BEHAVIOURAL SCREENING OF DRUGS HYPNOTICS/SEDATIVES

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1 BEHAVIOURAL SCREENING OF DRUGS I. PHARMACOLOGICAL PROPERTIES OF SOME CNS AFFECTIVE AGENTS HYPNOTICS/SEDATIVES The hypnotics and sedatives are one of the most widely prescribed classes of drugs on the market. They are used to treat anxiety and insomnia and often involve the same drug treatment. Within the general classification of this group are a number of drugs, the most important being the benzodiazepine and barbiturates. Within this classification it is important to distinguish between the following terms, which are often confused. Sedatives: This class of compounds calm or relax anxious or restless patients without actually inducing sleep. However, by making the individual more relaxed the patient may fell asleep. Hypnotics: This class of compounds actually induce sleep directly through a central mechanism. Anxiolytics: These drugs allay anxiety and tension without notably impairing consciousness. While the clinical objectives of anxiety and insomnia are different the same drugs are often used in treatment because drugs that relieve anxiety generally cause a degree of sedation and drowsiness, which is one of the main drawbacks in the clinical use of anxiolytic drugs. Barbiturates Background: Up until the 1960 s the barbiturates were the most widely prescribed hypnotics in general use. However, because of the severe CNS depression they produce they have since been replaced by the much safer benzodiazepines. The significant effects of the barbiturates include: respiratory depression hyperalgesia rapid development of tolerance pronounced rapid eye movement (REM) suppression rebound REM sleep, leading to physical and psychological effects strong physical withdrawal syndrome which may lead to death

2 Mechanism of action: Like the benzodiazepines, the barbiturates also facilitate the action of GABA by binding to the GABA receptor complex. However, they have a more generalized action on the CNS and at higher doses inhibit the actions of glutamate at kainate receptors and mimic the inhibitory actions of GABA. The consequent produce profound depression of the CNS. Therapeutics: Clinically there are not many uses for the barbiturates anymore, but some barbiturates are still used for their specific properties, for instance phenobarbitone is used for its anticonvulsant activity and thiopentone is used as an induction anaesthetic. Because the barbiturates also induce microsomal liver enzymes, phenobarbitone is also used to treat neonatal jaundice. For more information, open hyperlink: Benzodiazepines Background: The Benzodiazepines (BDZs) were first synthesized by accident in 1961, with the production of chlordiazepoxide by Hoffman la Roche. Its unique pharmacological profile was then discovered during a routine screening procedure. Since then more than 3,000 derivates have been synthesized, with 120 being screened for biological activity & about 35 in clinical use throughout the world. As a group the benzodiazepines have a wide spectrum of effects and show anxiolytic, hypnotic, anticonvulsant and muscle relaxant activity. They are generally divided into three groups based upon their duration of activity as detailed below: Short acting: alprazolam, oxazepam, temazepam (half life: 8-16 hrs) Intermediate acting: nitrazepam (16-32 hrs) Long acting: diazepam, flurazepam (24-70 hrs) The significant advantage of the BDZs over any other hypnotic or sedative relates to their safety margin. While they are not as sedative as the barbiturates, they have a much lower toxicity and are less likely to cause death in overdose.

3 The important characteristics of the BDZs: very safe, overdose causing a long sleep no respiratory depression producing anterograde amnesia suppressing REM sleep exhibiting tolerance and dependence, although not as severe as the barbiturates. Mechanism of action: The BDZs works by binding to a specific recognition site on the GABA A receptor (which is a ligand-gated chloride channel). BDZs potentiate the action of GABA by facilitating the binding of GABA to GABA A receptor and increase the frequency of chloride channel opening. For more information, open hyperlink: Therapeutics: The BDZs have a wide variety of therapeutic uses, these include: reduction of anxiety and aggression sedation and induction of sleep reduction of muscle tone and coordination (centrally mediated) and anticonvulsant activity

4 OPIOIDS The term of opioid refers to any substance that produces morphine-like effects that are blocked by antagonists, such as naloxone. Opium is an extract of the juice of the poppy Papaver somniferum, which has been used for social and medical reasons for thousands of years, as an agent to produce euphoria, analgesia and sleep, and to prevent diarrhoea. Drug in this group produce following effect: Analgesia (acute and chronic) Euphoria Respiratory depression (severe) Depression of the cough reflex Nausea and vomiting Pupillary constriction Classification: Morphine analogues: Agonists: morphine, heroin, codeine Partial agonists: nalorphine Antagonist: naloxone Synthetic derivatives: Pethidine, methadone, pentazocine, etorphine. Morphine Background: Opium contains more than 20 distinct alkaloids. In 1806, Serturner reported the isolation of a pure substance in opium that he named morphine, after Morpheus, the Greek god of dreams. This drug is the prototypical compound in this class despite the availability of more potent agents. Morphine Mechanism of action: Morphine acts on 4 types of G-protein coupled receptors: µ-receptor: responsible for analgesic effects and unwanted side effects. δ-receptor: periphery, contribute to analgesia. κ-receptor: contribute to analgesia at spinal cord level and in the periphery. σ-receptor: not selective opioid receptor.

5 Therapeutics: Morphine produces symptomatic relief of pain, cough or diarrhoea, but the general underlying disease remains. However, morphine is seldom used today except in the treatment of moderately severe or severe pain due to the availability of more specific compounds to treat these conditions, without the unwanted side effects or danger of drug abuse. For more information, open hyperlink: STIMULANTS Drugs classified as stimulants may fall into one of three broad categories: Convulsants and respiratory stimulants: e.g. strychnine, picrotoxin Psychomotor stimulants: e.g. amphetamines, cocaine Psychotomimetic drugs (hallucinogens): e.g. phencyclidine PSYCHOMOTOR STIMULANTS: This class of drugs have marked effects on both mental function and behaviour, producing excitement and euphoria, reduced sensation of fatigue and an increase in motor activity. Such drugs have a high incidence of abuse in society and are responsible for a large number of deaths every year. Amphetamine has a particularly high incidence of use among professional drivers to reduce fatigue on long journeys. After long-term use or even short binges there is pronounced physical dependence and withdrawal symptoms such as depression, anxiety and general fatigue. This is often followed by an intense craving for the drug. Amphetamine Background: Amphetamine is one of the most potent sympathominetic amines in stimulating the CNS. The main central effects of amphetamine like drugs are locomotor stimulation euphoria and excitement stereotyped behaviour and anorexia Amphetamine

6 together with some peripheral sympathomimetic action producing a rise in blood pressure and inhibition of gastrointestinal motility. While the effects of amphetamine are similar to those of cocaine, the half life is significantly longer at 10 hrs, compared to 50 mins for cocaine. Mechanism of action: The main pharmacological action of amphetamine is the release of monoamines from nerve terminals in the brain. Noradrenalin and dopamine are the most important mediators, with some contribution from 5HT. Therapeutics: There are few therapeutic uses for amphetamine. However, related compounds such as methylphenidate and dexamphetamine are used in the treatment of attention deficit/hyperactivity disorder (ADHD) in children. Amphetamine is sometimes used in the treatment of narcolepsy, a condition where the patient suddenly falls asleep through the day; however, it is not effective in all cases. Cocaine Background: Cocaine is found in the leaves of a South American shrub, coca, and is used by the natives for its stimulant properties, particularly for individuals that live at high altitudes. Cocaine was also used by Freud and tested on many of his patients, until one of his patients died after its administration. As with amphetamine cocaine is widely abused by the community and in a survey during 1990 it was estimated that 2 million Americans take cocaine regularly at least once a month. Cocaine Mechanisms of action: Cocaine is a potent inhibitor of catecholamine uptake by noradrenergic terminals, and strongly enhances the effects of sympathetic nerve activity, particularly in the CNS. Clinically, the effects of cocaine are similar to those of amphetamine although the effects are more transient due to its half life of 50 mins compared to 10 hrs for amphetamine, Like amphetamine, cocaine produces increased motor activity, euphoria and excitement, although is less likely to produce stereotyped behaviour, delusions, hallucinations and paranoia than amphetamine. Therapeutics: Cocaine is still used occasionally as a topical local anaesthetic, but has no other clinical uses. However, it is a valuable research tool in the study of catecholamine release and re-uptake.

7 CONVULSANTS: The convulsants are a chemically diverse group of drugs with a wide variety of mechanisms of action. They were once used to treat patients in terminal coma or with severe respiratory failure, however, despite the restoration in function, the survival rate was not improved and there was a severe risk of leaving the patient in a worse condition than before treatment. Drugs in this group include strychnine, picrotoxin and pentylenetetrazol. Picrotoxin Background: Picrotoxin is a plant toxin obtained from Anamirta Cocculus, a climbing shrub indigenous to Malabar and the East Indies. The drug is present in the seeds of the plant commonly known as fishberries, a name derived from the practice of throwing the bruised berries upon the water as a means of catching fish. Picrotoxin consists of two substances, picrotoxinin (C 15 H 16 O 6 ) and picrotin (C 15 H 18 O 7 ). Picrotoxin is a powerful stimulant and affects all portions of the CNS. It is a powerful convulsant which produces clonic convulsions and in higher doses tonicclonic seizure. Theses convulsions are associated with salivation and elevated blood pressure due to vasomotor stimulation. Picrotoxin Mechanisms of action: The active substance, picrotoxinin, blocks the action of GABA on chloride channels non-competitively. Therapeutic uses: Formerly employed in the treatment of poisoning by CNS depressants, picrotoxin is no longer used clinically. However, it remains an important laboratory tool for studying inhibition in the CNS. What you need to know to STAY SAFE from the drugs on the market today?

8 II. WATCHING PRE-RECORDED VIDEO ON ANIMAL BEHAVIOURS 1. Behavioural symptoms (refer Definitions of Behaviours) 2. Behaviour observation after drug injection (Fill in the table provided in your handout) Hexobarbital (Rat, i.p. 80 mg/kg) Morphine (Mouse, i.p. 100 mg/kg; Rabbit, i.p. 30 mg/kg) Amphetamine (Rat, 25 mg/kg i.p.) Cocaine (Mouse; 15 mg/kg i.p.) Picrotoxin (Rat; 2.5 mg/kg i.v.) III. ANSWERING MCQ

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