

Tranylcypromine

1. Mono-amine oxidase inhibitors (MAOI)

Monoamine oxidase (MAO) is a mitochondrial enzyme found in nerve , liver and gutIn the neuron, MAO functions is to deaminate and inactivate any excess neurotransmitter molecules (nor epinephrine, dopamine and serotonin) that may leak out of synaptic vesicles when the neuron is at test

The MAO inhibitors may irreversibly or reversibly inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and therefore to both accumulate within the presysaptic neuron and leak into the synaptic space

This causes activation of nor- epinephrine and serotonin receptors and it may be responsible for the antidepressant action of these drugs

Two MAO inhibitors are currently available for treatment of depression- Phenelzine and tranylcypromine

The use of MAO inhibitors is now limited due to the complicated dietary restrictions required of patients taking MAO inhibitors

Mechanism of action

MAO inhibitors such as phenelzine form stable complex with enzyme, causing irreversible inactivation

These results in increased stores of nor epinephrine, serotonin and dopamine within the neuron and subsequent diffusion of excess neurotransmitter into the synaptic space

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These drugs inhibit the MAO in brain and as well as in t he peripheral

Pharmacological actions

1.BehaviorIn case o f mental depression, these compounds elevate the moodThe patient feels more energetic and fresh

2. On CVSNo effect on heart or circulation at normal dose

3. Potentiation of sympathomimetic aminesThese compounds potentiate the action of symathomimitic amines like amphetamine and tyramineThese have a mild, amphetamine like stimulant effect

Pharmacokinetics

These drugs are will absorbed on oral administration

Antidepressant effects require two to four week of treatment

MAO inhibitors are metabolized and excreted rapidly in the urine

Uses

MAO inhibitors are indicated for depressed patients who are un- responsive or allergic to TCA or who experience strong anxiety

These drugs are also useful in the treatment of phobic statesMAO inhibitors also used in the treatment of a special subcategory of depression called atypical depression

Atypical depression is characterized by labile mood , rejection sensitivity and appetite disorders

Adverse effects

Behavioral effects

Headache, excitement and disturbed sleep

CNS effects

Twitching, ataxia and tremors

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ANS effects

Dry mouth, constipation and blurred vision

HypertensionTyramine is met abolished by the enzyme MAO

In presence of MAOI , tyramine is not metabolized

These leads to accumulation of tyramine

Tyramine produces rise in blood pressure by releasing nor adrenaline

11. Tricyclic antidepressants

These blocks nor epinephrine and serotonin uptake into the neuron

These drugs are voluble alternative for patients who do not respond to SSRIs

Mechanism of action

These are potent inhibitors of the neuronal re-uptake of nor epinephrine and serotonin into presynaptic nerve terminals

This produces increase in its concentration at the receptor sites

These contributes for the antidepressant action

TCAs also block serotonergic, alpha adrenergic ,histamine and muscarinic receptors

Pharmacological actions

1. Behavior

These elevate mood, improve mental alertness ,increase physical activity

The onset of the mood elevation is slow , requiring two weeks or longer

These drugs do not produce CNS stimulation or mood elevation in normal individuals

Physical and psychological dependence have been reported

The drugs can be used for prolonged treatment of depression without loss of effectiveness

2. CVS

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No effect at normal dose

But toxic doses may produce cardiac arrhythmias

3. ANS

Imipramine produces anti cholinergic effects like dry mouth, constipation , palpitation and blurred vision

ADME

Imipramine is well absorbed on oral administration

Because of their lipophilic nature ,they are widely distributed and readily penetrate into the CNS

This lipid solubility also causes these drugs to have long half lives – 4 – 17 hours for imipramine

These drugs are metabolized by the hepatic microsomal system and conjugated with glucuronic acid

The TCA are excreted as inactive metabolites via the kidney

It actions are mediated through desmethyl-imipramine which is a metabolite product

Adverse reactions

CNS effects

Lethargy, headache and drowsiness

ANS effects

Dry mouth, constipation and tachycardia

CVS effects

Cardiac arrhythmias and hypotension

Allergic reactions

Skin rashes and photosensitivity

Uses

These are very effective in treating severe major depression

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Some panic disorders also respond to TCA

Imipramine has been used to control bed- wetting in children by causing contraction of the internal sphincter of the bladder

TCAs , particularly amitriptyline , have been used to treat chronic pain

111. Selective serotonin re-uptake inhibitors ( SSRIs)

Drugs which belongs to these groups areFluoxetineCitalopramEscitalopramParoxetineSertaline

These drugs do not produce CNS stimulation or mood elevation in normal individuals They selectively inhibit 5 – HT reuptake

They have less antimuscarinic effects and also sell sedation

They are safer than tricyclic antidepressants

These have little ability to block the dopamine transporter

Pharmacological actions

SSRIs block the re-uptake of serotonin , leading to increased concentrations of the neurotransmitter in the synaptic clefts and to greater postsynaptic neuronal activity

Anti-depressants including SSRIs typically take two weeks to produce improvement in mood and maximum benefit may require twelve weeks or more

The patients that do not responds to one antidepressant may respond to another and approximately eithy percent or more will respond to at least one antidepressants drug

Pharmacokinetics

These are well absorbed on oral administration

Peak levels are seen in five hours on average

Food has little effect on absorption

Only sertraline undergoes significant first –pass metabolism

All these agents are well distributed

The half life of SSRIs are in-between 16 -36 hours

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These are metabolized by the P-450 – dependent microsomal enzymes

These produced the conjugation of glucuronide or sulfate conjugationBoth citlopram and fluoxetin are racemic mixtures

Escitalopram is the pure S- enatiomer of citalopram

Fluoxetine and paroxetine are potent inhibitors of a hepatic cytochrome P-450 iso enzymes responsible for elimination of tricyclic antidepressant drugs

Excretion of the SSRIs is primarily through the kidneys except for paroxetine and sertraline which also undergo fecal excretion

USESThe primary indication for SSRIs is depression, for which they are as effective as the tricyclic antidepressants

A number of other psychiatric disorders also respond favorably to SSRIs m including obsessive compulsive disorder, panic disorder, generalized anxiety

Adverse reactionSSRIs have fewer and less severe adverse effects than the tricyclic antidepressant and MAOI

1. Sleep disturbances

Paroxetine and fluvoxamine are sedating and may useful in patients who have difficulty sleeping

2. Sexual dysfunction

Loss of libido, delayed ejaculation and anorgasmia are underreported side effects often noted by clinicians but not prominently featured in list of standard side effects

3. Use in children and teenagers

Anti depressants should be used cautiously in children and teenagers , because about one out of fifty children become more suicidal as result of SSRI treatment

Pediatric patients should be observed for worsening depression and suicidal thinking whenever one of these drugs is started or their dose is increased or decreased

4. Overdoses

Large intakes of SSRIs do not cause cardiac arrhythmias, but fluoxetine may cause seizuresAll SSRIs have the potential to cause a serotonin syndrome characterized by hyperthermia , muscle rigidity , clonic muscle twitching and changes in mental status and vital signs when used in the presence of a monoamine oxidase inhibitor

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Anti- manic drugs

The following drug are used in the treatment of manic disorder

Lithium saltsCarbamazepine Valproic acid

Lithium carbonates

It is a small monovalent cation

In 1949 it was found to be sedative in animals and to exert beneficial effects in manic patients

Mechanism of action

The mechanism of antimanic and mood stabilizing action of LI is not knownIt has been proposed that

Lithium partly replaces body Na and is nearly equally distributed in and outside the cells ( contrast Na and K ) , this may affect ionic fluxes across brain cells or modify the property of cellular membranes

Lithium has been found to decrease the release of Na and DA in t he brain of treated animals without affecting 5 –HT release

This may correct imbalance in the turnover of brain monoamines

Pharmacological actions

On CNS

Lithium has practically no acute effects in normal individuals as well as in MDI patients

It is neither sedative nor euphorient, but on prolonged administration, It acts as a mood stabilser in bipolar disease

Given to patients in acute mania, it gradually suppresses the episode taking 1-2 weeks

The markedly reduced sleep time in manic patients is normalized

Other actions

Lithium inhibits action of ADH on distal tubules and causes a diabetes like state

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It has some insulin like action on glucose metabolism

Leukocyte count is increased by lithium therapy

Lithium reduces thyroxin synthesis by interfering with iodination of tyrosine

Pharmacokinetics

Lithium is given orally and the ion is excreted by the kidney

It is neither protein bound nor metabolized

It first distributes in the extra cellular water and then gradually enters cells and slowly penetrates into the CNS , ultimately attaining a rather uniform distribution in total body water , apparent volume of distribution at steady- state averages 0.8 L/kg

The lithium is handled by the kidney in much the same way as Na ,

Most of the filtered Lithium is reabsorbed in the proximal convoluted tubule

When N a is restricted, a larger fraction of filtered Na is reabsorbed , so is Li

After a single dose of li urinary excretion of rapid for 10- 12 hours followed by a much slower phase is 16- 30 hours

Renal clearance of lithium is 1/5 of creatinine clearance

On repeated medication steady-state plasma concentrations achieved in 5-7 days

Levels are higher in older patients and in those with renal insufficiency

Peaks in plasma lithium level over and above the steady-state level occur after every dose and produce episodes of toxicity if steady-state level if high or the dose is large

Divided daily dosing in 2-4 portions is needed to avoid high peaks

Lithium is excreted in sweat and saliva also salivary concentration is proportionate to serum concentration and may be used for noninvasive monitoring

Lithium is secreted in breast milk

Mothers on lithium should not breastfeed

Adverse reaction

Side effects are common but are mostly tolerable

Toxicity occurs at levels only marginally higher than therapeutic levels

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Nausea, vomiting and mild diarrhea occur initially, can be minimized by starting at lower doses

Thirst and polyuria are experienced by most, some fluid retention may occur initially but clears later

Fine tremors and rarely seizures are seen even at therapeutic concentrations

CNS toxicity – coarse tremors, giddiness, ataxia, motor in coordination, mental confusion, slurred speech,

On long term use some patients develop renal diabetes and goiter has been reported in about 4 %

Interactions

Diuretics ( thiazide, furosemide0 by causing ) Na loss promote proximal tubular reabsorption of Na as well as lithium – plasma levels of lithium rise

Tetracycline’s , indomethacin and ACE inhibitors can also cause lithium retention

Lithium reduces presser response to NA

Lithium tends to enhance insulin / sulfonylurea induced hypoglycemiaSuccinyl-choline and pancuronium have produced prolonged paralysis in lithium treated patients

Haloperidol have been frequently used along with lithium without problem , sometimes , the combination of haloperidol and lithium produces marked tremor and rigidity

Dose

Lithium used as its carbonate salt because this is less hygroscopic and less gastric irritant than lithium chloride or other salts

It converted into chlorides in the stomach

It is generally stared at 600 mg/day and gradually increased to yields therapeutic plasma levels, mostly 600-1200 mg /day is required

Hallucinogens

These are drugs which alter mood, behavior, thought and perception in a manner similar to that seen in psychosis

In appropriate doses these produce changes in visual, auditory perception, in smell and taste , broadly illusions and hallucinations

There will be alteration of the sense of time and space with personality changes

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Memory is not affected The drugs which possess their actions are cannabis, mescaline, LSE -25 , psilocybin , bufotenine and harmoline

Cannabis

It is obtained from cannabis indica or Indian hemp

Flowering tops (ganja), the leaves (bhang) , the resinous exudation (Charas) or the whole drug ( Hashish)

In U.S.A. it is called as marihuana

Cannabinal (chemically an alcohol) a red syrapy oil is said to be the active principle

It produces hallucinations of time , space, euphoria ( sense of well being), imagination, mental exaltation, impulsive behavior, delirium ( confusion and excitement), mania ( mental disorder)

Cannabis is not useful therapeutically

Mescaline

It is an alkaloid obtained from a cactus

When given orally the drug produces sympathomimetic effects and visual hallucinations and a sense of floating in space

It also produces excitement , restlessness, change of mood and intelligenceIt is used only for experimental purposes to produce psychotic states

LSD – 25 ( Lysergic acid diethylamide)

This is a derivative of ergot alkaloid, now being used in psychiatric research

It induces psychotic states in which repressed memories form the subconscious mind are brought of light

It stimulates emotional activity producing the sense of lightness and withdrawal from reality

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It brings about personality change

It may be used in obsessional thoughts and anxiety conditions accompanied by mental tension

It is orally active in a dose of 25 micro gram

But it is widely misused for its hallucinogenic effects

The person become disoriented and his activities disorganized

It is noticed that it can induce chromosomal abnormalities and fetal malformation and possibly leukemia and hence it I withdrawn even form research

Other minor hallucinogens like bufetinine, psilocybin and harmolin produce similar psychic effects but not used therapeutically

Unit - 7

Anti- Epileptic drugs

It is a collective term applied for a group of convulsive disorders

The common features of epilepsy areLoss or disturbance of consciousnessesCharacteristic body movements (usually, but not always) CLASSIFICATION

1. Hydantoins

Phenytoin

2. Barbiturates

PhenobarbitonePrimidone

3. Iminostilbbenes

Carbamazepine

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4. Succinimides

Ethosuximided

5. Aliphatic carboxylic acid

Sodium valproate

6. Benzodiazepines

ClonazepamClobazamDiazepam

7. Newer antiepilepticLamotrigineGbapentine8. MiscellaneousTrimethadioneAcetazolamide

Phenytoin

Phenytoin was synthesized in 1908, but its anticonvulsant property was discovered only in 1938

It is effective in suppressing tonic-clinic and partial seizures and is a drug of choice for initial therapy, particularly in treating adults

Mechanism of action

Phenytoin blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and stabilizes the neuronal membraneIt inhibits the generation of repetitive action potentialsAt much higher concentrations , phenytoin can block voltage-dependent calcium channels and interfere with the release of monoaminergic neurotransmitters

Pharmacological action

Phenytoin exerts antiseizure activity without causing general depression of the CNS

It is one of the most effective drugs against generalized tonic-clonic seizures and partial seizures

Phenytoin reduces the propagation of abnormal impulses in the brain

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Pharmacokinetics

Phenytoin is poorly water soluble hence absorption is slow

It is 90% bound to plasma proteins

It is metabolized in liver

Phenytoin is enzyme inducer

Therapeutic uses

Phenytoin is highly effective for all partial seizures ( simple and complex), for tonic-chronic seizures and in the treatment of status epileptics

Phenytoin is not effective for absence seizures, which often may worsen if treated with this drug

Adverse effects

It depend dose , duration and route

Nausea, vomiting, epigasric pain, anorexia

Nystagmus, diplopia, ataxia are common

Gingival hyperplasia is more common in children on prolonged use

Peripheral neuropathy

Phenytoin inhibits insulin release and produces hyperglycemia

Decreases the release of ADH

Osteomalacia , hypocalcaemia due to altered metabolism of vitamin D and inhibition of intestinal absorption of Ca

Hypersensitivity - Rashes , SLE, hepatic necrosis , and neutropenia

Megaloblastic anemia – Phenytoin decreases absorption and increases excretion of folates

Teratogenicity

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When taken by the pregnant lady, phenytion produces fetal hydantion syndrome characterized by hypo plastic phalanges, cleft palate, and harelip

Drug interactions

Phenytoin is an enzyme inducer

Phenytoin given with phenobarbitone , both increases each other metabolism

Phenytoin and carbamazepine enhance each others metabolism

Valproate displaces protein bound phenytoin

Cimetidine and chloramphenicol inhibit the metabolism of phenytioin resulting in toxicity

Antacids decreases the absorption of phenytoin

Phenobarbitone

Phenobartitone was the first effective antiepileptic drug to be introduced in 1912. It still remains one of the widely used drugs

It has antiepileptic activity and raises the seizure threshold

Mechanism of action

Barbiturates enhances the inhibitory neurotransmission in the CNS by enhancing the activation of GABA receptors and facilitating the GABA mediated opening of chloride ion channels

Pharmacokinetics

It is well absorbed orally

The drug freely penetrates the brain

Approximately 75 % of the drug is inactivated by the hepatic mocrosomal system, whereas the examining drug is excreted unchanged by the kidney

It is a potent inducer of the cytochrome P450 system and when given chronically, it enhances the metabolism of their agents

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Therapeutic uses

It provides favorable response for simple partial seizures, but it is not very effective for complex partial seizures

The drug had been regarded as the first choice in treating recurrent seizures in children, including febrile seizures

It also used to treat recurrent tonic-clonic seizures, especially in patients who donot respond to diazepam plus phenytoin

It also used as a mild sedative to relieve anxiety, nervous tension and insomnia

Adverse effects

Sedation, ataxia, vertigo , nausea and vomiting

Agitation and confusion occur at high doses Rebound seizures can occur on discontinuance of Phenobarbital

Primdone

It structurally related to Phenobarbital and it resembles Phenobarbital in its anticonvulsant activity

It is an alternative choice in partial seizures and tonic – clonic seizures

It has more efficacy due to the its metabolites Phenobarbital and phenyl-ethyl-malonamide which have longer half- lives than the parent drug

It is effective against tonic-clinic and simple partial seizures and phenyl-ethy-lmalonamide is effective against complex partial seizures

Primidone is often used with carbamazepine and phenytoin

It is well absorbed orally

It exhibits poor protein binding

These drug has the same adverse effects as those seen with Phenobarbital

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Benzodiazepines

Several of the benzodiazepines show antiepileptic activityDiazepam and lorazepam are the drugs of choice in the acute treatment whereas Clonazepam and clorazepate and clorazepate are used for chronic treatment of status epilepticus

Clonazepam

It suppresses seizure spread from the epileptogenic focus and is effective in absence and myoclonic seizures , but tolerance develops

Clonazepate

Clorazepate is effective in partitial seizures when used in conjunction with other drugs

Diazepam

It is effective against

Pedestal epilepsyMylclonic seizuresStatus epilepsyIt is drug of choice for status epilepticus

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Lorazepam

Lorazepam and diazepam are both effective in interrupting the repetitive seizures of status epilepticus.

Lorazepam has a longer duration of action and is preferred by some clinicians

All of the antiepileptics, the benzodiazepines are the safest and most free from severe side effects

All benzodiazepines have sedative properties

Side effectsDrowsiness,Somnolence, Fatigue,Ataxia, Dizziness and behavioral changes

Respiratory depression and cardiac depression may occur when given intravenously in acute situations

Ethosuximide

It reduces propagation of abnormal electrical activity in the brain, most likely by inhibiting t- type calcium channels in a manner similar to the action of phenytoin on sodium channels

It is the first choice in absence seizures

It is well absorbed orally and is not bound to plasma proteins

About 25% of the drug is excreted unchanged in the urine and 75% is converted to inactive metabolites in the liver by the microsomal cytochrome P450 system

It does not induce P450 enzyme synthesis

The drug is irritating to the stomach and nausea and vomiting may occur on chronic administration

Drowsiness, lethargy, dizziness , restlessness , agitation , anxiety and the inability to concentrate are often observed

Valproic Acid

It is a broad spectrum anticonvulsant

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It has multiple actions , including sodium channel blockade and enhancement of GABAergic transmission

It is the most effective agent available for treatment of myoclinec seizures

It also diminishes absence seizures, but because of its hepatotixic potential, it is a second choice

It also reduces the incidence and severity of tonic-clonic seizures

The drug is effective orally and is rapidly absorbed

About 90% is bound to the plasma proteins ,only 3% of the drug is excreted unchanged, the rest is converted into active metabolites by the liver

It is metabolized by cytochrome P450 enzymes

Metabolites are excreted by kidney

It can cause nausea, vomiting ,sedation, ataxia and tremor are common

It inhibits the metabolism of a number of antiepileptic drugs , including Phenobarbital, carbamazepine and ethosuximide

Carbamaepines

Actions

It reduces the propagation of abnormal impulses in the brain by blocking sodium channels, thereby inhibiting the generation of repetitive action potential in the epileptic focus and preventing their spread

ADME

It is absorbed slowly following oral administration

It enters the brain rapidly because of its high lipid solubility

It induces the drug metabolizing enzymes in the liver

The enhanced hepatic cytochrome p450 system activity also increases the metabolism of many drugs including other antiepileptic drugs

It is an inducer of the cytochromep450 isozyme cyp3a4, which decrease the effects of drugs that are metabolized by his enzyme

Therapeutic uses

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It is effective in Temporal lobe epilepsy

Trigeminal neuralgia

Used in post hepatic pain

Adverse effects

Chronic administration of carbamazepine can cause stupor, coma and respiratory depression

It also produces drowsiness, vertigo, ataxia, and blurred vision

The drug is irritating to the stomach and nausea and vomiting may occur

Drug interaction

The hepatic metabolism of carbamazepine is inhibited by several drugs

Toxic symptoms may arise if the dose is not adjusted

Anti - parkinsonism

It was described b James Parkinson in 1817 and is therefore named after him

Parkinsonism is a chronic , progressive, motor disorder

Characterized by

Akinesia

Muscular rigidity

Tremors

Other symptoms

Excessive salivation

Abnormalities of posture and gait

Seborrhea

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Mood changes

The incidence is about 1% of population above 65 years of age

It is usually idiopathic in origin but can also be drug induced

In idiopathic parkinsonism, there is degeneration of nigrostriatal neurons in the basal ganglia resulting in dopamine deficiency

The balance between inhibitory dopaminergic neurons and excitatory cholinergic neurons is disturbed

Antiparkinsonian drugsIt can only help to alleviate the symptoms and improve the quality of life The two strategies in the treatment are

1. To enhance dopamine activity

2. To depress cholinergic over- activity

Classification of Anti parkinsonism drugs

1. Drugs that increase dopamine levels

A. Dopamine precursor

Levodo[a

B. Drugs that release the dopamine

Amantidine

C. Dopaminergic agonists

Bromocryptine

Lisuride

D. Inhibit dopamine metabolism

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MAO inhibitors - Selegiline

11. Drug influencing cholinergic system

A. Central anticholinergics

Bintropine

Benzhexol

Biperidine

B. Antihistamines

Diphenhydramine

Promethazine

Levodopa

Acetylcholin and dopamine are excitatory and inhibitory neurotransmitters in the corpus striatum

The dopaminergic system is impaired in parkinsonism, so the balance is disturbed

Levodopa acts by getting converted to dopamine and restoring the balance

Parkinsonism is due to dopamine deficiency

Levodopa improves all the manifestations of parkinsonism

But it is not effective in drug induced parkinsonism

Decarboxylase inhibitors like carbidopa are administered with levodopa

They decrease the peripheral decarboxylation of levodopa

Dopamine is of no therapeutic value because it dies not cross the blood- brain barrier

Levodopa is a prodrug which is converted to dopamine in the body

It crosses the Blood- Brain-Barrier and is taken up by the surviving nigrostriatal neurons

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DecarboxylaseLevodopa ------------------------------------------- Dopamine

Actions

On administration of levodopa, there is an overall improvement in the patient as all the symptoms subside

Other actions

CTZ - Dopamine stimulates CTZ to induce vomiting

CVS - Large amounts of levodopa converted to dopamine in the pheiphery causes postural hypotension and tachycardia. Dopamine is a catecholamine

Endocrine -- Dopamine suppresses prolactin secretion

Pharmacokinetics

Levodopa is rapidly absorbed from the small intestine

The presence o food delays absorption

Some amino acids in the food compete with levodopa for the absorption and transport to the brain

It undergoes first pass metabolism in the gut and the liver

Its half life is 1-2 hours

Adverse reactions

Large amounts of levodopa is converted to dopamine is the periphery, several adverse effects are expected

Nausea, vomiting, postural hypotension palpitation and occasionally arrhythmia can occur

Tolerance develops to these effects after some time

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Behavioral effects like anxiety, depression , hallucinations and sometimes psychosis can occur

Use

Levodopa is the most effective drug in idiopathic parkinsonism but is not useful in drug induced parkinsonism

Drug interactions

Pyridoxine enhances peripheral decarboxylation of levodopa and reduces its availability to the CNS

Phenothiazines, metoclopramide and reserine are DA antagonists.

They reverse the effects of levodopa

Carbidopa and benserazide

These Are Peripheral Dopa Decarboxylase Inhibitors

When carbidopa or bensrazide are given with levodopa, they prevent the formation of dopamine in the periphery

They do not cross the BBB and hence allow levodopa to reach the CNS

The combination is synergistic and therefore levodopa is always given with carbidopa or benserazide

Advantages of combination

Dose of levodopa can be reduced by 75%

Response to levodopa appears earlier

Side effects like vomiting and tachycardia are largely reduced

Pyridoxine does not interfere with treatment

Amantadine

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It is an antiviral drug

It enhances the release of dopamine in the brain and diminishes the re-uptake of DA

The response starts early and its adverse effects are minor

Large doses produce insomnia, dizziness, vomiting , postural hypotension , hallucinations and ankle edema

Amantadine id used in mild cases of parkinsonism

It can also be used along wit h levodopa as an adjunct

BromocriptineIt is an ergot derivative having dopamine agonistic activity at D2 receptors

It is used asAn adjunct to levodopa in the management of on- off phenomenon

An alternative inn patients unable to tolerate levodopaAdverse effects

It include vomiting , postural hypotension, hallucinations, skin eruptions and first dose phenomenon - sudden cardiovascular collapse

Lisuride and pergolide are similar to bromocriptine

SelegllineIt is a selective MAO- B inhibitor

MAO- B is present in DA containing regions of the CNS

Selegilline prolongs the action of levodopa by preventing its degradation

Selegiline may delay the progression of parkinsonism

Uses - Mild cases of parkinsonism are started on selegiline’It is also used as an adjunct to levodopa

Anti- cholinergic

The cholinergic over activity is overcome by anticholinergics

Tremors, seborrhea and sialorrhiea are reduced more than rigidity

Atropine derivatives like benzhexol, benztropine, trihexyphenidyl are used

Antihistamines owe their beneficial effects in parkinsonism to their anticholinergic properties

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Atropine like side effects such as dry mouth , constipation, blurred vision may be encountered

UsesAnticholinergics are used as Adjunct to levodopaDrugs of choice in drug induced parkinsonism

Drug induced parkinsonismDrugs like reserpine., metoclopramide and phenothiazines can induce parkinsonism

Resrpine depletes catecholamine stores, metoclopramide and phenothiazines are dopamine antagonists

Treatment withdrawal of the drug usually reverses the symptoms

When drugs are needed, one of the anticholinergics are effective

Unit - 8

Analgesics and Anti-pyretics

Analgesic -- These are drugs which produce relief of pain

Antipyretics -- These are drugs which reduces increased body temperature

These drugs relieve pain of lesser intensity like tooth-ache and muscle pain

But they do not relieve severe pain like visceral pain which is relieved by opioid analgesics. These drugs do not produce addiction

All these drugs produce an anti-inflammatory effect, so these are called as non-steroidal anti-inflammatory drugs ( NSAID )

These are weak analgesics as compared to narcotic analgesics and have primary action on peripheral pain mechanism

They act without interacting with opioid receptors, they are called as non- opioid Analgesics

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These drugs have three main function – Analgesics , Anti-pyretic and Anti-inflammatory action

A. Non selective COX inhibitors

1.Salicylates

Acetyl-salicylic acidSodium salicylateMethyl salycilateSalicylic acid

2.Para- aminophenol derivatives

ParacetamolPhenacetin

3. Pyrazolon derivatives

Phenyl butazoneOxypehenbutazoneAminopyrineAntipyrine

4. Propionic acid derivativesIbuprofen, Ketoprofen

5. Indole derivatives Indomethacin

6. Anthranilic acid derivative Mephenamic acid

7. Aryl acetic acid derivative Diclofenac

8. Oxicam derivatives Poroxicam, Tenoxicam

B. Preferential COX -2 inhibitors Nimesulide, Meloxicam

C. Selective COX – 2 inhibitors

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Celecoxib, Rpfecpxon

Mechanism of action

These drugs does not act on Central nervous system

Phospholipase A2

Membrane -- Phospholipids--- ------------------------------------- Arachidonic acid Cyclo- oxygenase------------------------------------- Prostaglandins

The arachidonic acid is liberated from damaged cells during an inflammatory reaction

Prostaglandins and other mediators of inflammation are formed from Arachidonic acid with the help of an enzyme Cyclo-oxygemase

The prostaglandin formed are responsible for many of the features of inflammation I.e. – swelling, redness and pain )

These prostaglandins produce hyperalgesia -- They sensitize the nerve endings to pain and other mediators of inflammation like bradykinin and histamine

The NSAID block the action of enzyme cyclo-oxygenase and thus prevent or reduces the production of prostaglandins and other mediators of inflammation

Asprin

It is a acetyl salicylic acid

It is one of the oldest analgesic-anti-inflammatory drugs and is still widely used

It is rapidly converted in the body to salicylic acid which is responsible for most of the actions

Other actions are the result of acetylation of certain macromolecules including COX

Mechanism of action

It inhibits cycloxygenase which is responsible for the synthesis of prostaglandin and thromboxane

It also inhibits platelet aggregation

Pharmacological actions

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1. Analgesic action

Asprin is a weaker analgesic than morphine

These are effective only in dull- aching pain of low intensity

They do not relieve severe pain like visceral pain

They act by preventing the integration of pain sensation in the thalamus

But they do not alter the emotional reaction to pain2. Anti-pyretic effect

Salycylates do not lower normal body temperature

Only the elevated temperature is lowered

Mechanism

A. The hypothalamic heat regulating center ( thermostat of the body) is set for a higher temperature in fever This is reset for a lower temperature by salicylates

B. The salicylates produce sweating which also lowers body temperature

3. Anti- inflammatory action

Asprin exert the anti-inflammatory action at high doses 3- 6 grams /day

Signs of inflammation like pain, tenderness, swelling , vasodilatation and leukocyte infiltration are suppressed

Asprin inhibits cyclo-oxygenase activity, it diminishes the formation of prostaglandins and modulates those aspects of inflammation in which prostaglandins act as mediators

Asprin inhibits inflammation in arthritis

4. On respiration

Salycylates stimulate respiration

The stimulation is depend on the dose

Salicylates stimulates respiration directly by stimulating the respiratory centre

Stimulate the respiration indirectly by through CO2

At anti –inflammatory respiration is stimulated by peripheral( increased CO2 production)and central ( increased sensitivity of respiratory centre to CO2 ) actions

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Hyperventilation is prominent in salicylate poisoning

Further rise in salicylate level causes respiratory depression

Death is due to respiratory failure

5. Cardiovascular system

No effect at normal dose

Large doses increase cardiac output to meet increased peripheral O2 demand and cause direct vasodilatation

Toxic doses produce paralysis of vasomotor centre and BP may fall

6. GI TractSalicylates produce nausea and vomiting due toDirect stimulationStimulation of chemoreceptor trigger zone Salicylates can also cause gastric ulceration and hemorrhage

7. Anti- rheumatic effect

Salicylates have powerful anti-rheumatic effect

T his effect is produced by reducing pain and inflammation of the joints

8. Blood

Salicylates lower the erythrocyte sedimentation rate (ESR) which is high in rheumatic fever

They also decrease prothrombin level of plasma

Uricosuric effect

Slicylates promote the excretion of uric acid

This effect is produced by inhibiting the reabsorption of uric acid in the proximal tubule

Immunological effect

Salicylates inhibit antigen- antibody reaction and so prevent the release of histamine

9. Metabolic effects

Salicylates produce uncoupling of oxidative phosphorylation

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They produce hyperglycemia and glycosuria

They inhibit the synthesis but enhance the breakdown of fatty acids

10. Hormones

Salycylates stimulate the release of adrenaline from adrenal medulla

They also stimulate the release of adreno-corticotrophic hormone (ACTH)

They interfere with the binding of thyroxin with plasma proteins

This free thyroxin depresses the secretion of thyroid stimulating hormone (TSH)

11. Local actions

Salicylates , especially salicylic acid and methyl salicylate have antiseptic, fungi staticand keratolytic effects

ADME

Salicylates are absorbed from the stomach and small intestine

They are bound to plasma proteins

They are mainly concentrated in the liver, heart, muscle, and brain

They are metabolized in liver by conjugation with glycine and glucuronic acid

The metabolic products are mainly excreted through urine

Adverse reactions

Gi tracts disturbances like nausea, vomiting , diarrhea , ulceration perforation and hemorrhage

Intolerance leading to skin rashes of various types

Bone marrow depression leading to agranulocytosis , thrombocytopenia and a plastic anemia

Fatty infiltration of liver and kidney

Salicylism characterized by headache, difficulty in hearing, drowsiness, lethargy and confusion

Preparation and doses

Aspirin Tab - 0.3 g – 1 gram oral

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Acetyl- salicylic acid powder - 0.3 g - 1 gram oral

Sodium salicylate as mixture - 0.6 g - 2 gram oral

Methyl salicylate - Ointment

Salicylic acid - Ointment

UsesIt is used as analgesic for light and moderate pain

Used as anti-pyretic in fever

It is used as anti-rheumaticIt also used as antiseptic , anti-fungal and keratolytic

Pracetamol

It is a Para-amino phenol derivative

It has analgesic and antipyretic effects like salicylates

Parcetamol , a metabolite of phenacetin is found to be safer and effective

It has analgesic , good antipyretic and weak anti- inflammatory properties

Due to weak PG inhibitory activity in the periphery, it has poor anti-inflammatory actions

Paracetamol is active on cyclo-oxygenase in the brain which accounts for its antipyretic action

In presence of peroxides present at the site of inflammation , it has poor ability too inhibit cyclo-oxygenase

It does not stimulate respiration

It has no action on acid- base balance , cellular metabolism , cardiovascular system and platelet function

It does not produce gastrointestinal irritation and uricosuric effect

Mechanism of action

Paracetamol exhibits analgesic action by peripheral blockage of pain impulse generation

It produces antipyresis by inhibiting the hypothalamic heat- regulating centre

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Its weak anti-inflammatory activity is related to inhibition of prostaglandin synthesis in the CNS

ADME

It well absorbed orally

30% protein binding

It is metabolized by the hepatic microtonal enzymes by glucuronide conjugation (60% )And glutathione conjugation (20% )

Treatment

Stomach wash is given

Activated charcoal prevents further absorption

Antidote is N-acetylcysteine more effective when given early

(150 mg/kg IV infusion over 15 min followed by 70 mg/kg every 4 hours -17 doses)

N- cetylcysteine partly replenishes the glutathione stores of the liver and prevents binding of toxic metabolites to the cellular constituents

Adverse effects

In antipyretic doses , paracetamol is safe and well – tolerated

Nausea and rashes may occur

But when large doses are taken, acute paracetamol poisoning results

Children are more susceptible due to their ability to conjugate by glucuronidation to poor

10 – 15 grams in adults cause serious toxicity

Symptoms

Nausea

Vomiting

anorexia

Abdominal pain

Parecetamol is hepatotoxic and causes severe hepatic damage

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Hepatic lesions are reversible when promptly treated

UsesParacetamol is used as an analgesic in painful conditions like toothache, headache and myalgiaAs an antipyretic

Chronic pulpitis, periodontal abscess, post- extraction – parcetamol is used with IbuprofenIbuprofen

It is propionic acid derivatives

It is a better tolerated than aspirin

It exhibits anti- inflammatory, analgesic and antipyretic activities

Analgesic, antipyretic and anti-inflammatory efficacy is slightly lower than aspirinIt is 99% bound to plasma proteins

Its analgesic activity is independent of anti- inflammatory activity and has both central and peripheral effect

Temperature is reduced in febrile patients

It is a potent inhibitor of the enzyme cycloxygenase resulting in t he blockage of prostaglandin synthesis

It also prevents formation of thromboxane A2 by platelet aggregation

Adverse effects

Nausea

Vomiting

Gastric discomfort

CNS effects

Hypersensitivity reactions

Dose 400- 800 mg TDS

Uses

1. It has analgesic and antipyretic activity

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2. It is used in the treatment of gout

3. Surgical removal of impacted tooth – a combination of ibuprofen with a skeletal muscle relaxant like chlorzoxaxone is recommended

4. Chronic pulpits, periodontal abscess, gingival abscess – a combination of ibuprofen with paracetamol is preferred

Indomethacin

It has anti-inflammatory, analgesic, antipyretic and antigout actions

It is a portent inhibitor of cycloxygenase thus reducing prostaglandin synthesis

It relieves pain and reduces temperature in febrile patients reduces pain and joint swelling in rheumatoid arthritis but does not modify progress

It is well absorbed, 90% bound to plasma proteins & half life is 4 – 6 hours

Dose

25 -30 mg BD-TDS

Adverse effects

Adverse effects are high .

Gastrointestinal irritation with nausea, GI bleeding , vomiting , diarrhea and peptic ulcers can occur

CNS effects include headache, dizziness, ataxia, confusion, hallucinations, depression and psychosis

Hypersensitivity reactions like skin rashes, leucopenia and asthma in aspirin sensitive individuals

Drug interactions

Indomethacin blunts the diuretic action of furosemide and the anti-hypertensive action of thiazides, furosemide, beta blockers and ACE inhibitors by causing salt and water retention

Uses

Rheumatoid arthritis

Gout

Ankylosing sodalities

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For closure of patent ductus arteriosus

Nimesulide

It is a sulfonamide compound is a weak inhibitor of prostaglandin synthesis with a higher affinity for COX-2 then COX-1

The action of nimesulide is somewhat different form that of classic NSAD

It inhibits leukocyte function, prevents the release of mediators and in addition has antihistaminic and ant allergic properties

It has analgesic, antipyretic and anti-inflammatory actions like other ASAID

May also inhibit release of tumor necrosis factor alpha and thus reduce the formation of cytokines

Relief of mild to moderate pain and fever, inflammatory

It is well absorbed orally, extensively bound to plasma proteins and has a half life is 3 hours

It is excreted by kidney

Dose 50 -100 mg BD

Adverse reactionNausea

Diarrhea,

Vomiting

Rash

Dizziness

Somnolence

Headache

Long term use can cause hepatotoxicity

UsesIt is used as an analgesic, antipyretic and anti- inflammatory agent for short periods as in headache, toothache, myalgia, dysmenorrheal, sinusitis, post-operative pain and arthritis

It is beneficial in patients who develop bronchospasm with other NSAID

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Phenyl- butazone

It has good anti- inflammatory activity, is more potent but has poorer analgesic and antipyretic effects

I is an urocosuric agent

It causes retention of Na and water. Thus after 1-2 weeks of use edema results It can also precipitate CHF

PharmacokineticsIt is completely absorbed from orally

IM injection is not recommended because its absorption is slow as it binds to local tissue proteins and also causes local tissue damage

It is 98% bound to plasma proteins . Half life is 60 hrs

Dose100 – 200 mg , BD

Small doses may be given 3-4 times a day to avoid gastric irritation

Adverse effects

Phenyl butazone is more toxic than aspirin and is poorly tolerated – dyspepsia, epigastric distress nausea and vomiting . Peptic ulceration and diarrhea may occur

Hypersensitivity reactions like rashes, serum sickness stomatitis hepatitis, nephritis, dermatitis and jaundice can occur

It may inhibit iodine uptake by thyroid resulting in hypothyroidism and goiter on lojg term use

CNS effects like insomnia vertigo, optic neuritis, blurring of vision and convulsions may be encountered

UsesRheumatoid arthritis

Ankylosing sodalities

Osteoarthritis

Gout Other musculoskeletal disorders

Oxyphenbutazone

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It is a major metabolite of phenylbutazone, similar in pharmacodynamic, pharmacokinetic, toxic and drug interaction profile

Dose

100 – 200 mg BD

Diclofenac sodium

Diclofenac is an analgesic, antipyretic and anti-inflammatory agent

It is tissue penetrability is good and attains good concentration n synovial fluid which is maintained for a long time

Mechanism if action

Inhibition of the enzyme cycloxygenase in prostaglandin synthesis

Prostaglandins are known to be associated with inflammation

Diclofenac is available as the sodium or potassium salt

The potassium salts are absorbed rapidly and action sets in much earlier

Adverse effects are mild

Dose

50 mg BD- TDS

Gel is available for topical application

Ophthalmic preparation is available for use in postoperative pain

UsesTreatment of chromic inflammatory conditions like rheumatoid arthritis and osteoarthritis

Acute musculo-skeletal pain

Post- operatively for relief of pain and inflammation

Severely painful conditions live acute pulpits and acute periapical abscess

Mephenamic acidAn analgesic, antipyretic and anti-inflammatory drug which inhibits COX as will as antagonists certain actions of PGS

Mephenamic acid exerts peripheral as will as central analgesic action

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PharmacokineticsOral absorption is slow but almost complete

It is highly bound to plasma proteins- displacement interactions can occur

Plasma half life is 2 – 4 hrs

Adverse effectsDiarrhea is the most important dose related side effect

Epigastria distress is complained, but bleeding is not significant

Skin rashes, dizziness and other CNS manifestations have occurred

Hemolytic anemia is rare but serious complication

Dose 250 – 500 mg TDS

UsesMephenamic acid is indicated primarily as analgesic in muscle, joint and soft tissue pain where strong anti-inflammatory action is not needed

It may be useful in some cases of rheumatoid and osteoarthritis but has mo distinct advantage

Opioid analgesics

AnalgesicsThese are drugs which relieve pain without causing loss of consciousness

Opioid analgesicsThese are the natural accruing, semi-synthetic and synthetic drugs which have morphine like action i.e. relief of pain and depression of CNS

1. According to ring structure

A . Phenanthrene derivatives

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MorphineCodeineThebaine

B . Benzo-isoquinoline derivatives

PapaverineNoscapine

11. According to synthesis

A. Natural opium alkaloids

MorphineCodeine

B. Semi synthetic opium alkaloids

HeroinePholcodeine

C. Synthetic opiods

PethidineMethadineTramadol

Morphine

Morphine is a natural opium alkaloid

It is a dried extract obtained from the capsules of the poppy plant known as papaver somniferum

Mechanism of action

Opioids exert their major effects by interacting with opioid receptors in the CNS

Opioids causes hyper polarization of nerve eells , inhibition of nerve firing and presynaptic inhibition of transmitter release

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Morphine acts at kappa receptors in lamina 1 and 11 of the substantia gelatinosa of the spinal cord and decreases the release of substance p, which is modulates pain perception in the spinal cord

Pharmacological actions

1. Analgesia

Morphine causes analgesiaMorphine relieves severe pain like visceral pain and pain of trauma

Mechanisms

Opioids relieve pain both by raising the pain threshold at the spinal cord level and more importantly by altering the brains perception of pain

It alters the emotional reaction to pain

It produces sleep which also elevates the threshold

2.CNS

Morphine produces euphoria in presence of pain

But in the absence of pain , it produces dysphoria

With an increased dose, it produces sleep

3. RespirationAt normal doses morphine causes respiratory depression by reduction of the sensitivity of respiratory center neurons to CO2

At higher doses it produces respiratory ceases

Respiratory depression is the most common cause of death in acute overdose

4. Anti-tussive property

Morphine has anti-tussive property

Morphine suppress cough by depressing the cough center

5. Emesis

In small doses, morphine directly stimulates the chemoreceptor trigger zone in the area postrema that causes vomiting

Tolerance develops to vomiting on prolonged use

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But a large dose of morphine inhibits vomiting

6. Pupil

The pinpoint pupil, characteristic of morphine use, results from stimulation of u and k receptors

Morphine produces constriction of pupil ( miosis)

The effect is blocked by atropine

Morphine addicts have constricted pupil

7. Gastro-intestinal tract

Morphine decreases peristaltic propulsive movements

It produces spasm of intestinal smooth muscles and sphincters

It also increases absorption of water

So the feces get dried

All these effects lead t o constipation

8. Billary tract

Morphine increase billiary tract pressure due to contraction of the gallbladder and

constrictor of the biliary sphincter

This produces increase in intrabiliary pressure

Atropine antagonizes t his effect

9. Cardiovascular system

Normal dose of morphine produces no effect on heart rate , blood pressure or circulation

But hypo tension and bradycardia may be produced at toxic dose

Because of respiratory depression and carbon dioxide retention, cerebral vessels dilate and increase the cerebrospinal fluid pressure

Morphine is usually contraindicated in individuals with severe brain injury

10. Histamine release

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Morphine releases histamine from mast cells, causing urticaria, seating and vasodilatation

Morphine can cause the bronco-constriction , asthmatics should not receive the drug

11. Hormonal actions

Morphine inhibits release of GRH and corticotrophic releasing hormone and it decreases the concentration of luteinizing hormone, FSH, ACTH

It increases prolactin and growth h hormone release by diminishing dopaminergicinhibit ion

It increases antidiuretic hormone and leads to urinary retention ADME

Absorption of morphine from GI T is slow and incompleteQuick effect is produced on subcutaneous injectionIt is partly bound to plasma proteins It is metabolized by conjugation with glucuronic acidIt is almost completely excreted in urine within 24 hours

Dose

Morphine sulphate orMorphine hydrochloride

Adverse reactions

GIT Symptoms – Nausea, vomiting and constipation

Acute morphine poisoning characterized by respiratory depression, pin point pupil cyanosis, reduced body temperature, hypotension , shock and coma

Tolerance and drug dependence

Central effects like dysphoria and mental clouding

Intolerance like tremor, delirium and skin rashes

Depression of fetal respiration

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Drug interactions

The depressant actions of morphine are enhanced by phenothiazines, monoamine oxidase inhibitors and tricycle antidepressants

Tolerance and dependence

Repeated use produces tolerance to the respiratory depressant, analgesic, euphoric ,and sedative effects of morphine

Physical and psychological dependence readily occur with morphine

Withdrawal produce a series of autonomic , motor and psychological responses that incapacitate the individual and cause serious - unbearable symptoms

Uses

It is an analgesic for the relief of severe pain

Used as pre-anesthetic medication

For producing sleep and sedation

Used as anti-tussive

For the treatment of diarrhea

In the treatment of acute left ventricular failure

Codeine

It is a phenanthrene alkaloid of opium

It is methyl- morphine

Naturally , it appears in opium and is partly converted in the body to morphine

It is less potent than morphine and also less efficacious

It is more selective cough suppressant

Sub-analgesic doses (10 – 30 mg ) suppress cough

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It has a predominant anti-tussive effect

It is a less potent analgesic when compared to morphine

Codeine has very low affinity y for opioid receptors

The other action like spasmogenic effect, nausea and vomiting , miosis and addiction are less with codeine

It rarely produces dependence

Codeine produces less euphoria then morphine

Codeine is often used in combination with aspirin or acetaminophen

In most non – prescription cough preparations , codeine has been replaced by drugs such as dextro- methorphan - a synthetic cough depressant that has mo analgesic action and a low potential for abuse

Codeine has good activity by oral route

Single oral dose acts for 4 – 6 hours

Constipation is a prominent side effect when it is used as analgesic

It has been used to control diarrheas

The abuse liability of codeine is low

Though codeine phosphate is water soluble and can be injected

Parental preparation is not available in India and most other countries

Heroin

It is a diamorphine, or diacetylmorphine

It does not occur naturally

It is produced by di-acetylation of morphine

It is a semi-synthetic derivative of morphine

It is a about 3 times more potent than morphine

It is more lipid soluble

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Due to its greater lipid solubility allows it to cross the blood- brain barrier more rapidly than morphine

Heroin is converted to morphine in the body

It enters brain more rapidly but duration of action is similar

It is considered to be more euphorient (specially on iv injection) and highly addicting

The sedative, emetic and hypertensive actions are said to be less prominent

It has mo outstanding therapeutic advantage over morphine and has been banned in most countries except U.K

Pethidine

It is a synthetic compound

It is a opioid structurally unrelated to morphine

It is used for acute pain

Mechanism of action

Pethidine binds to opioid receptors, particularly U receptors

It also binds well to k receptors

Pharmacological actions

Respiratory depression

Sedation and euphoria

Analgesic effect

Spasmogenic effect on smooth muscles and sphincters

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It dilates cerebral vessels, increases CSF pressure and contracts smooth muscle

It does not cause pinpoint pupil but rather causes the pupils to dilate because of an atropine like action

It has mo significant cardiovascular action when given orally

On IV administration , it produces a decrease in peripheral resistance and an increase in peripheral blood flow and it may cause an increase in cardiac rate

It does not produces the anti- tussive effects

Pharmacokinetics

It is well absorbed from the GIT when given orally and parental administration

It most often administered IM

It crosses the placental barrier. It also secreted in the milk

T he drug has a duration of action of two to four hours which shorter than that of morphine

It is converted normeperidin the liver and is excreted in the urine DOSE

Pethidine hydrochloride tablets – 25 –100 mg

Pethidine hydrochloride injection – 25 – 100 mg by subcutaneous or intramuscular injection and 25 to 50 mg by iv injection

Adverse reactions

Euphoria, dysphoria, weakness and palpitation

Depression o fetal respiration

Dry mouth, nausea and vomiting

Local irritation on parenteral administration

Respiratory depression, coma and convulsions

Addiction and tolerance

Uses

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It provides analgesia for any type of severe apin

For producing sedation and sleep

As pre-anesthetic medication

Methadone

it is a synthetic, orally effective opioid it has equal potency to morphine

it produce less euphoria and has a somewhat longer duration of action

It has somewhat longer duration of action than morphine

Mechanism of action

The actions of methadone are mediated by the u receptors

Pharmacological actions

It is chemically dis-similar but pharmacologically very similar to morphine

It has analgesic , respiratory depressant , emetic , anti-tussive , constipating and biliary actions similar to morphine

Pharmaco-kinetic actions

It is readily absorbed following oral administration

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It accumulates in tissues, where it remains bound to proteins, from which it is slowly released

The drug is biotransformed in the liver and excreted in the urine

Adverse effects

It can produce physical dependence like that of morphine

Uses

It has been used primarily as substitution therapy opioid dependence

It can also be used as an analgesic for the same conditions as morphine

It is occasionally employed as anti-tussive

Tramadol

It is a centrally acting analgesic that binds to the u – opioid receptor

It weakly inhibits re-uptake of nor-epinephrine and serotonin

It is used to manage moderate to moderately severe pain

Its respiratory-depressant activity is less than that of morphine

Its analgesic action is only partially reversed by opioid antagonist known as naloxone

Tramadol causes less respiratory depression, sedation, constipation, urinary retentionand rise in intrabiliary pressure than morphine

It is well tolerated

Pharmaco-kinetics

Oral bioavailability is good

The half life is 3-5 hrs and effects last 4-6 hrs

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Adverse effects

Dizziness

Nausea

Sleepiness

Dry mouth

Sweating

Drug interaction

Tramadol should also be avoided in patients taking mono amine oxidase inhibitors

Dose

50 mg cap, 100 mg SR tab

50 mg/ml inj in 1 and 2 ml amps

Opioid antagonists

Pure opioid antagonists

1. Naloxone2. Naltrexone3. Nalmefene

1. Naloxone

It is N- alyl-nor- oxy- morphone and a competitive antagonist on all types of opioid receptors

It blocks u receptors at much lower doses than those needed to block k or delta receptors

Naloxone is a competitive antagonist at u, k and delta receptors with a ten- fold higher affinity for u receptors than for k

Naloxone produces no pharmacologic effects in normal individuals , but it precipitates withdrawal symptoms in opioid abusers

Naloxone is used to reverse the coma and respiratory depression of opioid overdose

It rapidly displaces all receptor- bound opioid molecules and is able to reverse the effect of a heroin overdose

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Within 30 sec of iv injection of naloxone, the respiratory depression and come characteristic of high doses of heroin are reversed, causing the patient to be revived and alert

Naloxone has a half-life o f60 – 100 minutes

No physical or psychological dependence has been observed

Injected intravenously (0.4 – 0.8 mg ) , it promptly antagonizes all actions of morphine

It is inactive orally because of high first pass metabolism in liver

Injected iv , it acts in 2 – 3 min

The primary pathway of metabolism is glucuronidation

Plasma half life is 1 hour in adults and 3 hours in new borns

USES

Naloxine is the drug of choice for morphine poisoning ( 0.4 mg iv every 2 -3 min, maximum 10 mg)

It also partially reverses alcohol intoxication

2. Naltrexone

It is chemically related to naloxone and is anther pure opioid antagonist

It is more potent than naloxone

It has actions similar to those of naloxone

Naltrexone differs from naloxone in being orally active and having a long duration of action (1 – 2 days)

It has a longer duration of action than naloxone and a single oral dose of naltrexone blocks the effect of injected heroin for up to 48 hours

Alcohol craving is also reduced by naltrexone , it is being used to prevent relapse of heavy drinking

Naltrexone in combination with clonidine and sometimes with bruprenorphine is employed for rapid opioid detoxification

It may also be beneficial in treating chronic alcoholism by an unknown mechanism , but benzodiazepines and clonidine are preferred

Naltrexone is hepatotoxic

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Dose

50 mg tab

Side effects

Nausea

Headache

Higher doses can causes hepatotoxicity

3. Nalmefene

This is recently developed pure opioid antagonist lacks

No hepatotoxicity

It has higher oral bioavailability and long duration of action

CNS Stimulants

These are brain stimulants which markedly stimulate the respiration and circulation These in large doses acts as convulsants’The;y are useful in the following conditions

1. Chronic hypoventilation with CO2 retention2. Respiratory failure in newborns3. Respiratory failure due to overdose of CNS depressants4. Post anesthetic respiratory depression

1. Direct CNS stimulants

A. Cortical stimulants 1. Xanthene alkaloids Caffeine Theophylline Theo-bromine Aminophylline

2. Sympathomimetics

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Amphetamine Methyl phenidate

B. Medularly stimulants

PicrotoxinPentylene-tetrazolNikethamideDoxapram

C. Spinal stimulants

Strychnine

11. Reflex CNS Stimulants

LobelineNicotineVeratrineAmmonia

Xanthene alkaloids

Methyl xanthenes includes theophyline found in tea and Theo bromine found in cocoa

Caffeine , the most widely consumed stimulant in the world, is found in highest concentration in coffee, but is also present in tea, cola drinks , chocolate candy and cocoa

Mechanism of action

Several mechanisms have been proposed for the actions of methylxanthine

All Xanthene alkaloids inhibit phosphodiesterase and blockade of adenosine receptors

Due to above mechanism there is increase in translocation of extra cellular calcium

Increase in cyclic adenosine monophosphare

Increase in cyclic guanosine monophosphate

Which causes various pharmacological actions including increase in force of contraction of heart and relaxation of vascular and non vascular smooth muscles

Pharmacological actions

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On CNS

The caffeine contained in one to two cups of coffee (100 – 200mg) causes a decrease fatigue and increased mental alertness as a result of stimulating t he cortex and other areas of the brain

Consumption of 1.5 grams of caffeine ( 12 – 15 cups of coffee ) produces anxiety and tremors

The spinal cord is stimulated only by very high doses (2 -5 g) of caffeine

It also produces stimulation or respiratory , vasomotor and vagal centers

Tolerance can rapidly develop to the stimulating properties of caffeine

Withdrawal consists of feelings of fatigue and sedation

On CVS

A high dose of caffeine has positive inotropic and chronotropic effects on the heart

Increased contractivity can be harmful to patients with angina pectoris

Xanthenes produce a direct stimulant effect on the myocardium, also they produces dilatation of coronary and pulmonary blood vessels due to the stimulation of vagal nerve

On bronchioles

Caffeine and its derivatives relax the smooth muscles of the bronchioles Decrease in fatigue of smooth muscles

Diuretic action

Caffeine has a mild diuretic action that increases urinary output of sodium, chloride and potassium

GIT

Methylxanthines stimulates secretion of hydrochloric acid from the gastric mucosaIndividuals with peptic ulcers should avoid beverages containing methylxanthines

Pharmacokinetics

The methylxanthines are well absorbed orally

Caffeine distributes throughout the body , including the brain

The drugs cross the placenta to the fetus and are secreted into the mothers milk

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All the methylxanthines are metabolized in the liver and the metabolites are then excreted in the urine

Adverse effects

Moderate doses of caffeine cause insomnia , anxiety and agitation

High dosage is produced emesis and convulsions

The lethal dose is about 10 grams of caffeine about 100 cups of coffee which induce cardiac arrhythmias

Lethargy, irritability and headache occur in users who have routinely consumed more than 600 mg of caffeine per day roughly six cups of coffee per day and then suddenly stop

Therapeutic uses

Caffeine and its derivatives relax the smooth muscles of the bronchioles

Antidepressants

Coronary vasodilators

Diuretics

Nicotine

It is the active ingredient in tobacco

The drug is not currently used therapeutically except in smoking

It is mostly widely used CNS stimulant

Nicotine represents a serious risk factor for lung and cardiovascular disease and various cancers

Dependency on the drug is not easily overcome

Mechanism of action

In low doses, nicotine causes gang ionic stimulation by depolarization

At high doses, nicotine causes gang ionic blockade

Nicotine receptors exist in the CNS, where similar actions occurs

Pharmacological actions

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On CNS

Nicotine is highly soluble in lipid and readily crosses the blood-brain barrier

Cigarette smoking or administration of doses of nicotine produces some degree of euphoria and arousal as well as relaxation

It improves attention, learning , problem solving and reaction time

High doses of nicotine result in central respiratory paralysis and severe hypotension caused by modularly paralysis

Peripheral effects

The peripheral effects of nicotine are complex

Stimulation of sympathetic ganglia as well as the adrenal medulla increases blood pressure and heart rate

The use of tobacco is particularly harmful in hypertensive patients

Stimulation of parasympathetic ganglia also increases motor activity of the bowel

At higher doses , blood pressure falls and activity ceases in both the GIT and bladder musculature

Pharmacokinetics

Nicotine is highly lipid-soluble

Absorption readily occurs via the oral mucosa, lungs, gastrointestinal mucosa and skin

Nicotine crosses the placental membrane and is secreted in the milk if lactating women

Most cigarettes contain 6-8 mg of nicotine

The acute lethal dose is 60 mg

More than 90% of nicotine inhaled in smoke is absorbed

Clearance if nicotine involves metabolism in the lung and the liver and urinary excretion

Tolerance to the toxic effects of nicotine develops rapidly

Adverse effects

The CNS effects of nicotine include irritability and tremors

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Nicotine may also cause intestinal cramps, diarrhea and increased heart rate and blood pressure

Cigarette smoking increases the rate of metabolism for a number of drugs

Withdrawal syndrome

Nicotine is an addictive substance and physical dependence on nicotine develops rapidly and is severe

Withdrawal is characterized by irritability, anxiety, restlessness, difficulty concentrating , headaches and insomnia

Appetite is affected and gastrointestinal pain often occurs

Cocaine

Cocaine is an inexpensive , widely available and highly addictive drug that is currently abused daily by more than three million people in the USA

It is an alkaloid obtained from the leaves of coca plant

It is insoluble in water but its salts are soluble in water

It is poorly absorbed in the intestines but well absorbed by the mucous membrane and it can be given as surface anesthetic

Mechanism of action

The primary mechanism of action of cocaine is blockade of re-uptake of the monoamines ( nor epinephrine, serotonin and dopamine) into t he presymaptic terminals from which these neurotransmitters are released

Pharmacological actions

On CNSCNS stimulant

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Cocaine acutely increases mental awareness and produces a feeling of well being and euphoria similar to that caused by amphetamine

Cocaine can produces hallucinations and delusions

Cocaine increases motor activity and at high doses m it causes tremors and convulsions, followed by respiratory and vasomotor depression

Sympathetic nervous system

Peripherally, cocaine potentates the action of nor-adrenaline and produces the fight or flight syndrome characteristic of adrenergic stimulation

This is associated with tachycardia, hypertension, papillary dilation and peripheral vasoconstriction

Local anesthetic action

Dilates pupil

Raise the body temperature

Rise the BP

Produces euphoria

Pharmacokinetics

Cocaine is often self-administered by chewing intra-nasal snorting, smoking or intravenous injection

The peak effect occurs at fifteen to twenty minutes after intra-nasal intake of cocaine powder

Rapid but short-lived effects are achieved following iv injection of cocaine

Toxic effects

Mental excitement

Confusion

Tremors

Convulsions

Respiratory paralysis

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Stimulation followed by depression

Cocaine can induce seizures as well as fatal cardiac arrhythmias

IV administration of diazepam and propranolol may be required to control cocaine – induced seizures and cardiac arrhythmias

Dose

8 – 16 mg by injection

Adrenaline has to be given along with cocaine which produces local vasoconstriction and prolong the local anesthetic effect

Uses

Cocaine has a local anesthetic action

Cocaine is applied topically as a local anesthetic during eye, ear ,nose and throat surgery

The anesthetic action of cocaine is due to a block of voltage – activated sodium channels

An interaction with potassium channels may contribute to the ability of cocaine to cause cardiac arrhythmias

Drug Abuse

The use of drugs for non-therapeutic purposes and mainly the drugs acting on CNS is termed as misuse or drug abuse.

They may be misused for the production of dangerous and thrilling effects for escaping from physical discomforts like hunger, fatigue, pain or mental discomforts like boredom ,frustration and anxiety.

Generally the drugs which are abused are – ethanol, diazepam, morphine, heroin, pethidine, methadone, methaqualon, LSD-25 , cannabis and mescaline.

Control of drug dependence and abuse

First it should be identified whether the dependence on a particular drug is addiction or abuse or socially acceptable.

The methods of controlling drug abuse are

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Limitation of availability of specified drugs for the addicted persons. Reduction of interest in and demand for such drugs for non-medical use.

Public must be given drug education on the harmful physical and mental effects of drug dependence and abuse

Legal prohibition of possession and transportation in these drugs which may be abused for non-medical purposes

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