Drugs that act on CNS

DRUGS THAT ACT ON CNS

Introduction to the Pharmacology of CNS Drugs

Drugs acting in the central nervous system (CNS) were among the first to be discovered by primitive humans and are still the most widely used group of pharmacologic agents.

In addition to their use in therapy, many drugs acting on the CNS are used without prescription to increase one‘s sense of well-being.

The mechanisms by which various drugs act in the CNS have not always been clearly understood.

In the last 3 decades, however, dramatic advances have been made in the methodology of CNS pharmacology.

It is now possible to study the action of a drug on individual cells and even single ion channels within synapses. The information obtained from such studies is the basis for several major developments in studies of the CNS.

Major Developments In Studies Of The CNS

Nearly all drugs with CNS effects act on specific receptors that modulate synaptic transmission.

Drugs are among the most important tools for studying all aspects of CNS physiology.

Unravelling the actions of drugs with known clinical efficacy has led to some of the most fruitful hypotheses regarding the mechanisms of disease

Methods for the Study of CNS Pharmacology

A detailed description of synaptic transmission was not possible until glass microelectrodes, which permit intracellular recording, were developed.

Detailed electrophysiologic studies of the action of drugs on both voltage- and transmitter-operated channels were further facilitated by the introduction of the patch clamp technique, which permits the recording of current through single channels.

Histochemical, immunologic, and radioisotopic methods are widely used to map the distribution of specific transmitters, their associated enzyme systems, and their receptors.

Molecular cloning has had a major impact on our understanding of CNS receptors

Mice with mutated genes for specific receptors or enzymes (knockout mice) can provide important information regarding the physiologic and pharmacologic roles of these components.

SEDATIVE-HYPNOTIC DRUGS

What are sedative-hypnotics?

Sedative-hypnotics are drugs which depress or slow down the body's functions.

Often these drugs are referred to as tranquilizers and sleeping pills or sometimes just as sedatives.

Their effects range from calming down anxious people to promoting sleep. Both tranquilizers and sleeping pills can have either effect, depending on how much is taken.

At high doses or when they are abused, many of these drugs can even cause unconsciousness and death.

Classification of CNS depressants

Benzodiazepines 

Barbiturates Miscellaneous agents 

•diazepam (Valium)•midazolam (Versed)•clonazepam (Klonopin)•chlordiazepoxide (Librium)•clorazepate (Tranxene) •Alprazolam (Xanax)•Flurazepam (Dalmane)•Triazolam (Halcion)•Lorazepam (Ativan)•Flumazenil* (Romazicon) *receptor antagonist

•Amobarbital (Amytal)•pentobarbital (Nembutal)•thiopental (Pentothal)•secobarbital (Seconal)•Phenobarbital (Luminal)

•paraldehyde (Paral)•meprobamate (Miltown)•ethchlorvynol (Placidyl)•chloral hydrate (Noctec)•methaqualone (Quaalude)

Mechanism of ActionBenzodiazepines  Barbiturates

•act on GABAA receptors•GABA receptor: a pentameric protein, consists of several subunits designated alpha (mainly responsible for the pharmacology of the receptor) ,beta and  gamma which is required for high affinity benzodiazepine binding.•Electrophysiological Effects: Benzodiazepines enhance GABA-activated hyperpolarizing chloride currents

•activate inhibitory GABAA while inhibiting excitatory AMPA receptors. •AMPA receptors are the subtype of glutamate receptors sensitive to kainate or quisqualate.•The combination of these receptor effects may result in the profound central nervous system depression that occurs with higher barbiturate doses.

Effects on CNSBenzodiazepines  Barbiturates

-With increasing doses, benzodiazpines can progressive cause sedation, then hypnosis and then stupor.-do not cause general anesthesia since awareness persists.-have anti-anxiety / sedative-hypnotic properties.-Some benzodiazepines (clonazepam (Klonopin)) are effective muscle relaxants, whereas most others are not. 

-Barbiturates depress respiratory drive-At doses somewhat (three times) higher than required for pharmacological hypnosis, neurogenic is abolished and the hypoxic respiratory drive is reduced and the chemoreceptor drive is attenuated.-At still higher doses, the hypoxic drive is abolished.

Effects on Cardiovascular SystemBenzodiazepines  Barbiturates

-Except in overdosage, cardiovascular effects of benzodiazepines in normal subjects are minor.-If used as preanesthetic medication, benzodiazepines decrease blood pressure and increase heart rate.

-In sedative or doses for pharmacological hypnosis, barbiturates have minimal cardiovascular effects-When thiopental is used in general anesthesia, following pre-anesthetic medication: *plasma renal flow decreases *cerebral blood flow decreases *CSF pressure decreases-Significant depression of myocardial contractility occurs in barbiturate poisoning

Effects on Respiratory SystemBenzodiazepines 

-At pharmacological hypnotic doses, benzodiazepines do not affect respiration in normal subjects.-Severely benzodiazepine-intoxicated patients may require assistance in breathing if other CNS depressant drugs have been taken-If a patient, however, has a sleep-related breathing syndrome such as obstructive sleep apnea (OSA), benzodiazepines may be contraindicated.

In patients with obstructive sleep apnea, hypnotic doses of benzodiazepines may decrease muscle tone in the upper airway and accentuate or worsen the impact of  apneic episodes on alveolar hypoxia, pulmonary hypertension and cardiac demand.

 -At higher doses, such as those used for endoscopy or when given as preanesthetic medication, benzodiazepines somewhat depress alveolar ventilation causing a respiratory acidosis secondary to a decrease in hypoxic drive (rather than hypercapnic drive). 

 These effects are more severe in patients with COPD (chronic obstructive pulmonary disease) and maybe sufficiently detrimental to induce alveolar hypoxia and/or CO2 narcosis.

Effects on the LiverBarbiturates 

-Acutely, barbiturates combine with cytochrome P-450 and produce competitive inhibition of metabolism of a number of drugs and endogenous agents (such as steroids)-Chronically, barbiturates increase activities of cytochrome P-450 oxidases and glucuronyl transferases and therefore increase the metabolism (due to enzyme induction) of many drugs, steroids, vitamins K & D, cholesterol, bile salts. The extent of the increase is about two fold-Part of barbiturate tolerance is due to increased hepatic metabolism of barbiturates, induced by barbiturates.-Non-microsomal enzyme system are also induced, including:

*d -aminolevulinic acid (ALA) synthetase. The effect of barbiturates on ALA *synthetase that produces exacerbation in patients with intermittent porphyria.aldehyde dehydrogenase

Therapeutic UsesBenzodiazepines  Barbiturates

•Flurazepam (Dalmane)Flurzepam has been prescribed for insomnia.

•Triazolam (Halcion)Triazolam is used to induce sleep.

•Flumazenil (Romazicon, benzodiazepine antagonist*)Primary use is for management of benzodiazepine overdosage.Additional use in the reduction of benzodiazepine effects in general anesthesia or diagnostic procedures. Benzodiazepine-induced electrophysiological and behavioral effects are antagonized.

•IV anesthesia: Thiopental (Pentothal) and methohexital (Brevital)•Convulsions: emergency treatment (eclampsia, tetanus, status epilepticus), but benzodiazepines are preferable.•Epilepsy•Rarely used as a sedative due to the availability of safer benzodiazepine agents

Can sedative-hypnotics cause dependence?

Yes. They can cause both physical and psychological dependence.

Regular use over a long period of time may result in tolerance, which means people have to take larger and larger doses to get the same effects.

When regular users stop using large doses of these drugs suddenly, they may develop physical withdrawal symptoms ranging from restlessness, insomnia and anxiety, to convulsions and death.

 Effects combining sedative-hypnotics with alcohol

Taken together, alcohol and sedative-hypnotics can kill.

The use of barbiturates and other sedative-hypnotics with other drugs that slow down the body, such as alcohol, multiplies their effects and greatly increases the risk of death.

Overdose deaths can occur when barbiturates and alcohol are used together, either deliberately or accidentally.

Barbiturate Adverse Effects

Adverse Effects:◦  Drowsiness, impaired judgment, impaired motor skills◦  Significant CNS/respiratory depression with high dosage.◦  Paradoxical excitement◦  If barbiturates are given for pain, restlessness,

excitement, or delirium may result◦  Hypersensitivity: allergic reaction in patients who are

predisposed to angioedema, urticaria, and asthma◦  Drug interactions: combination with other sedative agents

can result in severe CNS depression.Untoward effects:

◦ Absolutely contraindicated in acute intermittent porphyria or porphyria variegata because barbiturates increase porphyrin synthesis.

◦  i.v. administration can produce cardiovascular collapse; overdosage can cause severe respiratory depression.

Management of barbiturate poisoning

Severe intoxication is associated with coma and depressed respiration

Treatment is supportive with CNS stimulants contraindicated (increases mortality)

Hemodialysis or hemoperfusion may be neededComplicating factors include:

◦  circulatory collapse◦  shock◦  dehydration◦  renal failure.

Adverse Effects: Benzodiazepines   ◦ Common: Drowsiness, lethargy◦ Less common: Muscular incoordination, ataxia◦ Other: hypotonia, dysarthria, dizziness, behavior disturbances

including hyperactivity, irritability, difficulty in concentration.◦ Seizures may occur if drug is discontinued abruptly.

Flurazepam (Dalmane)◦ Flurazepam has long-acting metabolites.◦   Adverse Effects: 

Presence of long-acting metabolites may cause daytime sedation, which may be undesirable.

Triazolam (Halcion)◦ Triazolam is short-acting with no active metabolites◦ Adverse Effects: Tolerance may develop and rebound

insomnia has been reported.  Reported associations of triazolam with psychotic reactions,

dependency, anterograde amnesia are some factors that contributed to triazolam removal from the market in some European countries.5

Flumazenil (Romazicon, benzodiazepine antagonist*)

Adverse Effects: ◦in comatose patients, intoxicated with

alcohol, flumazenil may increase risk of seizures.

◦in comatose patients due to tricyclic antidepressant agents, flumazenil increases seizure risk.

Effects of Barbiturates When Abused

Similar to the effects of alcohol. Small amounts produce calmness and

relax muscles. Somewhat larger doses can cause slurred speech, staggering gait, poor judgment, and slow, uncertain reflexes.

These effects make it dangerous to drive a car or operate machinery. Large doses can cause unconsciousness and death.

How dangerous are barbiturates?

Barbiturate overdose is a factor in nearly one-third of all reported drug-related deaths.

These include suicides and accidental drug poisonings.

Accidental deaths sometimes occur when a user takes one dose, becomes confused and unintentionally takes additional or larger doses.

With barbiturates there is less difference between the amount that produces sleep and the amount that kills.

Furthermore, barbiturate withdrawal can be more serious than heroin withdrawal

Other Abused Sedative-hypnoticsAll the other sedative-hypnotics

can be abused, including the benzodiazepines. Diazepam (Valium), chlordiazepoxide (Librium), and chlorazepate (Tranxene) are examples of benzodiazepines.

These drugs are also sold on the street as downers.

As with the barbiturates, tolerance and dependence can develop if benzodiazepines are taken regularly in high doses over prolonged periods of time.

Other sedative-hypnotics which are abused include glutethimide (Doriden), ethchlorvynol (Placidyl), and methaqualone (Sopor, Quaalude).

Sedative-hypnotic "Look-alikes"These are pills manufactured to

look like real sedative-hypnotics and mimic their effects.

Sometimes look-alikes contain over-the-counter drugs such as antihistamines and decongestants, which tend to cause drowsiness.

The negative effects can include nausea, stomach cramps, lack of coordination, temporary memory loss, becoming out of touch with the surroundings, and anxious behavior.