Barbiturates interact differently than benzodiazepines at GABA receptors. For example, the gamma subunit is not required for barbiturate activity
DRUGS THAT ACT ONCNS
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.
What are sedative-hypnotics? Sedative-hypnotics are drugs which depress or slow down the bodys 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
Mechanism of Action Benzodiazepines Barbiturates•act on GABAA receptors •activate inhibitory GABAA while•GABA receptor: a pentameric inhibiting excitatory AMPAprotein, consists of several receptors.subunits designated alpha (mainly •AMPA receptors are the subtyperesponsible for the pharmacology of glutamate receptors sensitive toof the receptor) ,beta and gamma kainate or quisqualate.which is required for high affinity •The combination of these receptorbenzodiazepine binding. effects may result in the profound•Electrophysiological Effects: central nervous system depressionBenzodiazepines enhance GABA- that occurs with higher barbiturateactivated hyperpolarizing chloride doses.currents
Effects on CNS Benzodiazepines Barbiturates-With increasing doses, -Barbiturates depress respiratorybenzodiazpines can progressive drivecause sedation, then hypnosis and -At doses somewhat (three times)then stupor. higher than required for-do not cause general anesthesia pharmacological hypnosis,since awareness persists. neurogenic is abolished and the-have anti-anxiety / sedative- hypoxic respiratory drive is reducedhypnotic properties. and the chemoreceptor drive is-Some benzodiazepines attenuated.(clonazepam (Klonopin)) are -At still higher doses, the hypoxiceffective muscle relaxants, whereas drive is abolished.most others are not.
Effects on Cardiovascular System Benzodiazepines Barbiturates-Except in overdosage, -In sedative or doses forcardiovascular effects of pharmacological hypnosis,benzodiazepines in normal barbiturates have minimalsubjects are minor. cardiovascular effects-If used as preanesthetic -When thiopental is used in generalmedication, benzodiazepines anesthesia, following pre-decrease blood pressure and anesthetic medication:increase heart rate. *plasma renal flow decreases *cerebral blood flow decreases *CSF pressure decreases -Significant depression of myocardial contractility occurs in barbiturate poisoning
Effects on Respiratory System Benzodiazepines-At pharmacological hypnotic doses, benzodiazepines do not affect respirationin normal subjects.-Severely benzodiazepine-intoxicated patients may require assistance inbreathing if other CNS depressant drugs have been taken-If a patient, however, has a sleep-related breathing syndrome such asobstructive 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 aspreanesthetic medication, benzodiazepines somewhat depress alveolarventilation causing a respiratory acidosis secondary to a decrease in hypoxicdrive (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 Liver Barbiturates-Acutely, barbiturates combine with cytochrome P-450 and producecompetitive inhibition of metabolism of a number of drugs and endogenousagents (such as steroids)-Chronically, barbiturates increase activities of cytochrome P-450 oxidasesand glucuronyl transferases and therefore increase the metabolism (dueto 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 ofbarbiturates, 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 Uses Benzodiazepines Barbiturates•Flurazepam (Dalmane) •IV anesthesia: Thiopental Flurzepam has been prescribed for (Pentothal) and methohexital insomnia. (Brevital)•Triazolam (Halcion) •Convulsions: emergency Triazolam is used to induce sleep. treatment (eclampsia, tetanus,•Flumazenil (Romazicon, status epilepticus), butbenzodiazepine antagonist*) benzodiazepines arePrimary use is for management of preferable.benzodiazepine overdosage. •EpilepsyAdditional use in the reduction of •Rarely used as a sedativebenzodiazepine effects in general due to the availability of saferanesthesia or diagnostic procedures. benzodiazepine agentsBenzodiazepine-inducedelectrophysiological and behavioraleffects are antagonized.
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 needed Complicating 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
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 WhenAbused 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 arebarbiturates? 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-hypnotics All 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.