Pharmacology of the Autonomic nervous system

الرحيم الرحمن الله الرحيم بسم الرحمن الله بسمPharmacology of Autonomic Pharmacology of Autonomic

Nervous SystemNervous System

Mohaned M. ElzobairB. PharmM. Pharm, Pharmacology

Pharmacology of Autonomic Pharmacology of Autonomic nervous systemnervous system

• Nervous system:

Autonomic nervous systemAutonomic nervous system

• Autonomic effectors tissues include cardiac muscles, smooth muscles and glands.

• Axon that form synapse with ganglionic cell is called pregaglionic autonomic fiber.

• Axon that innervate the effector cell is called postganglionic autonomic fiber.



• Sympathetic and parasympathetic divisions typically function in opposition to each other. But this opposition is better termed complementary in nature rather than antagonistic.


• The sympathetic division typically functions in actions requiring quick responses.

• The parasympathetic division functions with actions that do not require immediate reaction.

• Consider sympathetic as "fight or flight" and parasympathetic as "rest and digest".

Activity of the Sympathetic Activity of the Sympathetic Nervous SystemNervous System• Prepares body for physical action (Fight or

Flight):– Increased heart rate– Increased blood pressure– Redistribution of blood flow - ↑ flow to skeletal

muscle, ↓ flow to skin and organs– ↓ GI activity– Dilation of pupils and bronchioles– ↑ blood glucose.

Activity of the Parasympathetic Activity of the Parasympathetic Nervous SystemNervous System• Opposite effects to SNS• Prepares the body for feeding and digestion

– Slows heart rate– Lowers blood pressure– Promotes GI secretions– Stimulates GI movement– Constricts the pupil– Empties bladder and rectum


• Acetylcholine is the preganglionic neurotransmitter for both divisions of the ANS, as well as the postganglionic neurotransmitter of parasympathetic neurons.

• In the parasympathetic system, postganglionic neurons use acetylcholine as a neurotransmitter, to stimulate muscarinic receptors.


• At the effector organs, sympathetic ganglionic neurons release noradrenaline (norepinephrine), along with other cotransmittors such as ATP, to act on adrenergic receptors, with the exception of the sweat glands and the adrenal medulla.


• At the adrenal cortex, there is no postsynaptic neuron. Instead the presynaptic neuron releases acetylcholine to act on nicotinic receptors.

• Stimulation of the adrenal medulla releases adrenaline (epinephrine) into the bloodstream which will act on adrenoceptors, producing a widespread increase in sympathetic activity.



• The parasympathetic fibers originate from the cranial and sacral regions (craniosacral), while the sympathetic fibers are (thoracolumbar fibers).

Autonomic fibersAutonomic fibers

Cholinergic transmissionCholinergic transmission

• Synthesis of acetylcholine

• ACh synthesized from Choline and acetyl Co A by reaction catalyzed by Choline Acetyl transferase (CAT)

• CAT is synthesized in the ribosome of cell body, transported by axoplasmic flow to the axon terminal

Synthesis of acetylcholine Synthesis of acetylcholine

• Acetyl CoA is formed in the mitochondria converted to citrate, diffuses and then reconverted to acetyl CoA.

• Choline is synthesized in the liver and obtained from diet actively cotransported with Na+ because it cannot diffuse through the cell membrane

Synthesis of acetylcholineSynthesis of acetylcholine

Drugs that impair acetyl Drugs that impair acetyl Choline synthesis:-Choline synthesis:-

1. Direct inhibitors of CAT e.g. BromoacetylCoA, chloroacetylCoA and transnaphthylvinylpyrinide (more specific)

2. Inhibitors of choline transport e.g. hemicholinium compete for choline carrier, causes gradual failure of transmission at cholinergic sites, enhanced by nerve stimulation .

Storage of acetylcholine Storage of acetylcholine

• ACh is stored in vesicles which contains also ATP and protein, Ach accumulated inside the vesicles by (Ach – transporter) which is inhibited by vesamicol.

Release of AChRelease of ACh

• Depolarization of nerve axon by nerve impulse triggers Ca++ influx, vesicles come in contact with the site of release fuse with membrane and ACh is released by exocytosis.

Drugs affecting ACh releaseDrugs affecting ACh release

1. Botulinum toxin from Clostridium botulinum: it cause prevention of transmission at all peripheral cholinergic junctions and agglutination of RBC (lethal effect paralysis of respiratory muscles)

2. Morphine.3. catecholamines 4. β bungarotoxins (snake poisons).

Hydrolysis of the ACHHydrolysis of the ACH

• Ach hydrolyzed by cholinesterase’s which are of two types:-

1.True or specific cholinesterase occur in nervous tissues, striated muscles, and RBCs specific substrate is acetyl β methyl choline.

2. Pseudo cholinesterase in plasma, intestine and skin specific substrate is succinylcholine and benzoylcholine.

- They both act on acetylcholine.

ACh receptorsACh receptors

• They are muscarinic and nicotinic receptors. • Muscarinic receptors: are classified into 5

subtypes:• M1 (Neuronal) • occur in CNS , Peripheral neurons and gastric

parietal cells.• Function: (excitatory) CNS excitation, gastric acid

secretion and GIT motility.

ACh receptorsACh receptorsM1 (Neuronal)• Effects: Activate phospholipase C (PLC), which converts

phosphatidylinositol 4,5 – bisphosphate (PIP2) to IP3 & DAG) increase IP3 and DAG ↑ Ca2+ conductance depolarization.

decrease K+ conductance increase intracellular K+ depolarization.

• Selective antagonist: pirenzepine.


• M2 (cardiac)• Occur in heart, presynaptic terminals of peripheral

and central nerves • Functions: (inhibitory; cardiac inhibition and

presynaptic inhibition) Inhibit Adenylate cyclase (Adenylyl cyclase) ↓

cAMP ↓ Ca+ conductance ↓ depolarization.Increase k+ conductance ↓ depolarization. • Selective antagonist: gallamine.


• M3 (Glandular & smooth muscles)• Function: excitatory mainly, glandular, sweat,

salivary and bronchial secretion, contraction of viscera smooth muscles.

• Selective antagonist: Darifenacin and hexahydrosiladifenol (HHSD)


• Muscarinic receptors are G-protein coupled receptors

• M1, M3, M5, stimulate PLC increase IP3 (inositol triphosphate).

• M2, M4 inhibit Adenylate cyclase decease cAMP.


Nicotinic receptors: include • Nm (muscle) occur at neuromuscular junction

(NMJ).• Nn (neuronal) at autonomic ganglia and brain.• They are both ion channel linked receptors

(ion channel linked receptors).

ACh receptors (Nicotinic ACh receptors (Nicotinic receptors)receptors)

Nm Nn

agonist SuxamethoniumDecamethonium

NicotineLobeline Epibatidine

antagonists Tubocurarine Pancuronium,α bungarotoxins

Trimetaphan Mecamylamine Hexamethonium

Acetylcholine receptor Acetylcholine receptor stimulantsstimulants

1. Directly acting agent: produce primary effect by activation of muscarinic or nicotinic receptors

2. Indirectly acting agents: inhibit acetyl cholinesterase increase level of endogenous Ach.

Directly acting cholinoceptor Directly acting cholinoceptor stimulantsstimulants

* Quaternary group induce: acetylcholine, methacholine, carbachol, and bethanechol.

* Tertiary cholinomimetics: includes pilocarpine, nicotine and lobeline.

• Acetylcholine is not useful therapeutically because of its multiplicity of actions and its rapid inactivation by the cholinesterases (unstable).

Directly acting cholinoceptor Directly acting cholinoceptor stimulantsstimulants• Methacholine is three times more resistant

to hydrolysis. • Carbamic acid derivatives (carbachol and

bethanechol) are completely resistant to hydrolysis by cholinesterases.

Pharmacodynamic effects of muscarinic stimulants

1. Eye • The parasympathetic innervates the constrictor

pupillae muscle of the iris which is important for adjusting the pupil in response to change in light intensity, and also important in regulating the intraocular pressure.

Pharmacodynamic effect of Pharmacodynamic effect of muscarinic stimulantsmuscarinic stimulants• Eye

Pharmacodynamic effect of Pharmacodynamic effect of muscarinic stimulantsmuscarinic stimulants

• Ciliary muscle adjusts the position of the ciliary body in the anterior chamber, contraction of ciliary muscle pulls the ciliary body forward and inward, relaxing the tension on the suspensory ligaments of the lens, the lens bulge more decrease focal length this parasympathetic relaxation is essential for accommodation for near vision.

Pharmacodynamic effect of Pharmacodynamic effect of muscarinic stimulantsmuscarinic stimulants• Aqueous humour secreted by cells of

epithelium covering the ciliary body, it removed continuously by drainage into the canal of schlemm.

• Normal intraocular pressure is 10-15 mm Hg increase in intraocular pressure (glaucoma) can cause retinal detachment blindness.

Pharmacodynamic effect of Pharmacodynamic effect of muscarinic stimulantsmuscarinic stimulants• Sometimes the drainage of aqueous humour

is impeded when the iris is dilated due to folding of the iris tissue, which blocks the drainage angle increase intraocular pressure, activations of constrictor pupillae muscle by cholinomimetic drugs, decrease the IOP, also increasing of the tension in the ciliary body allows drainage.

Pharmacodynamic effect of Pharmacodynamic effect of muscarinic stimulantsmuscarinic stimulants2. Cardiovascular effects:• Cholinomimetic drugs cause cardiac

slowing, decrease cardiac output and decrease force of contraction of the atrium, ventricle has sparse parasympathetic innervations.

• Decrease in BP by parasympathetic is opposed by reflex sympathetic discharge.

Pharmacodynamic effect of Pharmacodynamic effect of muscarinic stimulantsmuscarinic stimulants

3. Respiratory system• Muscarinic stimulants contract smooth muscles of

the bronchial tree, increase glandular secretion, may cause symptoms in individuals with asthma.

4. GIT• Increase secretion of the gastric gland, increase

motor activity and peristaltic movement, sphincters relaxed.

Pharmacodynamic effect of Pharmacodynamic effect of muscarinic stimulantsmuscarinic stimulants5. Genitourinary Tract• Stimulates muscles of bladder and relax

sphincters, promoting urine voiding. • Human uterus is not sensitive to muscarinic

agonists 6. Secretory glands• Stimulates secretion of sweat, lacrimal, and

nasopharyngeal glands.

Pharmacodynamic effect of Pharmacodynamic effect of muscarinic stimulantsmuscarinic stimulants7. CNS• Both muscarinic and nicotinic receptors are

found. Nicotine and lobeline have alerting action. High levels of nicotine causes convulsion and coma.

Clinical uses directly acting Clinical uses directly acting cholinomimetic drugscholinomimetic drugs

1. Glaucoma (e.g. pilocarpine) they reduce the IOP by facilitating the out flow of aqueous humour and decrease its rate of secretion.

2. Postoperative ileus atony and postoperative urinary retention .e.g. bethanechol.

Clinical uses directly acting Clinical uses directly acting cholinomimetic drugscholinomimetic drugs3. Pilocarpine is administered orally in 5- to

10-mg doses given three times daily for the treatment of xerostomia (abnormal dryness of the mouth due to insufficient secretions) that follows head and neck radiation treatments or that is associated with Sjogren's syndrome.

Cholinergic AntagonistsCholinergic Antagonists

• The cholinergic antagonists (also called cholinergic blockers, parasympatholytics or anticholinergic drugs) bind to cholinoceptors. Include

• Antimuscarinic Agents: block muscarinic synapses of the parasympathetic nerves.

• The ganglionic blockers, which block the nicotinic receptors of the sympathetic and parasympathetic ganglia.

• The skeletal neuromuscular blocking agents

Muscarinic AntagonistsMuscarinic Antagonists

• Antimuscarinic drugs have little or no action at skeletal neuromuscular junctions or autonomic ganglia.

• They include atropine, hyoscine (Scopolamine) (naturally occurring), homatropoine, (synthesized from atropine), tropicamide, cyclopentolate, ipratropium, propentheline, darifenacin (selective M3 antagonist) and pirenzepine (selective M1 antagonist).


Pharmacokinetics • They well absorbed, atropine widely distributed

through out the body, it disappear rapidly from blood, 80% excreted in urine, affect on parasympathetic system decline rapidly except in the eye persists for 48-72 hr.


• Pharmacodynamic effect:1. Inhibition of secretions (salivary, lacrimal,

bronchial, and sweat gland), by low doses of atropine (sensitive).

2. Heart: tachycardia due to block of cardiac muscarinic receptors very low doses of atropine can cause bradycardia due to central action increasing vagal activity.


3. Eye: mydriasis, cycloplegia (paralysis (relaxation) of the ciliary muscles), impair accommodation for near vision, and increase IOP.

4. GIT: decrease GIT motility (Hyoscine use as antispasmodic), pirenzepine (M1 selective antagonist) inhibit gastric acid secretion.


5. Bronchial smooth muscles relaxation (ipratropium).

6. CNS: low doses of atropine produce excitatory effect on CNS causing mild restlessness, high dose of atropine produce agitation and disorientation (atropine poising)


• Hyoscine in low dose has different central action causing marked sedation in low dose and similar effect to atropine in high doses.

• Hyoscine has useful antiemetic activity so it use in treatment of motion sickness.

Clinical uses of muscarinic Clinical uses of muscarinic antagonistsantagonists

1. Treatment of bradycardia (after MI) e.g. atropine.

2. To dilate the pupil (tropicamide, cyclopentolate eye drop)

3. Prevention of motion sickness (Hyoscine). 4. Parkinsonism (benzhexol, benzatropine). 5. Asthma (ipratropium inhaler).

Clinical uses of muscarinic Clinical uses of muscarinic antagonistsantagonists

6. Anaesthetic pre-medication to dry secretion (atropine)7. Antispasmodic (Hyoscine)8. To facilitate GIT endoscope and GI radiology

(hyoscine)9. Irritable bowels syndrome (e.g. clinidium)10. Peptic ulcer (pirenzepine)11. Treatment of overactive bladder (darifenacin

(selective M3 antagonist) decreases the urgency to urinate).

Anticholinergic side effectsAnticholinergic side effects

1. dry mouth.2. blurred vision, (mydriasis).3. urinary retention.4. Constipation.5. Tachycardia.6. Dizziness.7. Confusion.8. nausea.

Contraindications of Contraindications of anticholinergic drugsanticholinergic drugs

• Glaucoma. • Elderly people with prostatic hypertrophy.

Indirectly acting cholinoceptors Indirectly acting cholinoceptors stimulants (anticholinesterases) stimulants (anticholinesterases)

• Pharmacological actions:• Mainly due to enhancement of cholinergic

transmission at autonomic synapse and NMJ include:-

• Bradycardia, hypotension, excessive secretion, bronchoconstriction, GI hyper motility, decrease IOP and depolarization block.

Indirectly acting cholinoceptors Indirectly acting cholinoceptors stimulants (anticholinesterases)stimulants (anticholinesterases)

• They include:-1. Short acting anticholinesterase e.g. edrophonium

(simple alcohol) bearing quaternary ammonium group) use in diagnosis of myasthenia gravis.

2. Medium duration anticholinesterase e.g. neostigmine (quaternary) physostigmine (tertiary) pyridostigmine, demecarium and ambenonium.

AnticholinesterasesAnticholinesterases

• Tacrine, donepezil, rivastigmine, and galantamine are useful in patients with Alzheimer's disease (they have a deficiency of cholinergic neurons in the CNS).

• Gastrointestinal distress is their primary adverse effect.

Indirectly acting cholinoceptors Indirectly acting cholinoceptors stimulants (anticholinesterase)stimulants (anticholinesterase)

3. Irreversible anticholinesterase:• Some synthetic organophosphate compounds have the

capacity to bind covalently to acetylcholinesterase. The result is a long-lasting increase in acetylcholine at all sites where it is released.

• They include dyflos (diisopropyl fluorophosphate), parathion, sarin, soman, tabun, cyclosarin (chemical weapon) and ecothiopate.

Irreversible anticholinesteraseIrreversible anticholinesterase• Recovery of the enzymatic activity depend on the

synthesis of new enzyme molecules which may take weeks.

• Many of these drugs are extremely toxic and were developed by the military as nerve gases (sarin, soman, tabun).

• Related compounds, such as parathion, are employed as insecticides.

• Toxic effects could be treated with immediate administration of pralidoxime and atropine

Cholinesterase reactivatorCholinesterase reactivator

• Pralidoxine (cholinesterase reactivator) use for reactivate the enzyme (cholinesterase) from phosphorylation. It should be taken early in order to work; because the phosphorylated enzyme with few hours undergoes a change (aging) renders it no longer susceptible to reactivation.

Clinical uses of anticholinesteraseClinical uses of anticholinesterase

1. In anaesthesia to reverse the action of non- depolarizing blocker e.g. neostigmine.

2. In treatment of myasthenia gravis (pyridostigmine and neostigmine) excessive use cause cholinergic crisis.

3. In treatment of glaucoma e.g. ecothiopate eye drops.

4. Alzheimer's disease (Tacrine, donepezil, rivastigmine, and galantamine).

Myasthenia GravisMyasthenia Gravis

• It is autoimmune disease which causes a loss of nicotinic acetylcholine receptor from the NMJ resulting in muscle weakness and increase fatigability (in ability of the muscle to produce sustained contraction).

• Myasthenic patients characterize by dropping eyelids.



• Treatment by:1.Anticholinesterase, neostigmine and

physostigmine. 2.Immunosuppressant e.g. prednisolone.3.Thymecotomy (thymus gland synthesize T

lymphocytes which attack foreign substances)


• If the disease progress too far, the number of receptors remaining become too few to produce and adequate end plate potential and anticholinesterase drugs will then cease to be effective.

Cholinergic crisisCholinergic crisis

• It is a condition result from large doses (excessive doses) of anticholinesterase characterize by various muscarinic effects salivation, GI cramps, lacrimation, poor vision etc. with muscle weakness resulting from depolarization blocks.

Cholinergic crisisCholinergic crisis

• Edrophonium use to distinguish between this drug induced weakness and weakness of the myasthenia gravis, when giving edrophonium (short acting anticholinesterase), if the weakness is transiently improves it is due to myasthenia and more anticholinesterase is indicated.

• If it gets worse the weakness is due to cholinergic crisis and the anticholinesterase dose should be reduced.

Drugs affecting autonomic Drugs affecting autonomic gangliaganglia

• Ganglion stimulating drugs:• Include nicotine ,lobeline, epibatidine and

dimethyldiphenylpiperazinium, they stimulate both sympathetic and parasympathetic ganglia so its effects are complex including tachycardia , increase BP ,variable effects on GIT secretion and motility, increased bronchial , salivary and sweat secretions .It may followed by depolarization block .

• They have no therapeutic uses.

NicotineNicotine

• Nicotine initially stimulates, then blocks all sympathetic and parasympathetic ganglia

• It is a component of cigarette smoke and a poison with many undesirable actions.

• Nicotine is available as patches, lozenges, gums, and other forms, it is effective in reducing the craving for nicotine in people who wish to stop smoking.

Ganglionic BlockersGanglionic Blockers

• Ganglionic blockers act on the nicotinic receptors (Nn) of both parasympathetic and sympathetic autonomic ganglia.

• These drugs are not effective as neuromuscular blockers

Ganglion – blocking drugs: Ganglion – blocking drugs:

• Ganglion blocks can occur by several mechanisms:

1.By interference with acetylcholine synthesis and release e.g. Botulinum toxins and hemicholinium.

2.By prolonged depolarization e.g. nicotine.

Ganglion – blocking drugs:Ganglion – blocking drugs:

3. By interfering with the post synaptic Ach action e.g. hexamethonium, trimetaphan, mecamylamine and pempidine (non-depolarizing blockers).

• Trimetaphan, and mecamylamine competitive block receptors, while hexamethonium and pempidine block ion channel associated with it.


Pharmacodynamic effects (organ system effect):-

• They cause eye cycloplegia, loss of accommodation, mydriasis.

• Hypotension, loss of cardiovascular reflexes. • Inhibitions of secretions GI paralysis. • Impairment of micturition.


• They clinically absolute except trimetaphan use to lower BP in emergency (anesthesia) also in acute pulmonary edema to decrease pulmonary vascular pressure.

• Tubocurarine bocks ganglion as well as neuromuscular junction, on ganglion its action on ion channels where as at NMJ it bind mainly to receptors.

Neuromuscular blocking drugsNeuromuscular blocking drugs

• They fall into two categories:-• Non-depolarizing blocking agents

(competitive):-• E.g. tubocurarine, pancuronium, vecuronium

and gallamine. • They act as competitive antagonists at

acetylcholine nicotinic receptors (Nm) at the NMJ.

Non-depolarizing blocking Non-depolarizing blocking agents (competitive):-agents (competitive):-

• Tubocurarine (quaternary ammonium cpd) doesn’t enter placenta and cannot be absorbed when taken orally (safety in hunting animals).

• Their effects are mainly due to motor paralysis, the first muscle to be affected are extrinsic eye muscles causing double vision then, the small muscle of the face, limbs and pharynx (causing difficult in swallowing). Respiratory muscles are the last to be affected and the first to recover is the diaphragm.

Side effects of curare:-Side effects of curare:-

I. Fall in arterial pressure due to ganglion block (vasodilatation).

II. Release of histamine from mast cells which can lead to bronchospasm in sensitive individuals.

III. Gallamine and pancuronium block the muscarinic receptor particularly in the heart leading to tachycardia.

Clinical uses:-Clinical uses:-

1. Skeletal muscle paralysis for all surgical requirements.

2. To control ventilation in patient with ventilatory failure from various causes, to control ventilation to provide adequate volumes and expansion of lung.

3. Treatment of convulsions due to status epilepticus.

Depolarizing blocking agents:-Depolarizing blocking agents:-

• E.g. Suxamethonium (succinylcholine) & decamethonium

• They work by depolarizing plasma membrane of the muscle fiber similar to Ach, (they resistant to cholinesterases).

• ACh + receptor propagation of action potential (AP), AP contraction of skeletal muscles cell, (depolarization), this is followed by rapid cleavage of Ach by cholinesterase.


• Suxamethonium + receptor AP contraction, (Suxamethonium not degraded by cholinesterase) Persistent depolarization of end plate New AP and contraction cannot be elicited (depolarizing block).


• There are two phases of depolarizing block:-• Phase1. (Depolarizing phase) it cause

muscular fasciculation (twitches) followed by:

• Phase2. (Desensitizing phase) in which the muscle will not response to the ACh release.

Side effects of Side effects of Suxamethonium:-Suxamethonium:-

1. Bradycardia; due to direct muscarinic action, prevented by atropine.

2. K+ release hyperkalaemia which may cause cardiac arrhythmias and cardiac arrest.

3. Increase IOP contraction of extra ocular muscles causes the eye to be squeezed from the outside (contraindicated in glaucoma).

Side effects of Side effects of Suxamethonium:-Suxamethonium:-4. Malignant hyperthermia: rare and inherited,

treated by dantrolene.5. Prolonged paralysis.

Comparison between non depolarizing Comparison between non depolarizing and depolarizing blocking agents:and depolarizing blocking agents:

1. The action of non-depolarizing blockers can be reversed by anticholinesterases (competitive) while the action of depolarizing agents will not be affected.

2. In chicks extensor spasm occurs with depolarizing blockers, while flaccid paralysis occurs with non-depolarizing blockers.

Comparison between non depolarizing Comparison between non depolarizing and depolarizing blocking agents:and depolarizing blocking agents:

3. Fasciculation occurs only with depolarizing blockers.

4. Tetanic fade (failure of muscles to maintain a fused tetany at sufficiently-high frequencies of electrical stimulation) occurs in case of non-depolarizing blockers.

Adrenergic transmissionAdrenergic transmission

• Adrenergic neurons are found in the sympathetic nervous system (postganglionic sympathetic neurons) and in the central nervous system (CNS).

• The process involves five steps: synthesis, storage, release, and receptor binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic cleft.

Biosynthesis of catecholamines:Biosynthesis of catecholamines:

Metabolic precursor is L-tyrosine which taken up to the nerve terminals by specific transport system.

Biosynthesis of catecholamines:Biosynthesis of catecholamines:• Tyrosine is transported into the axoplasm of the

adrenergic neuron, where it is hydroxylated to DOPA by tyrosine hydroxylase.

• This is the rate-limiting step in the formation of norepinephrine.

• DOPA is then decarboxylated by dopa decarboxylase to form dopamine.

Synthesis (cont.)Synthesis (cont.)

• Dopamine is hydroxylated to form norepinephrine by the enzyme, dopamine β-hydroxylase.

• In the adrenal medulla, norepinephrine is methylated to yield epinephrine (adrenaline).

Drugs that affect the biosynthesis Drugs that affect the biosynthesis of catecholamines:-of catecholamines:-

1\ ά methyl tyrosine: • It inhibits tyrosine hydroxylase use in

treatment of phaeochromocytoma. 2\ Carbidopa and Benserazide: • They inhibit peripheral dopa decarboxylase

use in treatment of parkinsonism.

Drugs that affect the biosynthesis Drugs that affect the biosynthesis of catecholamines:of catecholamines:3\ Methyldopa: which taken by the neuron

decarboxylated, then hydroxylated to form ά-methyl NA (false neurotransmitter) (is not eliminated by MAO), displace NA in the vesicles and released as a false neurotransmitter.

.

Drugs that affect the Drugs that affect the biosynthesis of catecholamines:biosynthesis of catecholamines:

4\ 6- Hydroxydopamine (oxidopamine) and MPTP (methyl phenyl tetrahydropyridine):

• They are neurotoxins that taken up selectively by adrenergic neuron terminals, where they converted to reactive quinone that destroy the nerve terminal (chemical sympathoectomy). (Cell bodies survive sympathetic innervations recover)

• They use in research to induce parkinsonism in laboratory animals.

NA storage:NA storage:

• Stores in vesicles with ATP and proteins (chromogranin A), by special active carrier, Reserpine (the first drug in history use to treat hypertension), interfere with carrier causes depletion.

NA release:-NA release:-

• Depolarization, Ca++ entry, promote fusion of vesicles and discharge of NA by exocytosis.

• Regulation NA release:-• NA by acting on presynaptic receptor, can regulate

its own release (Auto-inhibitory feed back mechanism) through activation of α2 receptors decrease adenylate cyclase decrease Ca++ decrease exocytosis.

Effect of Guanethidine on NA Effect of Guanethidine on NA release:-release:-

• Guanethidine inhibits release of NA from sympathetic nerve terminals it has little effect on the adrenal medulla, and non on nerve terminals that release transmitters, other than NA, it selectively accumulated (Uptake 1) by adrenergic nerve terminals causing impairment of impulse conduction in the nerve terminals.

• It used as antihypertensive, but now due to its severe side effects which associated with loss of sympathetic reflexes it not use clinically

Up take and degradation of Up take and degradation of catecholamines:catecholamines:

• Two active transport system are occur uptake1 (Neuronal) and uptake 2 (extra neuronal) they differ in location, substrate (tyrosine – histamine) and inhibitors (cocaine –steroids hormone).

• Uptake 1 act as a co transporter of Na+ Cl-, and NA use electro chemical gradient for Na+ as a driving force.

Up take and degradation of Up take and degradation of catecholamines:catecholamines:• Uptake 1 is inhibited by TCA, cocaine,

amphetamine, phenoxybenzamine and guanethidine.

• Uptake 2 is important in clearing circulating adrenaline from blood stream, it inhibited by phenoxybenzamine, and corticosteroids.

Metabolism of catecholamines: Metabolism of catecholamines:

• Endogenous catecholamine are metabolized by MAO & COMT

• Monoaminoxidase bound to mitochondria presence in the liver, intestinal epithelium converts catecholamine to aldehyde.

Metabolism of catecholamines:Metabolism of catecholamines:

• Catechol -o- methyl transferase is wide spread enzyme occur in both neuronal and non neuronal tissues, it add methyl group to one hydroxyl group of the catechol.

• Vanillyl mandelic acid (VMA) is the final metabolite of adrenaline and noradrenaline.

• In case of phaeochromocytoma (tumor of adrenal medulla) VMA excretion in urine is increased.

VMA

The main pathways of The main pathways of noradrenaline metabolismnoradrenaline metabolism

Adrenergic receptors Adrenergic receptors (adrenoceptors)(adrenoceptors)

• Adrenoceptors are designated α and β.– The α 1 receptors are further divided into α 1A, α

1B, and α 1D

– α 2 receptors are further divided into α 2A, α 2B, α

2C, and α 2D (in animals).

Adrenoceptors:-Adrenoceptors:-

ά1:-• Found on the postsynaptic membrane of the effector

organs in blood vessels (constrict), bronchioles (constrict), GIT (relax), GI sphincters (contract), uterus (contract), seminal tract (contracts), iris (mydriasis) (by contraction of the iris radial (dilator) muscles), liver (glycogenolysis).

• Second messengers and effects: act by activation phopholipase C increase IP3 and DAG increase Ca++ .


ά1:-• agonist potency order A= Na > ISO• Selective agonist: phenylephrine and

oxymetazoline. • Selective antagonist: prazosin, doxazosin.• Non selective ά antagonist:

phenoxybenzamine and phentolamine.


• α2 Receptors: are located primarily on presynaptic nerve endings.• The stimulation of α2 receptor causes

inhibition of further release of norepinephrine.• α2 Receptors are also found on presynaptic

parasympathetic neurons. Norepinephrine can diffuse and interact with these receptors, inhibiting acetylcholine release.


ά2:-• Also occurs postsynaptically in blood

vessels (arteries) constrict, GIT ( relax ), pancreatic islets (inhibit insulin release), platelet (aggregation), male genitalia

• Second messenger and effects: decrease cAMP, decrease Ca++, and increase K+


ά2:-• Agonist potency order: A= Na> ISO.• Selective agonist: clonidine.• Selective antagonist: yohimbine. • Non selective ά antagonist:

phenoxybenzamine and phentolamine.

Adrenoceptors:-Adrenoceptors:-β1:-• occur in heart (increase heart rate and the force of

contraction), adrenergic nerve terminal (increase release), salivary gland (increase amylase secretion)

• Second messenger and effects: increase cAMP.• Agonist potency order: ISO> A=NA


β1:-• Selective agonist: Dobutamine, xamoterol.• Selective antagonist: atenolol, metoprolol. • Non selective antagonist: propranolol,

timolol.


β2:-• occur in blood vessels (dilate), bronchi

(dilate), GIT (relax), uterus (relax), bladder sphincter (relax), ciliary muscle (relax), mast cell (inhibition of histamine release)

• Second messenger: increase cAMP.


β2:-• Agonist potency order: ISO > A> NA• Selective agonist: sabutamol, salmeterol,

terbutaline.• Selective antagonist: butoxamine.

Adrenoceptors:-Adrenoceptors:- β3 • occurs in skeletal muscles (thermogenesis), liver

(lipolysis), bladder (relax), GIT (relax). • Second messenger: increase cAMP. • Agonist potency order: ISO= NA>A• Selective agonist: BRL37344 develop for control of

obesity. Solabegron develop for treatment of overactive bladder and IBS.

• SR59230A is β3 antagonist, it also block ά1 receptor.

Adrenergic agonistsAdrenergic agonists

• Classification of the adrenergic agonists• Direct-acting agonists: Include: epinephrine,

norepinephrine, isoproterenol, and phenylephrine.

• Indirect-acting agonists: Include amphetamine, cocaine and tyramine.

• Mixed-action agonists: Include ephedrine, pseudoephedrine and metaraminol, may act directly and indirectly.

CatecholaminesCatecholamines

• They are sympathomimetic amines that contain the 3,4-dihydroxybenzene group (such as epinephrine, norepinephrine, isoproterenol, and dopamine) are called catecholamines.

• These compounds share the following properties:• High potency• Rapid inactivation: by COMT and by MAO . • Poor penetration into the CNS because they are

polar

Specific sympathomimetic drugs:Specific sympathomimetic drugs:Catecholamines Catecholamines

• Adrenaline: • Has +ve inotropic and chronotropic action

(β1) increase systolic pressure, potent vasopressive, α → vasoconstrictor.

• In Β2 → vasodilatation in certain blood vessels, fall in total PVR explains decrease in diastolic pressure.

Noradrenaline: Noradrenaline:

• Has similar effects to adrenaline on β1

receptors, less potent at α receptors, little effect on β2 receptors → increase PVR → increase systolic and diastolic pressure.

• Compensating vagal activation overcomes chronotropic effect, inotropic effect is maintained.

Isoprenaline (isoproterenol):Isoprenaline (isoproterenol):

• Potent β – receptor agonist, little effect on α receptors has +ve inotropic and chronotropic action

• Potent vasodilator increase cardiac output, decrease diastolic pressure. Lesser increase in systolic pressure.

Schematic representation of the cardiovascular Schematic representation of the cardiovascular effects of intravenous infusions of adrenaline, effects of intravenous infusions of adrenaline, noradrenaline and isoproterenol (isoprenaline) in noradrenaline and isoproterenol (isoprenaline) in humanshumans

Dopamine: Dopamine:

• Low dose actives dopamine receptors, dilates renal and visceral vessels,

• High doses activates β1 receptors. • Higher rate of infusion activates α receptors

→ vasoconstriction.

Other sympathomimetic Other sympathomimetic amines:amines:

• Phenylephrine: • Relatively pure α agonist, not inactivated by

COMT, much longer duration of action.• Effective mydriatic and decongestant.• Can be used to increase BP (raises both

systolic and diastolic blood pressures).

Clonidine:Clonidine:• Clonidine is an α2 agonist that prevents further release of

noradrenaline. It is used in hypertension as it acts on α2 receptors in the CNS.

• It used in treatment of withdrawal symptoms of opiates and benzodiazepines (primarily reduces anxiety, agitation, muscle aches, sweating, runny nose and cramping).

• It also to reduce menopausal flushing; and frequency of migraine attacks.

Clinical uses of adrenoceptors Clinical uses of adrenoceptors direct-acting agonists:-direct-acting agonists:-

1. Cardiac arrest (adrenaline), cardiogenic shock (dobutamine) and heart block (dobutamine and isoprenaline)

2. Anaphylactic reaction (adrenaline).3. Asthma (salbutamol).

Clinical uses of adrenoceptors Clinical uses of adrenoceptors direct-acting agonists:- direct-acting agonists:-

4. Nasal decongestion (oxymetazoline). 5. Prolongation of local anesthetic action

(adrenaline).6. Inhibition of premature labour

(salbutamol).7. Hypertension (clonidine).

Indirectly acting Indirectly acting sympathomimetic amines sympathomimetic amines

• They include tyramine, cocaine and amphetamine.

• They sufficiently resemble NA to be transported into nerve terminals by uptake1.

Indirectly acting Indirectly acting sympathomimetic aminessympathomimetic amines

• Tyramine in the diet is destroyed by MAO in the gut and liver. In case patients on MAOI tyramine rich food causes sudden dangerous rise in BP (cheese reaction).

• Tolerance and tachyphylaxis develop to their action.

Peripheral effects:Peripheral effects:

• Their peripheral effect resembles NA include:-

1. Bronchodilatation 2. Increase arterial blood pressure 3. Peripheral vasoconstriction 4. Increase force of myocardial contraction 5. Inhibition of GI motility

amphetamine:-amphetamine:-• Central stimulant, abused drug. • Its peripheral actions are mediated primarily

through the release of stored norepinephrine and the blockade of norepinephrine uptake.

• Central effects depend on its ability to release not only NA, but also 5-HT and dopamine in the nerve terminal in the brain which lead to its abuse include:-

amphetamine:-amphetamine:-

1. Euphoria and excitement. 2. Wakefulness and alertness. 3. Loss of appetite. 4. Large doses schizophrenia like syndrome and

hallucination. • Amphetamine used for treatment of narcolepsy,

obesity and hyperkinetic syndrome in children (in normal people it cause hyperkinesias)

CocaineCocaine

• Drug of abuse.• Cocaine is a local anesthetic (sodium

channel blocker) and is a CNS stimulant (blocks the reuptake of norepinephrine, thus potentiating NA effects).

Mixed-Action Adrenergic Mixed-Action Adrenergic AgonistsAgonists

• Mixed-action drugs induce the release of norepinephrine, and they activate postsynaptic adrenergic receptors, they include ephedrine, pseudoephedrine and metaraminol.

• Ephedrine, and pseudoephedrine are plant alkaloids, that are now made synthetically.

• Ephedrine produces bronchodilatation • Pseudoephedrine is used to treat nasal and sinus

congestion.

Ephedrine:Ephedrine:

• has a higher bioavailability and longer duration of action.

• Significant fraction excreted unchanged in urine.• Similar spectrum to adrenaline but les potent, also act

through the release of NA. Penetrate BBB, produces stimulant action, pressor action,

• Can be use for asthma and nasal decongestant. • Side effects: restlessness, tremor, insomnia and anxiety

MetaraminolMetaraminol

• Metaraminol (ά1 agonist with some β effects) is used in treatment of hypotension, particularly as complication of anaesthesia.

Adrenergic Antagonists Adrenergic Antagonists (blockers or sympatholytic (blockers or sympatholytic

agents) agents)

Alpha (ά) blockers Alpha (ά) blockers • They include non selective ά antagonists: phentolamine,

tolazoline (reversible) and phenoxybenzamine (irreversible)• Selective ά1 antagonist: prazosin, terazosin doxazosin,

Tamsulosin (selective α 1A antagonist)

• Selective (ά2) antagonist: yohimbine.• Ergot derivatives (e.g. ergotamine, dihydroergotamine). They

have many actions in addition to α-receptor block, Their action on α-adrenoceptors is not used therapeutically.

Pharmacodynamic effects:Pharmacodynamic effects:

• They decrease PVR and BP, prevent pressor effect of α – agonists.

• They produce postural hypotension and reflex tachycardia by inhibiting α – mediated vasoconstriction.

• They decrease pupillary dilator tone.

Phentolamine: Phentolamine: • It is a potent competitive antagonist of α receptors,

equally potent on both α1 and α2 receptors, decrease PVR, cause reflex cardiac stimulation, poorly absorbed after oral administration.

• ADR: cardia stimulation, severe tachycardia, arrhythmias, angina, GIT stimulation → diarrhea and acid secretion.

• It used to terminate dental anesthesia when adrenaline is used to provide vasoconstriction.

Phenoxybenzamine:Phenoxybenzamine:• Bind covalently causing irreversible bock, long duration

24 – 48 hrs, blocks Ach, H1, 5HT receptors. • It decreases BP when sympathetic tone is high e.g.

upright position, reduced blood volume, absorbed after oral administration, low bioavailability. Could be given I.V.

• ADR: postural hypotension, tachycardia, nasal stuffiness, inhibit ejaculation, fatigue, sedation and nausea.

Other (ά) blockers: Other (ά) blockers:

• Tolazoline: Less potent than phentolamine, better absorbed, rapidly excreted in urine.

• Prazosin: Highly selective for α1 receptors, low affinity for α2 receptors, no tachycardia, relaxes arterioles and veins, metabolized by the liver, t1\2 = 3 hrs, first – dose effect.

• Yohimbine: α2 selective, useful in autonomic insufficiency by promoting neurotransmitter release, aphrodisiac.

Side effects of ά blockers:Side effects of ά blockers:

• The major adverse effect of phenoxybenzamine is postural hypotension. This often is accompanied by reflex tachycardia and other arrhythmias.

• Reversible inhibition of ejaculation may occur because of impaired smooth muscle contraction in the vas deferens and ejaculatory ducts.

Side effects of ά blockers:Side effects of ά blockers:

• A major potential adverse effect of prazosin and its congeners is the first-dose effect; marked postural hypotension and syncope sometimes are seen 30 to 90 minutes after a patient takes an initial dose.

• Nonspecific adverse effects such as headache, dizziness, and asthenia (physical weakness and loss of strength) rarely limit treatment with prazosin.

Clinical uses of ά blockers:Clinical uses of ά blockers:

1. Phaeochromocytoma (phenoxybenzamine and phentolamine). Phaeochromocytoma is diagnosed by measuring circulation catecholamines, urinary VMA, or by phentolamine greater than average drop in BP.

2. Hypertension (Prazosin & Doxazosin).

Clinical uses of ά blockers:Clinical uses of ά blockers:

3. Tamsulosin is used to treat benign prostate hyperplasia. The drug is clinically useful because it targets α1A receptors found primarily in the urinary tract and prostate gland

4. Peripheral vascular disease Raynaud`s syndrome (reversible vasospasm).

5. Use to reverse intense local vasoconstriction as in prolonged local anesthesia.

Raynaud's syndromeRaynaud's syndrome

Beta (β) blockersBeta (β) blockers

• Metoprolol, acebutolol, esmolol, bisoprolol and atenolol are selective β1 blockers.

• Nadolol, Pindolol, Timolol and propranolol are non selective β blockers.

• Pindolol, and acebutolol have agonist activity (intrinsic sympathomimetic activity ISA)

• Propranolol is potent as procaine in blocking nerve action potential.

Beta (β) blockers:Beta (β) blockers:

• Labetalol and carvedilol: blockers of both α- and β- adrenoceptors

• Labetalol it uses to treat hypertension in pregnancy.

• Intravenous labetalol is also used to treat hypertensive emergencies, because it can rapidly lower blood pressure.


Cardiovascular effects:• They ↓ CO → ↓ BP, ↓ renin angiotensin system.• Negative inotropic and chronotropic effect, slow

AV conduction, ↑ PR interval.• In the vascular system it oppose β2 – mediated

vasodilation → ↑ PVR from unopposed α receptor mediated effect.


Effects on respiratory tract: Blockage of β2 receptors → ↑ airway resistance, especially in asthmatic patients.

Metabolic and endocrine effects:• β-blockade leads to decreased glycogenolysis and

decreased glucagon secretion, thus pronounced hypoglycemia may occur after insulin injection in a patient using propranolol.

• β-Blockers also mask the normal physiologic response to hypoglycemia.

Pharmacodynamic effects:Pharmacodynamic effects:Effect on the eye:• ↓ intraocular pressure, mechanism not well understood,

may ↓ aqueous humour formation or ↑ out flow.Effects not related to β – blockage:• Retention of some intrinsic activity, desired to prevent

untoward effects, e.g. pindolol and acebutalol.• Local anesthetic action: e.g. propranolol, this effect does

not produced when used systemically.

Pharmacokinetics:Pharmacokinetics:

• most are well absorbed after oral administration, peak conc 1 -3 hrs, (sustained release) preparations are available, propranolol undergoes extensive first – pass metabolism.

• Pindolol has better bioavailability, large Vd.• Propranolol crosses BBB, rapidly eliminated

t1\2 = 2 – 5 hrs.

Clinical uses of Clinical uses of ββ blockers:- blockers:-

1. Hypertension most often use with diuretic or vasodilator. 2. Ischaemic heart disease decrease frequency of anginal

episodes, improve exercise tolerance in patients with angina, (decrease cardiac work, and decrease O2 demand).

3. Cardiac arrhythmic, effective in supraventricular and ventricular arrhythmia by prolonging AV conduction time, they decrease ventricular response, and decrease rate in arterial flutter and fibrillation.


4. Glaucoma; topical and systemic administration decrease IOP e.g. timolol (preferred because they lack local anesthetic effect and pure antagonist) mechanism may due to decrease in aqueous formation (not well understood).


5. Hyperthyroidism, results in excessive adrenergic activity especially in the heart (use to prevent palpitation).

6. Migraine prophylaxis. 7. Benign essential tremor.

Toxicity and side effects of β Toxicity and side effects of β blockers:-blockers:-

1. Manifestation of drug allergy, rash and fever.2. Increase airway resistance

(Bronchoconstriction). 3. Bradycardia, heart failure in person who

depends on sympathetic output to maintain cardiac output. Abrupt withdrawal in patients with ischemic heart disease → risk, (gradual tapering rather than abrupt withdrawal).


4. Incidence of hypoglycemia in insulin dependent diabetes (mask symptom of hypoglycemia).

5. Mask clinical signs of developing hyperthyroidism.

6. Physical fatigue and Sexual impairment (↓ Sexual function).

7. Cold extremities (decrease peripheral blood flow), rarely cause necrosis.


8. CNS effects: sedation, depression and sleep disturbance (bad dreams).

9. ↓ HDL\LDL value.10.Oculomucocutaneous syndrome (practolol) (eye

dryness which can lead to blindness). The use of practolol (selective β1 blocker) has been referred to as the practolol disaster which considered the worst medical blunder since thalidomide.

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Pharmacology of the Autonomic nervous system

Health & Medicine