Drugs Acting on Central Nervous System PDF

C H A P T E R 5 Drugs Acting on Central Nervous System Neurotransmitters and Central Nervous System PH1.19 NEUROTRANSMITTERS IN CNS Neurotransmitters in the central nervous system (CNS) could be inhibitory, excitatory or both (Fig. 5.1). 1. Inhibitory neurotransmitters GABA Glycine Dopamine CNS − In...

C H A P T E R 5 Drugs Acting on Central Nervous System Neurotransmitters and Central Nervous System PH1.19 NEUROTRANSMITTERS IN CNS Neurotransmitters in the central nervous system (CNS) could be inhibitory, excitatory or both (Fig. 5.1). 1. Inhibitory neurotransmitters GABA Glycine Dopamine CNS − Inhibitory effect on CNS 2. Excitatory neurotransmitters Glutamate Aspartate CNS + Stimulatory effect on CNS 3. Acetylcholine Noradrenaline Serotonin (5-HT) Mediate both inhibitory and excitatory effects Fig. 5.1 Neurotransmitters in CNS. GABA, !-Aminobutyric acid; 5-HT, 5-hydroxytryptamine; !, inhibition; ", stimulation. Inhibitory Postsynaptic Potential (IPSP) When an inhibitory transmitter binds and interacts with specific receptors on postjunctional membrane, the membrane permeability to K" or Cl# increases (Fig. 5.2). K+ K+ Inhibitory neurotransmission IPSP Effector cell Cl− Fig. 5.2 K" ions move out and Cl# ions move in, resulting in hyperpolarization (IPSP). (Source: Alfred Gilman Sr. and Louis S. Goodman: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th edition, p. 183, Fig. 8.3, McGraw Hill, 2018.) 164 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 165 K+ K+ Excitatory neurotransmission EPSP Effector cell Na+ Fig. 5.3 Na" ions move in (Na" influx), resulting in depolarization followed by K" efflux (EPSP). (Source: Alfred Gilman Sr. and Louis S. Goodman: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12th edition, p. 183, Fig. 8.3, McGraw Hill, 2018.) Excitatory Postsynaptic Potential (EPSP) When an excitatory neurotransmitter binds and interacts with specific receptors on postjunctional membrane, the membrane permeability to cations increases (Fig. 5.3). Manifestations of CNS Depression and Stimulation CNS depression CNS stimulation Drowsiness Sedation Hypnosis Disorientation Confusion Unconsciousness Coma Death Excitement Euphoria Insomnia Tremors Twitching Convulsions Coma Death Sedatives and Hypnotics PH1.19 Sedative is a drug that reduces excitement and calms the person. Hypnotic is a drug that produces sleep-resembling normal sleep. SLEEP The phases of sleep include nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. NREM sleep is divided into the following stages: 0, 1, 2, 3 and 4. Normally, about 50% of sleep time is spent in stage 2. Slow wave sleep includes stages 3 and 4. REM sleep constitutes about 30% of the sleep time and lasts for 5–30 minutes in each cycle of sleep. Types of sleep disorders and their treatment are given in Table 5.1. CLASSIFICATION OF SEDATIVES AND HYPNOTICS 1. Benzodiazepines (BZDs)*: Diazepam, lorazepam, clonazepam, clobazam, chlordiazepoxide, oxazepam, temazepam, midazolam, alprazolam, triazolam, flurazepam, nitrazepam. *Mnemonic to recollect BZDs: Sleep aids – De Lux C3OT, MAT, FaN. PHARMACOLOGY FOR MEDICAL GRADUATES 166 Table 5.1 Types of sleep disorder and their treatment Sleep disorder Lack Treatment Sedatives and hypnotics of sleep (insomnia) Transient insomnia ($3 days) Short-term insomnia (3 days–3 weeks) Long-term insomnia (%3 weeks) Hypersomnia (narcolepsy) Amphetamine, modafinil, amitriptyline Nocturnal enuresis (bed wetting) Tricyclic antidepressants 2. Barbiturates: Long acting: Phenobarbitone Short acting: Pentobarbitone Ultrashort acting: Thiopentone, methohexitone 3. Nonbenzodiazepine hypnotics: Zolpidem, zopiclone, zaleplon, eszopiclone 4. Others: Melatonin, ramelteon suvorexant Benzodiazepines PH1.19 All BZDs have a benzene ring fused to a seven-membered diazepine ring. Sites of Action Midbrain (ascending reticular formation), limbic system, brain stem, etc. Mechanism of Action BZDs facilitate action of GABA – they potentiate inhibitory effects of GABA. Benzodiazepines Bind to specific site on GABAA receptor (different from GABA-binding site) Increase in frequency of opening of Cl− channels Increase in GABA-mediated chloride current Membrane hyperpolarization CNS depression BZDs have no GABA-mimetic action. 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 167 Pharmacological Actions and Therapeutic Uses 1. Sedation and hypnosis: BZDs decrease time required to fall asleep (sleep latency). The total sleep time is increased. They shorten all stages of NREM sleep except stage 2, which is prolonged. The duration of REM sleep is usually decreased. BZDs reduce night awakenings and produce refreshing sleep. At present, BZDs are preferred to barbiturates for treatment of short-term insomnia because: They have a wide therapeutic index. They cause near-normal sleep; less rebound phenomena on withdrawal. They produce minimal hangover effects (headache and residual drowsiness on waking). They cause minimal respiratory depression. They are less likely to cause tolerance and dependence when used for short period. They have no enzyme-inducing property; hence, drug interactions are less. They have a specific BZD-receptor antagonist, flumazenil, for the treatment of overdosage. Long-term use of BZDs for insomnia is not recommended because of development of tolerance, dependence and hangover effects; but these drugs are ideal for occasional use by air travellers, shift workers, etc. 2. Anticonvulsant: Diazepam, lorazepam, clonazepam, clobazam, etc. have anticonvulsant effect. Intravenous (i.v.) diazepam/lorazepam is used to control life-threatening seizures in status epilepticus, tetanus, drug-induced convulsions, febrile convulsions, etc. Clonazepam is used in the treatment of absence seizures. 3. Diagnostic (endoscopies) and minor operative procedures: i.v. BZDs are used because of their sedative–amnesic–analgesic and muscle relaxant properties. 4. Preanaesthetic medication and general anaesthesia (GA): These drugs are used as preanaesthetic medication because of their sedative–amnesic and anxiolytic effects. Hence, the patient cannot recall the perioperative events later. i.v. diazepam, lorazepam, midazolam, etc. are combined with other CNS depressants to produce GA. 5. Antianxiety (anxiolytic) effect: Some of the BZDs (diazepam, oxazepam, alprazolam, lorazepam, chlordiazepoxide, etc.) have selective antianxiety action at low doses. The anxiolytic effect is due to their action on limbic system. Tolerance to antianxiety action of BZDs develops only on prolonged use. 6. Muscle relaxant (centrally acting): They reduce skeletal muscle tone by inhibiting polysynaptic reflexes in the spinal cord. The relaxant effect of BZDs is useful in spinal injuries, tetanus, cerebral palsy and to reduce spasm due to joint injury or sprain. 7. To treat alcohol-withdrawal symptoms: Long-acting BZDs, such as chlordiazepoxide and diazepam are used. 8. Conscious sedation: See p. 181. PHARMACOLOGY FOR MEDICAL GRADUATES 168 The above-mentioned uses/actions can be summarized as follows: AC D I A (Z E) P A M (Uses of BZDs: Mnemonic) Muscle relaxant Anxiolytic Preanaesthetic medication Anticonvulsant Insomnia Diagnostic and minor operative procedures Conscious sedation Alcohol withdrawal symptoms Pharmacokinetics BZDs are usually given orally or intravenously and occasionally by rectal route (diazepam) in children. The rate of absorption following oral administration is variable; absorption is erratic from intramuscular (i.m.) site of administration; hence rarely used. They have a large volume of distribution. They have a short duration of action on occasional use because of rapid redistribution, hence, are free of residual (hangover) effects, even though elimination half-life is long. BZDs are metabolized in liver. Some undergo enterohepatic recycling. Some of them produce active metabolites which have long half-life; hence, cumulative effects may be seen. Oxazepam is not significantly metabolized in liver. The metabolites are excreted in urine. BZDs cross placental barrier. Adverse Effects BZDs have a wide margin of safety. They are generally well tolerated. The common side effects are drowsiness, confusion, blurred vision, amnesia, disorientation, tolerance and drug dependence. Withdrawal after chronic use causes symptoms like tremor, insomnia, restlessness, nervousness and loss of appetite. Use of BZDs during labour may cause respiratory depression and hypotonia in newborn (Floppy baby syndrome). In some patients, these drugs may produce paradoxical effects, i.e. convulsions and anxiety. Important features of BZDs are given in Table 5.2. Inverse Agonist (!-Carboline). Its interaction with BZD receptors will produce anxiety and convulsions. Benzodiazepine Antagonist (Flumazenil). Flumazenil competitively reverses the effects of both BZD agonists (CNS depression) and BZD inverse agonists (CNS stimulation, Fig. 5.4). Flumazenil is not used orally because of its high first-pass metabolism. It is given by i.v. route and has a rapid onset of action. Flumazenil is used in the treatment of BZD overdosage and to reverse the sedative effect of BZDs during GA. It can also be used to reverse the hypnotic effect of zolpidem, zaleplon and eszopiclone. Adverse 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM Table 5.2 169 Important features of benzodiazepines Drug Formulations with oral dose Diazepam (prototype drug) Oral, i.v., i.m., rectal, 5–10 mg Rapidly absorbed from GI tract Produces active metabolites No residual effects on occasional use due to redistribution It is used to control convulsions but not for long-term therapy of epilepsy because of rapid development of tolerance to anticonvulsant effect It can be used rectally to control convulsions Other points: See p. 168 Flurazepam Oral, 15 mg Useful in insomnia Causes hangover effects – because of active metabolite with long half-life Nitrazepam Oral, 5–10 mg Useful in insomnia Residual effects are less on occasional use Oxazepam Oral, 15 mg Slowly absorbed No active metabolite Preferred in elderly and in patients with liver disease Mainly used as antianxiety agent Lorazepam Oral, i.m., i.v., 0.5–2 mg Rate of GI absorption is slow No active metabolite Anticonvulsant effect lasts longer than with diazepam because it is less lipid soluble and redistribution is slow Mainly used as anticonvulsant, antianxiety and preanaesthetic medication Less irritant, hence thrombophlebitis is rare on i.v. administration Alprazolam Oral, 0.5–2 mg Useful in insomnia Produces active metabolite Has antianxiety and antidepressant effects Temazepam Oral, 7.5–30 mg No active metabolite Mainly used for insomnia Triazolam Oral, 0.125– 0.25 mg Has rapid onset of action; short acting Mainly used for insomnia – reduces sleep latency Midazolam i.v., i.m., 1–2.5 mg (i.v.) Has rapid onset of action; short acting Used as preanaesthetic medication, i.v. general anaesthesia when combined with other CNS depressant, in status epilepticus when not responding to other drugs Chlordiazepoxide Oral, i.m., i.v., 50–100 mg Slow oral absorption Produces active metabolite; long acting Used in alcohol withdrawal and anxiety Important points PHARMACOLOGY FOR MEDICAL GRADUATES 170 BZD agonists BZDR Flumazenil (antagonist) BZD inverse agonists Fig. 5.4 Competitive antagonism. BZDR, Benzodiazepine receptor. effects include confusion, dizziness and nausea. It may precipitate withdrawal symptoms (anxiety and convulsions) in dependent subjects. Barbiturates PH1.19 All barbiturates are derivatives of barbituric acid. They are nonselective CNS depressants and act at many sites, ascending reticular activating system (ARAS) being the main site. Mechanism of Action Barbiturates have GABA facilitatory action – they potentiate inhibitory effects of GABA. Barbiturates Bind to GABAA receptor (different from BZD-binding site) The duration of Cl− channel kept open is increased Increase in GABA-mediated chloride current Membrane hyperpolarization CNS depression At high concentrations, barbiturates have GABA-mimetic effect (i.e. barbiturates can directly increase Cl# conductance into the neuron). Pharmacological Actions and Uses 1. Sedation and hypnosis: Barbiturates were used in the treatment of insomnia. They decrease sleep latency, duration of REM sleep, stage 3 and 4 of NREM sleep. They cause marked alteration of sleep architecture. At present, barbiturates are not recommended because: They have a low therapeutic index. They cause rebound increase in REM sleep on stoppage of therapy. 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 171 They cause marked respiratory depression. They produce marked hangover effects (headache and drowsiness next day morning). They cause high degree of tolerance and drug dependence. They are potent enzyme inducers and cause many drug interactions. They have no specific antidote. 2. General anaesthesia (GA): Ultrashort-acting barbiturates (thiopentone and methohexitone) may be used for induction of GA. 3. Anticonvulsant: Phenobarbitone has anticonvulsant effect and is used in the treatment of status epilepticus and generalized tonic–clonic seizures (GTCS, grand mal epilepsy). 4. Neonatal jaundice of nonhaemolytic type: Phenobarbitone may be used to reduce serum bilirubin levels. It induces glucuronyl transferase enzyme and hastens the metabolism of bilirubin. Adverse Effects 1. The common side effects are drowsiness, confusion, headache, ataxia, hypotension and respiratory depression. 2. Hypersensitivity reactions like skin rashes, itching and swelling of face may occur. 3. Tolerance develops to their sedative and hypnotic actions on repeated use. 4. Physical and psychological dependence develops on repeated use. 5. Prolonged use of phenobarbitone may cause megaloblastic anaemia by interfering with absorption of folic acid from gut. 6. They may precipitate attacks of acute intermittent porphyria by inducing ALA synthase that catalyses the production of porphyrins; hence, barbiturates are contraindicated in porphyria. 7. Acute barbiturate poisoning: The signs and symptoms are drowsiness, restlessness, hallucinations, hypotension, respiratory depression, convulsions, coma and death. Treatment of acute barbiturate poisoning Maintain airway, breathing and circulation. Maintain electrolyte balance. Gastric lavage – after stomach wash, administer activated charcoal that may enhance the elimination of phenobarbitone. Endotracheal intubation is performed before gastric lavage to protect the airway in unconscious patients. Alkaline diuresis – there is no specific antidote for barbiturates; main treatment is alkaline diuresis. i.v. NaHCO3 alkalinizes urine. Barbiturates are weakly acidic drugs. In alkaline urine, barbiturates exist in ionized form, so they are not reabsorbed while passing through renal tubules and are rapidly excreted in urine. Haemodialysis is employed in severe cases. Drug Interactions Barbiturates are potent inducers of hepatic microsomal enzymes and reduce the effectiveness of co-administered drugs (e.g. oral contraceptives [OCs], oral anticoagulants and oral hypoglycaemics). PHARMACOLOGY FOR MEDICAL GRADUATES 172 Nonbenzodiazepine Hypnotics PH1.19 They include zolpidem, zopiclone, zaleplon, eszopiclone and etizolam. They have less potential for abuse than BZDs. They have less antianxiety, anticonvulsant and muscle relaxant effects than BZDs. Effect on REM sleep is less as compared to BZDs. ZOLPIDEM Zolpidem mainly produces hypnotic effect – decreases sleep latency and increases duration of sleep time in insomnia. It produces near-normal sleep like BZDs with minimal alteration in REM sleep; causes minimal hangover effects and rebound insomnia; less likely to produce tolerance and drug dependence; lacks anticonvulsant, antianxiety and muscle relaxant effects. It is given orally, well absorbed, metabolized in liver and excreted in urine. It has a short duration of action and is used for short-term treatment of insomnia. The actions of zolpidem are antagonized by flumazenil. The common side effects are headache, confusion, nausea and vomiting. Mechanism of Action Zolpidem, zopiclone, zaleplon, eszopiclone (nonbenzodiazepine hypnotics) Bind selectively to BZD binding site on GABAA receptor Facilitate GABA-mediated neuronal inhibition CNS depression ZOPICLONE It is orally effective and is used for short-term treatment of insomnia. It produces nearnormal sleep like BZDs. The side effects are headache, drowsiness, GI disturbances and metallic taste. ZALEPLON It is useful in sleep onset insomnia. It is the shortest acting non-BZD hypnotic. ESZOPICLONE It is used orally for short- and long-term treatment of insomnia. ETIZOLAM It is a BZD analogue with hypnotic, anticonvulsant, muscle relaxant and antianxiety effects. It is useful for short-term treatment of insomnia. 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 173 MELATONIN It is the hormone secreted by the pineal gland; involved in the maintenance of sleep– wake cycle and circadian rhythm. RAMELTEON It is a melatonin-receptor (MT1 and MT2) agonist, can be used orally for the treatment of sleep onset insomnia. It reduces sleep latency and prolongs total duration of sleep. There is no rebound insomnia on withdrawal; does not cause tolerance on chronic use. The important adverse effects are fatigue and dizziness. TASIMELTEON It is another melatonin-receptor agonist used for the treatment of circadian rhythm disorder in blind patients. SUVOREXANT It prevents orexin from maintaining wakefulness by blocking orexin receptors. It is useful in chronic insomnia. General Anaesthetics PH1.18 GA refers to drug-induced reversible loss of consciousness and all sensations. The features of GA are as follows: 1. Reversible loss of consciousness. 2. Reversible loss of sensation. 3. Analgesia and amnesia. 4. Muscle relaxation and abolition of reflexes. There is no single anaesthetic agent that can produce all the above effects. Hence, anaesthetic protocol includes: 1. Premedication. 2. Induction of anaesthesia (e.g. propofol). 3. Maintenance of anaesthesia (e.g. N2O " isoflurane). 4. Skeletal muscle relaxation. 5. Analgesia – as premedication, during and after the operation. 6. Use of other drugs: To reverse neuromuscular blockade. To reverse the residual effects of opioids (naloxone) and BZDs (flumazenil). Minimal alveolar concentration (MAC) is the minimum concentration of an anaesthetic in alveoli required to produce immobility in response to a painful stimulus in 50% patients. It indicates the potency of inhalational general anaesthetics (N2O % 100%, halothane 0.75%). MECHANISM OF ACTION OF GENERAL ANAESTHETICS The main site of action of anaesthetics is reticular formation, which normally maintains a state of consciousness. Most anaesthetics decrease transmission in reticular formation by enhancing the activity of inhibitory transmitters like GABA (e.g. BZDs, barbiturates PHARMACOLOGY FOR MEDICAL GRADUATES 174 Stages of anaesthesia Table 5.3 I. Stage of analgesia II. Stage of excitement III. Stage of surgical anaesthesia The patient is conscious but drowsy Patient loses consciousness Sympathetic activity is increased h Heart rate (HR), h blood pressure (BP), pupils are dilated; muscle tone is increased; breathing is irregular Respiration becomes regular Muscles relax Reflexes are gradually lost Intercostal muscles are paralysed Pupils dilated and eyeballs are fixed IV. Stage of medullary paralysis Respiration and vasomotor centre are depressed; death occurs within a few minutes and propofol) and blocking the activity of excitatory transmitters (e.g. blockade of N-methyl-D-aspartate [NMDA] glutamate receptors by ketamine and nitrous oxide). Stages of GA (Table 5.3): Stages I–IV are seen mainly with ether because of its slow action. Stage II is the most dangerous period. Surgical procedures are performed in stage III. The aim of induction is to reach stage III as early as possible followed by maintenance anaesthesia and muscle relaxation. CLASSIFICATION General anaesthetics Parenteral Inhalational Volatile liquids Halothane Isoflurane Desflurane Sevoflurane Ether Gas Nitrous oxide Inducing drugs Propofol Etomidate Thiopentone Methohexitone Slow-acting drugs Benzodiazepines: Diazepam, lorazepam, midazolam Ketamine Opioids: Fentanyl, alfentanil, sufentanil, remifentanil INHALATIONAL ANAESTHETICS These are discussed under the following headings (Tables 5.4 and 5.5). 1. Gas/volatile liquid 2. Noninflammable/inflammable 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM Table 5.4 175 Comparative features of ether, halothane and nitrous oxide Ether Halothane Nitrous oxide Volatile liquid Volatile liquid Gaseous general anaesthetic Induction and recovery are slow because of its high solubility in blood Induction and recovery are faster than ether Induction and recovery are rapid because of low blood solubility Irritant, inflammable and highly explosive Nonirritant, noninflammable, not pungent, well tolerated – preferred for induction and maintenance in children Nonirritant and noninflammable Has wide margin of safety Margin of safety is not wide Very wide margin of safety Potent anaesthetic, MAC: 1.9% Potent anaesthetic, MAC: 0.75% Poor anaesthetic, MAC: %100% Excellent analgesia Poor analgesia Excellent analgesia Has curarimimetic effect on skeletal muscles, so the dose of d-tubocurarine (d-TC) required is less Muscular relaxation is inadequate but potentiates the action of d-TC Poor skeletal muscle relaxant Does not sensitize the heart to catecholamines Sensitizes the myocardium to catecholamines and may precipitate arrhythmias Has little effect on heart, respiration and BP Cheap Expensive Cheap Irritant anaesthetic, increases salivary, respiratory secretions – may induce cough and laryngeal spasm; therefore, preanaesthetic atropine is used to overcome these effects Causes bronchodilatation – preferred in asthmatics – Postoperative nausea and vomiting are common Nausea and vomiting rare – No hepatotoxicity Hepatotoxicity: especially if used repeatedly (halothane hepatitis) – Other points: On exposure to light, it forms ether peroxide which is an irritant; to avoid this, ether is supplied in amber-coloured bottles covered with black paper Ether is inflammable and highly explosive; hence, electric cautery cannot be used Adverse effects: (Note ‘H’s) Hypotension: It has direct depressant effect on the myocardium and causes hypotension Respiratory depression Both Hepatotoxicity and malignant Hyperthermia are rare Heart: Halothane sensitizes the myocardium to adrenaline and can cause arrhythmias Second gas effect and diffusion hypoxia occur with N2O only May increase intracranial tension PHARMACOLOGY FOR MEDICAL GRADUATES 176 Table 5.5 Comparative features of halogenated anaesthetics (fluorinated anaesthetics) Halothane Isoflurane Desflurane Sevoflurane Volatile liquid Volatile liquid Volatile liquid Volatile liquid Noninflammable and nonexplosive Noninflammable and nonexplosive Noninflammable and nonexplosive Noninflammable and nonexplosive Induction and recovery are slow MAC: 0.75% Induction and recovery are rapid than halothane MAC: 1.4% Induction and recovery are rapid MAC: 6% Induction and recovery are rapid MAC: 2% Hypotension " Hypotension " Hypotension " Hypotension " Sensitizes the heart to catecholamines and may cause cardiac arrhythmias – – – Respiratory depression " Respiratory depression " Respiratory depression " Respiratory depression " Poor muscle relaxant Skeletal muscle relaxation " Skeletal muscle relaxation " Skeletal muscle relaxation " Nonirritant to respiratory passages, causes bronchodilatation and is preferred in asthmatics Causes bronchodilatation; irritates air passages Causes bronchodilatation; irritates air passages Does not irritate airways and is a potent bronchodilator Hepatotoxicity on repeated use No hepatotoxicity No hepatotoxicity No hepatotoxicity Not pungent, well tolerated – preferred for induction and maintenance in children Commonly used for maintenance of anaesthesia Pungent odour – hence not commonly used for induction Does not cause seizures Can be used for neurosurgical procedures No renal toxicity Irritates airways – not used for induction Does not cause seizures No renal toxicity Can be used in outpatients because of rapid onset of action and rapid recovery Nonirritant to airways, not pungent – can be used for induction Suitable for induction and maintenance of anaesthesia in children Can be used even in outpatients because of rapid recovery Interacts with soda lime – should not be used in closed circuit system Note: Halogenated anaesthetics: The newer agents like isoflurane, desflurane and sevoflurane are expensive. ", Present; –, absent. 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 3. 4. 5. 6. 7. 8. 9. 10. 11. 177 Margin of safety Induction and recovery Skeletal muscle relaxation Analgesia Sensitization of myocardium Hepatotoxicity Irritation of respiratory passages Postoperative nausea and vomiting Other points Use of ether is obsolete. Halothane sensitizes the myocardium to the arrhythmogenic effect of catecholamines. Speed of induction and recovery depends on solubility of anaesthetic agent in blood and fat. Anaesthetics with low blood solubility produce rapid induction and recovery (e.g. N2O and desflurane). Anaesthetics with high solubility in blood produce slow induction and recovery (e.g. ether). Desflurane, isoflurane and ether irritate respiratory passages and can induce cough. The basis for combining halothane/isoflurane and nitrous oxide: (a) The concentration (MAC) of halothane/isoflurane required to produce anaesthesia is reduced when given with N2O because of second gas effect. As the concentration of halothane/isoflurane required is reduced, the side effects of halothane/isoflurane (hypotension and respiratory depression) are reduced. Second gas effect: N2O rapidly diffuses, whereas halothane/isoflurane diffuses poorly into the blood (alveoli ↔blood ↔brain). When these (halothane/ isoflurane and N2O) anaesthetics are administered simultaneously, halothane/isoflurane also enters the blood rapidly along with rapidly diffusible gas (N2O). This is known as ‘second gas effect’. (b) Because of reduction in the dosage, recovery will be faster. (c) Halothane/isoflurane is a potent anaesthetic and poor analgesic, whereas N2O is a good analgesic and poor anaesthetic; hence, the combined effect of these two drugs results in potent anaesthesia and good analgesia. Diffusion Hypoxia. Nitrous oxide has low blood solubility – when the administration of N2O is discontinued, it rapidly diffuses from the blood into alveoli and causes marked reduction of PaO2 in the alveoli resulting in hypoxia which is known as diffusion hypoxia. It can be avoided by giving 100% O2 for a few minutes immediately after N2O is discontinued. Comparative features of halogenated anaesthetics are given in Table 5.5. PARENTERAL GENERAL ANAESTHETICS Inducing Drugs Propofol. It is available as 1% emulsion for i.v. administration. Propofol is a commonly used, popular, rapidly acting anaesthetic. Propofol acts on GABA receptors to increase chloride conductance and hyperpolarization of neurons, thus produces CNS depression. It has a rapid onset and short duration of action; for long procedures – it can be given in repeated doses or as continuous PHARMACOLOGY FOR MEDICAL GRADUATES 178 i.v. infusion. It is highly bound to plasma protein; crosses placental barrier and can be used in pregnant woman. It is metabolized in liver and excreted rapidly in urine. 1. Induction of anaesthesia and recovery are rapid. Residual symptoms are less. 2. Most suitable for outpatient surgical procedures. 3. No irritation of air passages; suitable for use in asthmatics. 4. Has antiemetic effect; hence, postoperative nausea and vomiting are rare. 5. Can be used for both induction and maintenance of anaesthesia. 6. Frequently used to sedate patients in ICU (intensive care unit) who are intubated. 7. It is used in status epilepticus when not controlled by other drugs. 8. Causes respiratory depression and fall in BP. 9. Pain on injection occurs – can be reduced with lignocaine. 10. In high doses, can cause acidosis and rise in blood lipid levels. Note: Propofol – Popular, Rapid acting, preferred for OP surgical procedures, causes FOL (fall) in BP. Thiopentone Sodium (Fig. 5.5). It is an ultra short-acting barbiturate. It is a commonly used i.v. anaesthetic for induction of anaesthesia. It is highly lipid soluble, hence has a rapid onset and short duration (5–8 minutes) of action. It is highly alkaline (pH 10.5–11), hence highly irritant. It should be prepared as a fresh solution before injection. It is injected as 2.5% solution. After a single i.v. dose, it rapidly enters highly perfused organs like brain, liver and heart, and produces anaesthesia. As blood level of the drug falls rapidly, it diffuses out of the central nervous system into the blood and then to less perfused organs like skeletal muscle and adipose tissue. This redistribution results in termination of drug action. Repeated doses will result in accumulation and delayed recovery. Uses 1. Thiopentone sodium is used for induction of anaesthesia. 2. It is occasionally used as anticonvulsant in cases not controlled by other drugs. 3. In subanaesthetic doses, thiopentone can be used for narcoanalysis in psychiatry. Advantages of Thiopentone 1. Rapid induction of anaesthesia and rapid recovery. 2. Does not sensitize the myocardium to circulating catecholamines. CNS T BBB i.v. thiopentone Blood Skeletal muscle Adipose tissue Fig. 5.5 Redistribution of thiopentone. CNS, Central nervous system; BBB, blood–brain barrier; T, thiopentone; !, inhibition. 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 179 Disadvantages/Adverse Effects of Thiopentone 1. 2. 3. 4. 5. 6. 7. Depresses the respiratory centre. Depresses the vasomotor centre and myocardium. Poor analgesic. Poor muscle relaxant. Causes laryngospasm. Accidental intra-arterial injection causes vasospasm and gangrene of the arm. It can precipitate acute intermittent porphyria by inducing the synthesis of ALA synthase, hence contraindicated in susceptible individuals (absolute contraindication). Etomidate. It is an i.v. anaesthetic used for induction – has a rapid onset and short du- ration of action. It causes minimal cardiovascular and respiratory depression. Disadvantages/Adverse Effects 1. Has poor analgesic effect. 2. High incidence of pain on injection, postoperative nausea and vomiting. 3. Restlessness and rigidity are common. Slow-Acting Drugs Ketamine. It produces ‘dissociative anaesthesia’, which is characterized by sedation, amne- sia, marked analgesia, unresponsiveness to commands and dissociation from the surroundings. It acts by blocking NMDA type of glutamate receptors. It is commonly given by i.v. route; other routes are i.m., oral and rectal. Ketamine has good analgesic effect. It causes bronchodilatation, suitable for use in asthmatics. Ketamine causes sympathetic stimulation – heart rate, BP, cardiac output and skeletal muscle tone are usually increased. It is used in patients with hypovolaemia. It is well tolerated by children. Site of action: cortex and subcortical areas. Ketamine is highly lipid soluble, rapidly enters highly perfused organs like brain, liver and heart; later, it redistributes to less perfused organs. It is metabolized in liver; excreted in urine and bile. Uses 1. For operations on the head, neck and face. 2. For dressing burn wounds. 3. Well suited for children/asthmatics undergoing short procedures. Adverse Effects and Contraindications 1. Increases BP and heart rate, hence is contraindicated in patients with hypertension and ischaemic heart disease. 2. Increases intracranial pressure. 3. Causes emergence delirium and hallucinations. Benzodiazepines. BZDs are slow-acting parenteral anaesthetics. They include diazepam, lorazepam and midazolam. Use of large doses delays recovery and prolongs amnesia. They have poor analgesic effect. They do not cause postoperative nausea and vomiting. The effects of BZDs can be reversed by flumazenil. They are useful for angiography, endoscopies, fracture reduction, etc. Opioid Analgesics. They include fentanyl, alfentanil, sufentanil and remifentanil. They are potent analgesics and can be used along with anaesthetics – to decrease the PHARMACOLOGY FOR MEDICAL GRADUATES 180 requirement of anaesthetic. Alfentanil, sufentanil and remifentanil are shorter acting than fentanyl. Dexmedetomidine Central &2-agonist n Sedation and analgesia. Causes minimal respiratory depression. Used intravenously to sedate critically ill patients. Common adverse effects are hypotension and bradycardia due to decreased central sympathetic outflow. COMPLICATIONS OF GENERAL ANAESTHESIA CVS: Hypotension, cardiac arrhythmias, cardiac arrest Respiratory depression, aspiration pneumonia, apnoea CNS: Convulsions, persistent sedation GIT: Nausea, vomiting, hepatotoxicity Nephrotoxicity Malignant hyperthermia PREANAESTHETIC MEDICATION PH1.18 It is the use of drugs before administration of anaesthetics to make anaesthesia more pleasant and safe. Objectives/Aims of Premedication 1. To reduce anxiety and apprehension: BZDs like diazepam, lorazepam or midazolam are preferred because of their sedative, amnesic, calming, anxiolytic effects and wide margin of safety. They reduce anxiety by acting on limbic system. 2. To prevent vagal bradycardia and to reduce salivary secretion caused by anaesthetics: Antimuscarinic agents such as atropine or glycopyrrolate are used to prevent vagal bradycardia and hypotension. They also prevent laryngospasm by reducing respiratory secretion. Glycopyrrolate is preferred because it is potent, does not produce CNS effects and causes less tachycardia. 3. To relieve pre- and postoperative pain: Opioid analgesics such as morphine, pethidine or fentanyl may be used to relieve pain. The limitations with opioids are respiratory depression, hypotension, nausea, vomiting, constipation, biliary spasm and bronchospasm in asthmatics. NSAIDs like diclofenac can also be used. 4. For antiemetic effect: Metoclopramide, domperidone or ondansetron may be used to control vomiting. Acute dystonias and extrapyramidal symptoms (EPS) are the main side effects of metoclopramide; domperidone rarely produces EPS. 5-HT3 antagonist like ondansetron is the preferred antiemetic as it rarely causes adverse effects and is well tolerated. 5. To prevent acid secretion and stress ulcer: H2-blocker such as ranitidine or proton-pump inhibitor like omeprazole may be used to reduce gastric acid secretion and aspiration pneumonia especially before prolonged surgery. 6. To hasten gastric emptying before emergency surgery: Metoclopramide or domperidone may be used. They are prokinetic drugs – increase the tone of lower oesophageal sphincter and accelerate gastric emptying, thus prevent aspiration pneumonia. 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 181 CONSCIOUS SEDATION It is a level of CNS depression where a patient does not lose consciousness but is able to communicate and cooperate during the procedure/treatment. It is used in: 1. Uncooperative patients. 2. Anxious patients. 3. Emotionally compromised patients. It should be avoided in chronic obstructive pulmonary disease (COPD), pregnancy, prolonged surgery, psychoses, etc. The drugs used are BZDs such as diazepam (oral, i.v.), midazolam (i.v.) and temazepam (oral); nitrous oxide " oxygen (inhalation); propofol (i.v. infusion) and fentanyl (i.v.). Local Anaesthetics PH1.17 Local anaesthetics (LAs) are drugs which, when applied topically or injected locally, block nerve conduction and cause reversible loss of all sensation in the part supplied by the nerve. The order of blockade of nerve function proceeds in the following manner – pain, temperature, touch, pressure and finally skeletal muscle power. CHEMISTRY (Fig. 5.6) LAs are weak bases. They consist of three parts: (i) hydrophilic amino group; (ii) lipophilic aromatic group; and (iii) intermediate ester or amide linkage. CLASSIFICATION OF LOCAL ANAESTHETICS 1. According to clinical use (a) Surface anaesthetics: Cocaine, lignocaine, tetracaine, benzocaine, oxethazaine, proparacaine, butylaminobenzoate. (b) Injectable anaesthetics (i) Short acting with low potency: Procaine, chloroprocaine. (ii) Intermediate acting with intermediate potency: Lignocaine, mepivacaine, prilocaine, articaine. (iii) Long acting with high potency: Tetracaine, bupivacaine, dibucaine, ropivacaine. 2. According to structure (a) Esters*: Cocaine, procaine, chloroprocaine, benzocaine, tetracaine. (b) Amides*: Lignocaine, mepivacaine, bupivacaine, prilocaine, articaine, ropivacaine. Ester or amide linkage Lipophilic (aromatic group) H N H Hydrophilic (amino group) Fig. 5.6 Basic structure of local anaesthetics. *Note: Esters have one ‘i’; amides have two ‘i’ (i, i). PHARMACOLOGY FOR MEDICAL GRADUATES 182 MECHANISM OF ACTION LAs act on voltage-sensitive Na! channels. Sodium channels exist in resting, open and inactivated states (resting n open n inactivated state). The channels have to recover from the inactivated state to resting state before they can be opened in response to an impulse. The LAs in ‘unionized’ form easily penetrate nerve sheath and axon membrane. Within the axoplasm, the molecules become ‘ionized’ and block the voltage-gated Na! channels. Local anaesthetics are weak bases At tissue pH (7.4) Partly unionized Partly ionized Penetrate the nerve membrane Enter the axon (axonal pH is low) Reionization of local anaesthetics LA gains access to its receptor in the open state of the channel LAs block the voltage-gated Na+ channel from inside; binds more tightly to inactivated state, prolongs the inactivated state Prevent entry of Na + ions into the neuron – decreasing the rate of depolarization Prevent generation of action potential No generation and conduction of impulses to CNS Local anaesthesia Blockade is frequency dependent. Action of LA is pH dependent and the penetrability of LA is increased at alkaline pH (i.e. when the unionized form is more). Penetrability is very poor at acidic pH of tissues. In infected tissues, there is a low pH, which causes ionization of the drug. This reduces penetration of LA through the cell membrane, thus decreases the effectiveness of LAs. Therefore, LAs are less effective in inflamed and infected areas. Diameter of nerve fibres: LAs block small fibres first followed by larger fibres. Myelinated fibres are blocked earlier than nonmyelinated nerves of the same diameter. Sensory fibres are blocked earlier than motor fibres because of their high firing rate and longer duration of action potential. 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 183 Fibres in the centre are blocked later than the ones located in the circumference of the nerve bundle. FACTORS AFFECTING LOCAL ANAESTHETIC ACTION 1. pKa: Higher the pKa, more is the ionized fraction of the drug at physiological pH. Hence, onset of action is slow and vice versa, e.g. the pKa of procaine is 9.1. So, it has slow onset of action; whereas pKa of lignocaine is 7.7 – it has rapid onset of action. Although pKa of chloroprocaine is 9.1, it has a rapid onset of action. 2. Degree of plasma protein binding: Higher the plasma protein binding, longer the duration of action of the drug, e.g. procaine is poorly bound to plasma proteins, hence has a short duration of action, whereas bupivacaine is highly plasma protein bound and has longer duration of action. 3. Rate of diffusion from the site of administration: It depends on the initial concentration gradient of the drug. Higher the concentration, rapid is the onset of action. 4. Lipid solubility: Higher the lipid solubility, more is the potency of the drug, e.g. lignocaine is more potent than procaine as it is more lipid soluble. 5. Presence of vasoconstrictor: Prolongs the duration of action of LAs. The commonly used vasoconstrictor with LAs is adrenaline. COMBINATION OF VASOCONSTRICTOR WITH LOCAL ANAESTHETIC Addition of a vasoconstrictor (e.g. adrenaline) to the LA has the following advantages: 1. Slow absorption from the local site which results in prolonged duration of action of LAs. 2. Decreased bleeding in the surgical field. 3. Slow absorption of LA reduces its systemic toxicity. Disadvantages and contraindications of combining vasoconstrictor with LA: 1. Intense vasospasm and ischaemia in tissues with end arteries may cause gangrene of the part (e.g. fingers, toes, penis, ear lobule and tip of the nose). Hence, use of vasoconstrictors is contraindicated in these sites. 2. Absorption of adrenaline can cause systemic toxicity – tachycardia, palpitation, rise of BP and precipitation of angina or cardiac arrhythmias. Hence, combined preparation (LA with adrenaline) should be avoided in patients with hypertension, congestive cardiac failure (CCF), arrhythmias, ischaemic heart disease and uncontrolled hyperthyroidism. 3. May delay wound healing by reducing the blood flow to the affected area. PHARMACOLOGICAL ACTIONS 1. Nervous system (a) Peripheral nerves: Autonomic fibres are blocked earlier than somatic fibres. Sensation of pain disappears first followed by temperature, touch, pressure and motor functions. (b) CNS: Most of the LAs cross the blood–brain barrier (BBB) – initially they cause CNS stimulation and then depression in higher doses. They cause excitement, tremor, twitching, restlessness and convulsions. Large doses can cause respiratory depression, coma and death. PHARMACOLOGY FOR MEDICAL GRADUATES 184 2. Cardiovascular system (a) Heart: LAs, by blocking Na! channels, decrease abnormal pacemaker activity, contractility, conductivity, excitability, heart rate, cardiac output and increase effective refractory period. (i) At higher concentrations, i.v. administration of LAs may precipitate cardiac arrhythmias. (ii) Bupivacaine is more cardiotoxic than other LAs – may cause cardiovascular collapse and death. (iii) Lignocaine decreases automaticity and is useful in ventricular arrhythmias. (b) Blood vessels: LAs produce hypotension due to vasodilatation and myocardial depression. PHARMACOKINETICS Most of the ester-linked LAs are rapidly metabolized by plasma cholinesterase, whereas amide-linked drugs are metabolized mainly in liver. LAs (procaine, lignocaine, etc.) are not effective orally because of high first-pass metabolism. In liver diseases, the metabolism of lignocaine may be impaired; hence, dose must be reduced accordingly. Comparative features of esters and amides are shown in Table 5.6. ADVERSE EFFECTS 1. CNS: LAs initially cause CNS stimulation followed by depression. They are restlessness, tremor, headache, drowsiness, confusion, convulsions followed by respiratory depression, coma and death. 2. CVS: Bradycardia, hypotension, cardiac arrhythmias and rarely cardiovascular collapse and death. Bupivacaine is highly cardiotoxic. 3. Allergic reactions: These are skin rashes, itching, erythema, urticaria, wheezing, bronchospasm and rarely anaphylactic reaction. The incidence of allergic reactions is more with ester-linked LAs than with amide-linked LAs. 4. Mucosal irritation (cocaine) and methaemoglobinaemia (prilocaine) may be seen. 5. Methylparaben, preservative in LA preparation, may cause allergic reaction. Important properties of LAs are given in Table 5.7. 6. Adverse effects due to the use of vasoconstrictor (see p. 183) Table 5.6 Comparative features of procaine and lignocaine Procaine Lignocaine Ester type of LA Amide type of LA Short acting Intermediate acting Has poor tissue penetrability, hence no surface anaesthetic effect Has good tissue penetrability Has slow onset of action Has rapid onset of action Is metabolized by plasma cholinesterase Is metabolized by hepatic microsomal enzymes Allergic reactions are common with esters Allergic reactions are rare Useful for infiltration and nerve block anaesthesia; at present, it is rarely used Widely used for all types of anaesthesia – spinal, epidural, i.v. regional block, nerve block, infiltration and surface anaesthesia Properties of local anaesthetics Drug Group Duration of action (minutes) Potency Onset Tissue penetrability Other points Procaine Ester 15–30 (short) Low Slow Poor No surface anaesthesia Chloroprocaine Ester 15–30 (short) Low Rapid – – Tetracaine Ester 120–240 (long) High Very slow Moderate Widely used in spinal and corneal anaesthesia High systemic toxicity because of slow metabolism Cocaine Ester – – Intermediate Good Inhibits the reuptake of NA in both central and peripheral nerves Causes tachycardia, rise in BP, mydriasis and euphoria Rarely used Lignocaine Amide 30–60 (intermediate) Intermediate Rapid Good Most widely used local anaesthetic; also used in ventricular arrhythmias Mepivacaine Amide 45–90 (intermediate) Intermediate Intermediate – No surface anaesthesia Bupivacaine Amide 120–240 (long) High Intermediate Moderate Highly cardiotoxic, widely used for spinal, epidural, infiltration and nerve block – because of long duration of action; low concentration used for epidural analgesia during labour Ropivacaine Amide 120–360 (long) Intermediate Intermediate Moderate Similar to bupivacaine, less cardiotoxic Prilocaine Amide Intermediate – Intermediate Moderate Widely used; can cause methaemoglobinaemia Dibucaine Amide 180-600 (long) High Slow Good Useful as topical anaesthetic for anal mucous membrane Articaine Amide 60 – Rapid – Used for infiltration and nerve block anaesthesia; can cause methaemoglobinaemia, paraesthesia and neuropathy 185 Note: NA, noradrenaline. 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM Table 5.7 186 PHARMACOLOGY FOR MEDICAL GRADUATES Procaine (see Table 5.6). It is a prototype drug for esters. It is rarely used now because of availability of better agents. Cocaine. It is an alkaloid; excellent surface anaesthetic but rarely used because of its addiction liability. Chloroprocaine has a pKa of 9.1, but has rapid onset of action. Tetracaine. An ester type of LA, it has long duration but slow onset of action. It is useful for spinal anaesthesia because of its long duration of action. It is mainly used as a surface anaesthetic for eye, nose and upper respiratory tract. Lignocaine. It is a prototype agent for amides. It is a very popular anaesthetic used widely for topical application, infiltration, spinal and conduction block anaesthesia. It is also available as a patch – can be used to control severe pain of postherpetic neuralgias. Bupivacaine. It is a widely used LA. It is potent and has a long duration of action. It produces more sensory than motor blockade, hence very popular for obstetric analgesia. It is highly cardiotoxic and may precipitate ventricular arrhythmias. Levobupivacaine: It is similar to bupivacaine; but less cardiotoxic and less likely to cause seizures. Ropivacaine. It is less potent and less cardiotoxic than bupivacaine. Its duration of ac- tion is similar to bupivacaine. It is used for both epidural and regional anaesthesia. It is more selective for sensory fibres than motor fibres, hence used in obstetric analgesia. Prilocaine. It is an amide type of LA. It has intermediate onset and duration of action. It has poor vasodilatory effect, hence can be used without a vasoconstrictor. Prilocaine is not suitable for labour pain because of the risk of neonatal methaemoglobinaemia. It is mainly used for infiltration and i.v. regional anaesthesia. Eutectic Mixture (EMLA – Eutectic Mixture of Local Anaesthetics – Lignocaine [2.5%] and Prilocaine [2.5%]). The melting point of the mixture is less than that of either com- pound alone. It can anaesthetize intact skin. EMLA has to be applied 1 hour before the procedure and is used for dermal anaesthesia during venesection and skin graft procedures. It should not be used on mucous membranes or abraded skin. It is contraindicated in patients with methaemoglobinaemia and infants. Dibucaine. It is a very potent, highly toxic and the longest acting LA. It is rarely used for spinal anaesthesia, and is also available for topical application on mucous membrane and skin. Benoxinate. It is a surface anaesthetic; useful for corneal anaesthesia. Benzocaine and Butylaminobenzoate. Surface anaesthetics; cause minimal systemic toxicity; available as ointment and lozenges; used for haemorrhoids, anal fissure and sore throat. Oxethazaine. It is a topical anaesthetic and is used to anaesthetize gastric mucosa. It produces symptomatic relief in gastritis. It is available in combination with antacids. 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 187 TECHNIQUES OF LOCAL ANAESTHESIA (Table 5.8) Surface Anaesthesia (Topical Anaesthesia) LA is applied on the abraded skin and mucous membrane of the nose, mouth, eyes, throat, upper respiratory tract, oesophagus, urethra, ulcers, burns, fissures, etc. Motor function is intact. Tetracaine 2%, lignocaine 2%–10%, benzocaine 1%–2%, etc. are used for topical application. Surface anaesthetics are available as solution, ointment, gel, jelly, cream, spray, lozenges, etc. Addition of adrenaline does not prolong the duration of surface anaesthesia because of poor penetration. Topical anaesthetics are useful in many diagnostic procedures like tonometry in eye and during endoscopies. EMLA is used to anaesthetize the intact skin and structures in the superficial subcutaneous tissues. Infiltration Anaesthesia LA is injected directly into tissues to be operated; it blocks sensory nerve endings. The most frequently used LAs for infiltration are lignocaine (0.5%–1%), procaine (0.5%– 1%) and bupivacaine (0.125%–0.25%). Addition of adrenaline to LA (1:50,000–250,000) prolongs the duration of anaesthesia. Infiltration anaesthesia is suitable only for small areas. The main disadvantage of infiltration anaesthesia is the requirement of large amounts of the drug to anaesthetize relatively small area. It can be used for drainage of an abscess, excision of small swelling, Table 5.8 Methods of administration and uses of local anaesthetics Therapeutic application (uses) LA technique Drugs Surface anaesthesia (topical) Lignocaine (2%–10%) Tetracaine (2%) Benzocaine Anaesthetize mucous membrane of the eyes, nose, mouth, cornea, urinary and upper respiratory tracts, fissures, ulcers, etc. Infiltration anaesthesia Most of the anaesthetics Lignocaine (0.5%–1%) Procaine (0.5%–1%) Bupivacaine (0.125%–0.25%) Ropivacaine Abscess drainage Excision of small swellings (e.g. lipoma) Suturing of cut wounds, episiotomy, etc. Nerve block anaesthesia Most of the anaesthetics Used for surgery and neuralgias Spinal anaesthesia Lignocaine (1.5%–5%) Tetracaine (0.25%–0.5%) Bupivacaine (0.5%–0.75%) Surgery on lower limbs, lower abdomen, perineum, etc., caesarean section Epidural anaesthesia Lignocaine (2%) Bupivacaine (0.5%–0.75%) Ropivacaine Obstetric analgesia i.v. regional anaesthesia (Bier’s block) Lignocaine (0.5%) Prilocaine (0.5%) For upper and lower limb surgeries To anaesthetize gastric mucosa Oxethazaine Peptic ulcer 188 PHARMACOLOGY FOR MEDICAL GRADUATES suturing of cut wounds, episiotomy, etc. Infiltration anaesthesia is contraindicated, if there is local infection and clotting disorders. Conduction Block (i) Field Block Anaesthesia. It is achieved by injecting an LA subcutaneously, which anaesthetizes the area distal to the injection. This principle is used in case of minor procedures of scalp, anterior abdominal wall, upper and lower extremities in which a smaller dose produces larger area of anaesthesia. (ii) Nerve Block Anaesthesia. LA is injected very close to or around the peripheral nerve or nerve plexuses. It produces larger areas of anaesthesia than field block. 1. Brachial plexus block for procedures on upper limb. 2. Cervical plexus block for surgery of the neck. 3. Intercostal nerve block for anterior abdominal wall surgery. 4. Sciatic and femoral nerve block for surgery distal to the knee. In this procedure, the requirement of LA is less than that of field block and infiltration anaesthesia. Spinal Anaesthesia It is one of the most popular forms of anaesthesia. LA is injected into the subarachnoid space to anaesthetize spinal roots. Site of Injection. The anaesthetic is injected into the space between L2 and L3 or L3 and L4 below the lower end of the spinal cord. The level of anaesthesia is influenced by (i) site of injection, (ii) amount of fluid injected, (iii) force of injection, (iv) specific gravity of the drug solution (hyperbaric [in 10% glucose], hypobaric [in distilled water] or isobaric) and (v) position of the patient – lying prone/lateral or tilted with head-down position. LAs Used for Spinal Anaesthesia. They are lignocaine, tetracaine, bupivacaine, etc. Ad- dition of adrenaline to spinal anaesthetic increases the duration or intensity of block. Uses. Spinal anaesthesia can be used for surgical procedures below the level of umbili- cus, i.e. lower limb surgery, caesarean section, obstetric procedures, prostatectomy, surgery on perineum, appendicectomy, etc. Advantages of Spinal Anaesthesia. No loss of consciousness, good muscle relaxation and good analgesia. Patients with cardiac, pulmonary and renal disease tolerate spinal anaesthesia better than GA. Complications 1. Headache is due to leakage of CSF and can be reduced by using very fine needle. 2. Hypotension is due to blockade of sympathetic vasoconstrictor fibres to blood vessels. Venous return to the heart is reduced due to paralysis of skeletal muscles in the legs. Hypotension is treated by raising foot end and administration of sympathomimetics such as ephedrine, mephentermine and phenylephrine. 3. Respiratory paralysis: It is due to paralysis of intercostal muscles. Respiratory failure may occur due to respiratory centre ischaemia as a result of hypotension. 4. Septic meningitis and nerve injury are extremely rare at present, because of good anaesthetic practice. 5. Postoperative urinary retention may occur. Contraindications. Spinal anaesthesia should not be used in young children, vertebral abnormalities, sepsis in the region of lumbar puncture site, hypotension and shock. 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 189 Epidural Anaesthesia LA is injected into epidural space (thoracic or lumbar region or sacral canal) where it acts on spinal nerve roots. Lignocaine and bupivacaine are commonly used. It is safer, but the technique is more difficult than spinal anaesthesia. Epidural anaesthesia is slower in onset than spinal anaesthesia. It requires a much larger amount of the drug. Epidural analgesia is being used in obstetrics during labour. Low concentration of bupivacaine or ropivacaine is used to block pain sensation without significant motor block. Ropivacaine is less cardiotoxic and motor blockade is less than bupivacaine. Intravenous Regional Anaesthesia (Bier’s Block) It is mainly used in anaesthetizing the upper limb. Lignocaine and prilocaine are commonly used. LA is injected into vein of the limb in which the blood flow is occluded by a tourniquet. Drug Interactions 1. Lignocaine ! propranolol: Propranolol by reducing hepatic blood flow, impairs the clearance of lignocaine, which may result in toxicity. 2. Procaine ! sulphonamides: Procaine is hydrolysed to PABA – reduces the effect of sulphonamides. Alcohols (Ethanol and Methanol) PH1.20 The actions of alcohol are depicted in Fig. 5.7. Ethyl alcohol follows zero-order kinetics of elimination. In chronic alcoholics, increased amount of toxic metabolite of paracetamol is formed as a result of induction of its metabolizing enzyme, CYP2E1. As alcohol is present in exhaled air, it can be detected by breath analyser. Diuresis due to inhibition of ADH release Fatty degeneration Alcoholic hepatitis and cirrhosis Dose-dependent CNS depression Initially apparent stimulation and later depression Kidney Liver Respiratory centre Depression Ethanol CVS ↑Gastric acid secretion Gastritis Aggravation of peptic ulcer GIT Evaporates and cools the skin Increased sweating Fall in body temperature Locally Cutaneous vasodilation and flushing Large doses – myocardial and VMC depression CNS ↑Appetite Astringent Antiseptic Fig. 5.7 Actions of alcohol. CNS, Central nervous system; ADH, antidiuretic hormone; VMC, vasomotor centre (medulla); CVS, cardiovascular system; GIT, gastrointestinal tract. PHARMACOLOGY FOR MEDICAL GRADUATES 190 THERAPEUTIC USES OF ALCOHOL 1. Antiseptic: 70% ethyl alcohol is used as an antiseptic on skin before giving injection and surgical procedure. Its antiseptic efficacy decreases above 90%. It should not be used on open wounds, mucosa, ulcers and on scrotum as it is highly irritant. It is not useful for disinfecting instruments as it promotes rusting. 2. Trigeminal and other neuralgias: Injection of alcohol directly into nerve trunk relieves pain by destroying them. 3. Prevent bedsores: Alcohol is used locally to prevent bedsores in bedridden patients. 4. Methanol poisoning: Ethanol competes with methanol for metabolic enzymes and saturates them. Hence, it prevents the formation of toxic metabolites of methanol (formaldehyde and formic acid). 5. Fever: Alcoholic sponges are useful to reduce body temperature. Acute Ethanol Overdosage (Acute Alcohol Intoxication). The signs and symptoms of acute alcohol intoxication are drowsiness, nausea, vomiting, ataxia, hypotension, respiratory depression, hypoglycaemia, etc. Treatment (Note A–G). It is a medical emergency. The main aim of therapy is to prevent severe respiratory depression and aspiration of vomitus. 1. Maintain Airway, Breathing, Circulation, Fluid and Electrolyte balance, and Gastric lavage if necessary. 2. Intravenous glucose to correct hypoglycaemia. 3. Thiamine is administered as i.v. infusion in glucose solution. 4. HaemoDialysis helps to hasten the recovery. Withdrawal Syndrome. Sudden reduction/stoppage of alcohol in chronic alcoholics results in alcohol withdrawal syndrome. It manifests as restlessness, tremors, insomnia, nausea, vomiting, hallucinations, delirium, convulsions and collapse. Treatment of Alcohol Withdrawal Syndrome BZDs (diazepam, chlordiazepoxide, etc.) are used to control anxiety, tremor, palpitation, sleep disturbances, confusion and convulsions associated with alcohol withdrawal. Psychological support. PH1.23 Treatment of Chronic Alcoholism Psychotherapy, occupational therapy and rehabilitation Drug treatment of chronic alcoholism (a) Disulfiram (alcohol aversion therapy): It causes aversion to alcohol. Alcohol Alcohol dehydrogenase Acetaldehyde Aldehyde dehydrogenase Acetic acid Disulfiram Disulfiram inhibits aldehyde dehydrogenase and causes accumulation of acetaldehyde in blood and tissues (acetaldehyde syndrome). The signs and symptoms include nausea, vomiting, flushing, headache, sweating, tachycardia, palpitation, breathlessness, chest pain, hypotension, hypoglycaemia, confusion, shock and even death. This reaction is unpleasant; hence, person on disulfiram develops aversion to alcohol. 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM (b) (c) (d) (e) 191 Drugs like metronidazole, griseofulvin and cefoperazone also have disulfiramlike action and produce similar reaction with alcohol. Doctors should warn the patient not to take alcohol and alcohol-containing products when they are on above-mentioned drugs. Naltrexone (opioid antagonist): It reduces alcohol craving and helps to maintain abstinence. Acamprosate: It activates GABAA receptors and reduces relapse. Ondansetron (5-HT3 antagonist): It reduces alcohol consumption. Topiramate: It decreases craving for alcohol. METHANOL POISONING (METHYL ALCOHOL POISONING) PH1.21 This occurs when methylated spirit is consumed or when liquor is adulterated with methyl alcohol. Methanol is a mild CNS depressant. It is metabolized to formaldehyde and formic acid which, in turn, cause metabolic acidosis and injury to retina. The signs and symptoms of methanol poisoning are nausea, vomiting, abdominal pain, headache, vertigo, confusion, hypotension, convulsions and coma. Metabolic acidosis is due to formic acid which also causes dimness of vision, retinal damage and blindness. Treatment 1. 2. 3. 4. Patient is kept in a dark room to protect the eyes from light. Maintain airway, breathing and circulation. Gastric lavage is done after endotracheal intubation. Intravenous sodium bicarbonate is given to correct acidosis and to prevent retinal damage. 5. Ethanol (10%) is administered via nasogastric tube. Ethanol competes with methanol for metabolic enzymes and saturates them, thus prevents formation of toxic metabolites (formaldehyde and formic acid). Methanol is excreted unchanged in urine and breath. Ethanol Methanol Alcohol dehydrogenase Formaldehyde Acetaldehyde Aldehyde dehydrogenase Formic acid Respiratory depression Acidosis Acetic acid Retinal damage 6. Fomepizole, an alcohol dehydrogenase inhibitor, is the preferred agent for the treatment of methanol poisoning. CNS depression is rare with fomepizole as compared to ethanol. It can also be used in ethylene glycol poisoning. 7. Calcium leucovorin is administered intravenously (folate adjuvant therapy) to enhance metabolism of formate, thereby decreasing its levels. 8. Haemodialysis is done to promote excretion of methanol and its toxic metabolites. PHARMACOLOGY FOR MEDICAL GRADUATES 192 Antiepileptic Drugs PH1.19 Epilepsy is a Greek word that means convulsions. Epilepsy is a disorder of brain function characterized by paroxysmal cerebral dysrhythmia. Major types of epilepsy are shown below. Epilepsy Generalized seizures 1. Generalized tonic–clonic seizures 2. Absence seizures 3. Myoclonic seizures Partial seizures 1. Simple partial seizures 2. Complex partial seizures GENERALIZED SEIZURES 1. Generalized tonic–clonic seizures (GTCS, grand mal epilepsy): It is characterized by the following sequence of symptoms: Aura–epileptic cry–loss of consciousness–fall to the ground–tonic phase–clonic phase–period of relaxation– postepileptic automatism with confusional states. 2. Absence seizures (petit mal epilepsy): It is characterized by sudden onset of staring, unresponsiveness with momentary loss of consciousness. 3. Myoclonic seizures: It consists of single or multiple sudden, brief, shock-like contractions. PARTIAL SEIZURES 1. Simple partial seizures (SPS): The manifestations depend on the region of cortex involved. There may be convulsions (focal motor symptoms) or paraesthesia (sensory symptoms) without loss of consciousness. 2. Complex partial seizures (CPS, temporal lobe epilepsy, psychomotor epilepsy): It is characterized by aura–amnesia–abnormal behaviour and automatism with impaired consciousness. CHEMICAL CLASSIFICATION OF ANTIEPILEPTIC DRUGS 1. 2. 3. 4. 5. 6. 7. Hydantoins: Phenytoin, fosphenytoin. Barbiturate: Phenobarbitone. Iminostilbenes: Carbamazepine, oxcarbazepine. Carboxylic acid derivatives: Sodium valproate, divalproex. Succinimide: Ethosuximide. BZDs: Lorazepam, diazepam, clonazepam, clobazam. Others: Lamotrigine, topiramate, gabapentin, pregabalin, tiagabine, vigabatrin, zonisamide, levetiracetam, lacosamide. CLINICAL CLASSIFICATION OF ANTIEPILEPTIC DRUGS The classification of antiepileptic drugs is presented in Table 5.9. 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM Table 5.9 193 Antiepileptic drugs: clinical classification Seizure type Preferred drug Alternative/adjunct drugs Generalized tonic–clonic seizures (grand mal epilepsy) Sodium valproate Lamotrigine Carbamazepine Oxcarbazepine Levetiracetam Phenytoin Clobazam Topiramate Phenobarbitone Simple/complex partial seizures (SPS) Carbamazepine Lamotrigine Sodium valproate Levetiracetam Gabapentin, phenytoin Topiramate Tiagabine Zonisamide Absence seizures (petit mal epilepsy) Sodium valproate Ethosuximide Clonazepam Lamotrigine Clobazam Levetiracetam Topiramate Myoclonic seizures Sodium valproate Clonazepam Clobazam Levetiracetam Topiramate Status epilepticus General anaesthetics Midazolam Propofol Lorazepam Diazepam Fosphenytoin Phenytoin Phenobarbitone MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS (Fig. 5.8A and B) Phenytoin (Diphenylhydantoin) Phenytoin is one of the most commonly used antiepileptic drugs. It has a selective antiepileptic effect and does not produce significant drowsiness. Mechanism of Action. Phenytoin acts by stabilizing neuronal membrane (Fig. 5.9) and prevents spread of seizure discharges. The sodium channels exist in three forms: resting, activated and inactivated states. Phenytoin delays recovery of Na! channels from inactivated state, thereby reduces neuronal excitability (Fig. 5.9) and inhibits high-frequency firing. At high concentrations, phenytoin inhibits Ca2! influx into neuron, reduces glutamate levels and increases responses to GABA. Pharmacokinetics. Phenytoin is absorbed slowly through the GI tract, widely distributed and highly (about 90%) bound to plasma proteins. It is almost completely metabolized in liver by hydroxylation and glucuronide conjugation. Repeated administration of phenytoin causes enzyme induction and increases the rate of metabolism of coadministered drugs. Phenytoin exhibits dose-dependent elimination, i.e. at low concentration ("10 mcg/mL), elimination occurs by first-order kinetics and plasma half-life is PHARMACOLOGY FOR MEDICAL GRADUATES 194 Phenytoin Fosphenytoin Bind to voltage-dependent Na+ channels (prolong the inactivated state) and prevent further entry of Na+ ions into neurons (stabilize neuronal membrane) Carbamazepine Oxcarbazepine Sodium valproate Lamotrigine Topiramate Zonisamide Lacosamide Inhibit generation of repetitive action potentials Therefore, prevent or reduce the spread of seizure discharges Fig. 5.8 (A) Mechanism of action of antiepileptic drugs: effect on sodium channels. (") GAD, (!) GABA-T Benzodiazepines Phenobarbitone Facilitate GABA (!) GABA-T activity Facilitates GABA activity has GABA mimetic action Sodium valproate Vigabatrin GABA activity Promotes GABA release Gabapentin Blocks uptake of GABA Tiagabine into neurons ↑CI! conductance into the neuron (IPSP) Hyperpolarization Reduced neuronal excitability Antiepileptic effect Fig. 5.8 (B) Mechanism of action of antiepileptics: effect on GABA. GAD, Glutamic acid decarboxylase; GABA-T, GABA transaminase; IPSP, inhibitory postsynaptic potential. 10–24 hours; as the rate of administration increases, the metabolizing enzymes get saturated, kinetics changes to zero order, and plasma half-life increases to 60 hours; the plasma concentration increases markedly with slight increase in dose resulting in toxicity. Hence, therapeutic monitoring of phenytoin is essential for adjustment of dosage. 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 195 Reduces intraneuronal Na! concentration (membrane-stabilizing effect) Voltage-dependent Na! channels – Resting state – Activated state Na! – Inactivated state Phenytoin binds to voltage-dependent Na! channels (prolongs the inactivated state) and prevents further entry of Na! ions into the neuron Inhibits the generation of repetitive action potentials Therefore, prevents or reduces the spread of seizure discharges; it inhibits the high-frequency firing Fig. 5.9 Mechanism of action of phenytoin. Uses. Phenytoin is used for the treatment of: 1. 2. 3. 4. Generalized tonic–clonic seizures (grand mal epilepsy). Partial seizures. Trigeminal and other neuralgias. Status epilepticus: Phenytoin is administered intravenously in normal saline (it precipitates in glucose solution). Adverse Effects (Note the ‘H’s). Phenytoin has dose-dependent toxicity. The adverse ef- fects are as follows: 1. Hypertrophy and Hyperplasia of gums (due to defect in collagen catabolism) – seen on chronic therapy and can be minimized by proper oral hygiene. 2. Hypersensitivity reactions include skin rashes, neutropenia and rarely Hepatic necrosis. 3. Hirsutism – due to increased androgen secretion. 4. Hyperglycaemia – due to decreased insulin release. 5. Megaloblastic anaemia – due to folate deficiency. 6. Osteomalacia – due to increased metabolism of vitamin D. 7. Hypocalcaemia – due to decreased absorption of Ca2! from the gut. 8. Fetal Hydantoin syndrome – cleft lip, cleft palate, digital Hypoplasia, etc. due to use of phenytoin during pregnancy. At high concentration, phenytoin may cause the following side effects: 1. CNS: Vestibulocerebellar syndrome – vertigo, ataxia, tremor, headache, nystagmus, psychological disturbances, etc. occur on chronic therapy. 2. CVS: Hypotension and cardiac arrhythmias may occur on i.v. administration; extravasation of the drug causes local tissue necrosis. 3. GIT: Nausea, vomiting and dyspepsia can be minimized by giving phenytoin after food. Fosphenytoin It is a prodrug of phenytoin, which is converted to phenytoin by phosphatases. Dose of fosphenytoin is expressed as phenytoin equivalents (PE). It is available for i.m. and i.v. 196 PHARMACOLOGY FOR MEDICAL GRADUATES administration. Fosphenytoin can be administered in normal saline or glucose. It has significantly less irritant effect on the veins than phenytoin. It is preferred to phenytoin in status epilepticus because of above advantages. The rate of i.v. infusion should not exceed 150 mg PE/minute. Hypotension and cardiac arrhythmias may occur with rapid administration. Carbamazepine (Iminostilbene) Carbamazepine is chemically related to tricyclic antidepressants (TCAs). Mechanism of Action. Like phenytoin, carbamazepine slows the rate of recovery of Na! channels from inactivation, thereby reduces neuronal excitability. Pharmacokinetics. Carbamazepine is absorbed slowly and erratically from GI tract, binds to plasma proteins, is well distributed in the body including the cerebrospinal fluid (CSF) and metabolized in liver. One of its metabolites retains anticonvulsant activity. Repeated use causes enzyme induction and reduces the effectiveness of the drug itself (autoinduction) as well as that of valproate, phenytoin, lamotrigine, topiramate, OC pills, etc. Adverse Effects. The common adverse effects of carbamazepine include sedation, drowsiness, vertigo, ataxia, diplopia, blurred vision, nausea, vomiting and confusion. Hypersensitivity reactions are skin rashes, eosinophilia, lymphadenopathy and hepatitis. Rarely, it causes bone marrow depression with neutropenia, aplastic anaemia and agranulocytosis. On chronic therapy, it may cause water retention due to the release of antidiuretic hormone (ADH). Uses 1. Carbamazepine is one of the most commonly used antiepileptic drugs. It is the drug of choice in GTCS and partial (SPS and CPS) seizures. 2. Carbamazepine is the drug of choice in the treatment of trigeminal neuralgias. It inhibits high-frequency discharges. The other drugs useful are phenytoin, gabapentin, TCAs (amitriptyline), etc. Other treatment options are surgical division, cryosurgery, injection of alcohol or phenol in close proximity to nerve or ganglia. It is not effective for diabetic neuropathy. 3. It is used in the treatment of acute mania and bipolar disorder. Oxcarbazepine (Iminostilbene) Oxcarbazepine is an analogue of carbamazepine. Mechanism of action and therapeutic uses are similar to carbamazepine. It is a prodrug and is converted to active form after administration. Its enzyme-inducing property is much less; hence, drug interactions are few. It is less potent and less hepatotoxic than carbamazepine. Eslicarbazepine It is similar in structure to carbamazepine. It is useful for treatment of partial seizures. Phenobarbitone (Barbiturate) Phenobarbitone is a barbiturate and was widely used as an antiepileptic drug. Its use has declined because of availability of safer drugs. It acts by potentiating GABA activity. Phenobarbitone is absorbed slowly but completely after oral administration; about 50% is bound to plasma proteins. Repeated administration causes enzyme induction and reduces the effectiveness of co-administered drugs. Adverse Effects. The most common side effect of phenobarbitone is sedation, but tolerance develops gradually with continued administration. The other side effects are 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 197 nystagmus, ataxia, confusion, megaloblastic anaemia and skin rashes. On chronic therapy, it may cause behavioural disturbances with impairment of memory in children (see Pharmacological actions of barbiturates on pp. 170–171). Uses. Phenobarbitone is effective in GTCS and partial seizures. It is the cheapest antiepileptic drug. It is also useful in the prophylactic treatment of febrile convulsions. In status epilepticus, phenobarbitone is injected intravenously when convulsions are not controlled with diazepam and phenytoin. Ethosuximide (Succinimide) It is effective for the treatment of absence seizures. It acts by inhibiting T-type Ca2! current in thalamic neurons. It is completely absorbed after oral administration. The common side effects are GI disturbances like nausea, vomiting and anorexia. The other side effects are headache, hiccough, eosinophilia, neutropenia, thrombocytopenia with bone marrow depression and rarely skin rashes. Valproic Acid (Sodium Valproate): Carboxylic Acid Derivative Sodium valproate is a broad-spectrum antiepileptic drug. Mechanism of Action 1. Like phenytoin and carbamazepine, valproate delays the recovery of Na! channels from inactivation. 2. Like ethosuximide, it blocks T-type Ca2! current in thalamic neurons. 3. Increases the activity of GABA in the brain by: (a) Increased synthesis of GABA by stimulating GAD (glutamic acid decarboxylase) enzyme. (b) Decreased degradation of GABA by inhibiting GABA-T (GABA-transaminase) enzyme. Pharmacokinetics. Valproate is rapidly and almost completely absorbed from the GI tract, highly (about 90%) bound to plasma proteins, metabolized in liver and excreted in urine. Adverse Effects (Note the Mnemonic VALPROATE) 1. The common side effects related to GI tract are nausea, Vomiting, Anorexia and abdominal discomfort. 2. CNS side effects include sedation, ataxia and tremor. 3. A rare but serious complication is fulminant hepatitis (Liver), hence avoided in children younger than 3 years. Monitoring of hepatic function is essential during valproate therapy; Elevation of liver enzymes occurs. 4. Teratogenicity: Orofacial and digital abnormalities; neural tube defects with increased incidence of spina bifida, so it should not be given during pregnancy. 5. The other adverse effects include skin Rashes, Alopecia and curling of hair; acute Pancreatitis may occur rarely. Uses. Sodium valproate is highly effective in absence, myoclonic, partial (SPS and CPS) and generalized tonic–clonic seizures. Other uses of valproate are mania, bipolar disorder and migraine prophylaxis. Divalproex: It contains valproic acid and sodium valproate in 1:1 ratio. It is administered orally. It causes less GI side effects than valproic acid. PHARMACOLOGY FOR MEDICAL GRADUATES 198 Diazepam, Lorazepam, Clonazepam (Benzodiazepines) Diazepam and lorazepam are effective in controlling status epilepticus. Intravenous diazepam is used in the emergency treatment of status epilepticus, tetanus, eclamptic convulsions, febrile convulsions, drug-induced convulsions, etc. Diazepam has a rapid onset but short duration of action; hence, repeated doses are required. Diazepam can be administered rectally in children during emergency. Lorazepam is preferred in status epilepticus because: 1. It has a rapid onset and long duration of action. 2. It has less damaging effect on injected vein. Clonazepam, a long-acting BZD, is used in absence and myoclonic seizures. Mechanism of Action (See p. 166) Adverse Effects. Intravenous diazepam and lorazepam may cause hypotension and respi- ratory depression. The main side effects of clonazepam are sedation and lethargy, but tolerance develops on chronic therapy. Other side effects are hypotonia, dysarthria, dizziness and behavioural disturbances like irritability, hyperactivity and lack of concentration. Newer Antiepileptics These are lamotrigine, topiramate, zonisamide, lacosamide, gabapentin, pregabalin, tiagabine, vigabatrin and levetiracetam. They are administered orally. Important features are given in Table 5.10. Table 5.10 Drugs Newer antiepileptics Mechanism of action Uses Adverse effects and other important points Lamotrigine Delays the recovery of Na! channels from inactivation As monotherapy or add-on therapy in GTCS, absence, myoclonic and partial (SPS and CPS) seizures Sedation, ataxia, headache, nausea, vomiting and skin rashes Enzyme inhibitors – like sodium valproate increases its plasma concentration Enzyme inducers – carbamazepine, phenytoin, etc. decrease its plasma concentration Topiramate Delays the recovery of Na! channels from inactivation Increases GABA, decreases glutamate activity Can be used as monotherapy in GTCS, myoclonic and partial (SPS and CPS) seizures Migraine prophylaxis Chronic alcoholism Sedation, ataxia, weight loss, nervousness and confusion Reduces the effectiveness of oral contraceptives 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM Table 5.10 199 Newer antiepileptics—cont’d Drugs Mechanism of action Uses Adverse effects and other important points Zonisamide Delays the recovery of Na! channels from inactivation As add-on drug in simple partial and complex partial seizures Ataxia, headache, sedation and nervousness Structurally related to sulphonamides Lacosamide Delays the recovery of Na! channels from inactivation As add-on drug in refractory partial seizures Dizziness, diplopia, ataxia and cardiac arrhythmias Gabapentin Acts by releasing GABA Used as adjunct in partial (SPS and CPS) seizures Diabetic neuropathy Bipolar disorders Postherpetic neuralgias Prophylaxis of migraine Sedation, fatigue, headache Drug interactions are rare Pregabalin Acts by releasing GABA Useful in partial seizures and neuralgias Skin rashes and sedation Tiagabine Inhibits the uptake of GABA into the neurons, thus, increases GABA activity Used as add-on drug in partial seizures Sedation, dizziness Vigabatrin Increases GABA activity in brain by inhibiting GABA transaminase As an adjunct in partial seizures Visual disturbances, sedation, confusion and psychosis Levetiracetam Not exactly known; binds to synaptic vesicle protein and modulates release of neurotransmitters like GABA As an adjunct in GTCS, partial and myoclonic seizures Sedation, dizziness and fatigue STATUS EPILEPTICUS It is a medical emergency and should be treated immediately. It is characterized by recurrent attacks of tonic–clonic seizures without the recovery of consciousness in between or a single episode lasts longer than 30 minutes. PHARMACOLOGY FOR MEDICAL GRADUATES 200 Treatment 1. 2. 3. 4. 5. Hospitalize the patient. Maintain airway and establish a proper i.v. line. Administer oxygen. Collect blood for estimation of glucose, calcium, electrolytes and urea. Maintain fluid and electrolyte balance. Step 1 Lorazepam 0.1 mg/kg i.v. slowly or Diazepam 10 mg i.v. slowly; repeat after 10 min if necessary Fosphenytoin 20 mg/kg i.v. in normal saline or glucose or Phenytoin 20 mg/kg i.v. infusion 50 mg/min in normal saline Watch for hypotension and respiratory depression Monitor cardiac rhythm and BP If seizure continues Step 2 Phenobarbitone 10–15 mg/kg i.v. infusion 100 mg/min Watch for respiratory depression If seizure continues Step 3 General anaesthesia with i.v. midazolam or propofol Maintain airway and BP Dose and drug interactions of antiepileptics are summarized in Table 5.11. Table 5.11 Total daily dose and drug interactions of antiepileptics Drug Dose Interactions Phenytoin 200–400 mg 1. Phenytoin # OC pills, steroids, vitamin D, theophylline, etc. Phenytoin induces microsomal enzymes and enhances the breakdown of OC pills, vitamin D, steroids, etc. reduces the effectiveness of co-administered drug 2. Phenytoin # carbamazepine Mutual induction of metabolism and reduced plasma concentration of both the drugs    # Phenytoin  These drugs inhibit the metabolism of phenytoin n plasma concentration of phenytoin increases n phenytoin toxicity may occur 3. Chloramphenicol NH Warfarin 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM Table 5.11 201 Total daily dose and drug interactions of antiepileptics—cont’d Drug Dose Interactions Carbamazepine 600–1200 mg Carbamazepine # phenytoin, phenobarbitone, sodium valproate, OC pills 1. Carbamazepine induces the metabolism of these drugs and reduces their effects  2. INH  # Carbamazepine Erythromycin  These drugs inhibit carbamazepine metabolism; carbamazepine toxicity may occur Phenobarbitone 100–200 mg Phenobarbitone # OC pills, warfarin, griseofulvin, theophylline Phenobarbitone induces the metabolism of these drugs and reduces their effects Ethosuximide 500–1500 mg Ethosuximide # valproate Valproate inhibits the metabolism and increases plasma concentration of ethosuximide Sodium valproate 1500–2000 mg Sodium valproate ! phenytoin: Phenytoin toxicity can occur due to displacement interaction Sodium valproate ! phenobarbitone: Valproate inhibits the degradation of phenobarbitone and increases its plasma concentration Sodium valproate ! carbamazepine: Increased incidence of teratogenicity when administered simultaneously Analgesics Analgesics are drugs that relieve pain without significantly altering consciousness. They relieve pain without affecting its cause. Analgesics Opioid (narcotic analgesics) Opioid Analgesics Nonopioid (nonsteroidal anti-inflammatory drugs) PH1.19 Morphine is the most important alkaloid of opium – the dried juice obtained from the capsules of Papaver somniferum. Opium contains many other alkaloids, e.g. codeine, thebaine, papaverine, etc. The term ‘opiates’ refers to drugs derived from opium poppy, whereas ‘opioid analgesic’ applies to any substance (endogenous peptides or drugs), which produces morphine-like analgesia. PHARMACOLOGY FOR MEDICAL GRADUATES 202 CLASSIFICATION OF OPIOIDS 1. Opioid agonists (a) Natural opium alkaloids: Morphine, codeine, thebaine,* papaverine,* noscapine.* (b) Semisynthetic opiates: Heroin, pholcodine,* hydromorphone, oxymorphone. (c) Synthetic opioids: Pethidine, tramadol, tapentadol, methadone, dextropropoxyphene, fentanyl, alfentanil, sufentanil, remifentanil. 2. Opioid agonist–antagonists: Pentazocine, butorphanol, nalorphine, nalbuphine. 3. Partial $-receptor agonist and %-receptor antagonist: Buprenorphine. Note: *Have no analgesic activity. OPIOID RECEPTORS The three main types of opioid receptors are $ (mu), % (kappa) and & (delta). These receptor-mediated effects are given below. $: Analgesia (spinal ! supraspinal level), respiratory depression, dependence, sedation, euphoria, miosis, decrease in GI motility. %: Analgesia (spinal ! supraspinal level), respiratory depression, dependence, dysphoria, psychotomimetic effect. &: Analgesia (spinal ! supraspinal level), respiratory depression, proconvulsant action. OPIOID AGONISTS Mechanism of Action Morphine and other opioids produce their actions by interacting with various opioid receptors – mu ($), delta (&) and kappa (%). They are located at spinal, supraspinal (medulla, midbrain, limbic system and cortical areas) and peripheral nerves. Morphine is the prototype drug. Pharmacological Actions of Morphine. Morphine has mainly CNS-depressant effects but also has stimulant effects at certain sites in the CNS. 1. CNS (a) The depressant effects: (i) Analgesic effect: Mediated mainly through $-receptors at spinal and supraspinal sites (central action), it is the most important action of morphine. At the spinal level, it decreases release of excitatory neurotransmitters from primary pain afferents in substantia gelatinosa of dorsal horn. The excitability of neurons in dorsal horn is decreased. In the supraspinal level, it alters transmission of pain impulses. It is a very potent and efficacious analgesic. It causes sedation, drowsiness, euphoria, makes the person calm and raises the pain threshold. Perception of pain and reaction to it (fear, anxiety and apprehension) are altered by these drugs. Moderate doses of morphine relieve dull and continuous pain, whereas sharp, severe intermittent pain such as traumatic or visceral pain requires larger doses of morphine. Opioids also act peripherally to alter the sensitivity of small nerve endings in the skin to painful stimuli associated with tissue injury/inflammation. 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 203 MARPHINE CVS* Miosis Analgesia Respiratory depression Physical and psychological dependence Histamine release, hypotension, hypothermia Itching Nausea and vomiting Euphoria Cough suppression, constipation Vagal stimulation (bradycardia) Sedation and hypnosis Pain Sick feeling associated with illness (because of euphoriant effect) Morphine relieves Fear Anxiety Apprehension (reaction to pain) Therefore, morphine relieves ‘total pain’. (ii) Euphoria (feeling of well-being): It is an important component of analgesic effect. Anxiety, fear, apprehension associated with painful illness or injury are reduced by opioids. (iii) Sedation: Morphine, in therapeutic doses, causes drowsiness and decreases physical activity. (iv) Respiratory depression: It depresses respiration by a direct effect on the respiratory centre in the medulla; both rate and depth are reduced because it reduces sensitivity of respiratory centre to CO2. Respiratory depression is the commonest cause of death in acute opioid poisoning. (v) Cough suppression: It has a direct action on cough centre in the medulla. (vi) Hypothermia: In high doses, morphine depresses temperature-regulating centre and produces hypothermia. (b) The stimulant effects: (i) Miosis: Morphine produces constriction of pupils due to stimulation of III cranial nerve nucleus. Some tolerance develops to this action. Pinpoint pupils are an important feature in acute morphine poisoning. Miosis is not seen on topical application of morphine to the eye. (ii) Nausea and vomiting: It is due to direct stimulation of the CTZ in medulla. 5-HT3 antagonists are the drugs of choice to control opioidinduced nausea and vomiting. H1-blockers, such as cyclizine or prochlorperazine may also be used. *Mnemonic for actions of morphine: ‘MARPHINE CVS’. PHARMACOLOGY FOR MEDICAL GRADUATES 204 (iii) Vagal centre: It stimulates vagal centre in the medulla and can cause bradycardia. (c) Other effects: Physical and psychological dependence: Repeated use of opioids causes physical and psychological dependence. 2. CVS: Morphine produces vasodilatation and fall of BP. Histamine release aso dilatatio n Morphine causes V Depression of VMC Hypotension Direct action on blood vessel 3. 4. 5. 6. It mainly causes vasodilatation of peripheral vessels, which results in shift of blood from pulmonary to systemic vessels leading to relief of pulmonary oedema associated with acute left ventricular failure. GIT: It causes constipation by direct action on GI tract and CNS – decreases GI motility and increases tone of the sphincters. Urinary bladder: It may cause urinary retention by increasing tone of urethral sphincter. Biliary tract: It increases intrabiliary pressure by increasing tone of sphincter of Oddi. Histamine release: Morphine is a histamine liberator and causes itching, skin rashes, urticaria, vasodilatation, bronchoconstriction, etc. Pharmacokinetics. On oral administration, morphine is absorbed slowly and erratically. It also undergoes extensive first-pass metabolism; hence, oral bioavailability of morphine is poor. Morphine is commonly administered by i.v., i.m. or s.c. routes. It can also be administered by oral, epidural or intrathecal routes. It is widely distributed in the body, crosses placental barrier and is metabolized in liver by glucuronide conjugation. Morphine-6-glucuronide has more potent analgesic action than morphine and is excreted in urine. PH1.19 Nausea, vomiting and constipation. Respiratory depression. Hypotension due to vasodilatation. Drowsiness, confusion and mental clouding. Itching (due to histamine release) and skin rashes. Difficulty in micturition. Respiratory depression in newborn due to administration of morphine to the mother during labour. 8. Drug tolerance develops to most of the effects of morphine (some tolerance develops to miotic effect). There is cross-tolerance among the opioids. 9. Seizure threshold is lowered. 10. Drug dependence (physical and psychological dependence) is the main drawback of opioid therapy. Psychological dependence is associated with intense craving for the drug. Physical dependence is associated with the development of withdrawal symptoms (abstinence syndrome) when administration of an opioid is stopped abruptly. The symptoms and signs are irritability, body shakes, Adverse Effects 1. 2. 3. 4. 5. 6. 7. 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 205 yawning, lacrimation, sweating, fever, diarrhoea, palpitation, insomnia, rise in BP, loss of weight, etc. (the symptoms are just opposite to morphine actions). Dependence is mediated through $-receptors. Treatment of morphine dependence: (a) Hospitalization of the patient. (b) Gradual withdrawal of morphine. (c) Substitution therapy with methadone. Opioid agonist like methadone is preferred because: (i) It is orally effective. (ii) It has longer duration of action. (iii) Withdrawal symptoms are mild. 1 mg of methadone will substitute 4 mg of morphine. Later, methadone is gradually reduced and completely stopped within 10 days. Buprenorphine can also be used for the treatment of opioid dependence. (d) Pure opioid antagonist like naltrexone is used after detoxification to produce opioid blockade to prevent relapse in patients who have a sincere desire to leave the habit. It is the preferred antagonist because it is orally effective and has a long duration of action. (e) Psychotherapy, occupational therapy, community treatment and rehabilitation. PH1.23 11. Acute morphine poisoning: The characteristic triad of symptoms are respiratory depression, pinpoint pupils and coma. The other signs and symptoms are cyanosis, hypotension, shock and convulsions. Death is usually due to respiratory depression. Treatment of acute morphine poisoning: 1. Hospitalization. 2. Maintain airway, breathing and circulation. 3. Ventilatory support (positive pressure respiration). 4. Gastric lavage with potassium permanganate. 5. Specific antidote: Naloxone 0.4–0.8 mg intravenously; dose is repeated till respiration becomes normal. Naloxone is a pure antagonist, competitively blocks opioid receptors and rapidly reverses the respiratory depression (Fig. 5.10). The duration of action of naloxone is short; hence, repeated administration is needed. Note: Administration of naloxone to morphine addicts should be done with caution because it may precipitate severe withdrawal symptoms. Contraindications 1. Head injury: Morphine is contraindicated in cases with head injury because: (a) Vomiting, miosis and mental clouding produced by morphine interfere with assessment of progress in head injury patients. (b) Morphine n Respiratory depression n CO2 retention n Cerebral vasodilation nhh Intracranial tension. 2. Bronchial asthma: Morphine may cause severe bronchospasm due to histamine release. Morphine (Agonist) Opioid receptors Naloxone (Antagonist) Fig. 5.10 Competitive antagonism. 206 PHARMACOLOGY FOR MEDICAL GRADUATES 3. COPD: It should be avoided in patients with low respiratory reserve – emphysema, chronic bronchitis, cor pulmonale, etc. 4. Hypotensive states: It should be used cautiously in shock or when there is reduced blood volume. 5. Hypothyroidism and hypopituitarism: There is a prolonged and exaggerated response to morphine. 6. Infants and elderly: They are more prone to respiratory depressant effect of morphine. In elderly male, there is an increased chance of urinary retention. 7. Undiagnosed acute abdominal pain: Morphine, if given before diagnosis interferes with diagnosis by masking the pain. Its spasmogenic effect may aggravate the pain (biliary colic). Codeine: Natural Opium Alkaloid 1. Codeine has analgesic and cough-suppressant effects; it is administered orally. 2. Compared to morphine: (a) It is less potent and less efficacious as an analgesic. (b) It has less respiratory depressant effect. (c) It is less constipating. (d) It has low addiction liability. 3. It has selective cough suppressant effect (antitussive), hence used to suppress dry cough. 4. It potentiates analgesic effect of aspirin and paracetamol. Codeine is used for relief of moderate pain. The main side effects are constipation and sedation. Pholcodine: see p. 255 Pethidine (Meperidine) (Table 5.12). Pethidine is a synthetic opioid; it has some anticho- linergic actions. Dry mouth and tachycardia can occur. It can be administered by oral, i.v., s.c. and i.m. routes. It is well absorbed from the GI tract, but bioavailability is about 50% because of first-pass effect; widely distributed in the body, crosses placental barrier and is metabolized in liver. The metabolites are excreted in urine. Adverse Effects. The adverse effects of pethidine are similar to those of morphine. It can cause tremors, hallucinations, muscle twitches and rarely convulsions due to its metabolite, norpethidine. Tolerance, physical and psychological dependence can also develop with pethidine. Diphenoxylate. It is a pethidine congener and is useful in the treatment of diarrhoea. It is available in combination with atropine. It is rarely used at present because of its side effect (paralytic ileus). Loperamide. Loperamide is a pethidine congener. It reduces GI motility and secretions but increases the tone of anal sphincter. It is used in the symptomatic treatment of diarrhoea. Common side effects are constipation and abdominal cramps. Therapeutic Uses of Opioids 1. As analgesic (Fig. 5.11): Morphine and other opioids are potent and efficacious analgesics, hence used for moderate to severe painful conditions, such as acute myocardial infarction (MI), burns, pulmonary embolism, fracture mandible and 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 207 Comparative features of morphine and pethidine Table 5.12 Morphine Pethidine (Meperidine) Natural opium alkaloid Synthetic opioid Analgesic dose: 10 mg i.m., i.v. (morphine is 10 times more potent) Analgesic dose: 100 mg i.m., i.v. (1/10 as potent as morphine) It produces sedation, euphoria, respiratory depression and drug addiction In equianalgesic doses, pethidine also produces same amount of sedation, euphoria, respiratory depression and drug addiction as morphine At times, pethidine can cause CNS stimulation with tremor, twitches and convulsions due to its metabolite, norpethidine Effects on smooth muscles: 1. Constipation ! 2. Biliary spasm ! 3. Urinary retention ! 4. Miosis ! Effects on smooth muscles: 1. Spasmodic effects – constipation, biliary spasm, urinary retention, etc. are less prominent 2. Miosis is less prominent Has antitussive effect Has no significant antitussive effect Releases histamine It causes less histamine release It has a rapid onset and longer duration of action (6–8 hours) It has a rapid onset but shorter duration of action (3–4 hours) Morphine causes severe respiratory depression in the newborn, when it is given to mother during labour Pethidine causes less respiratory depression in newborn If pain persists/moderate to severe pain – a potent opioid (e.g. morphine, methadone) ! NSAID ! adjuvant If pain is not controlled, a weak opioid (e.g. codeine) ! NSAID ! adjuvant Start with NSAID/paracetamol for mild to moderate pain Adjuvants* – antidepressants, antiepileptics, anxiolytics, steroids, etc. can be used at each stage Fig. 5.11 World Health Organization analgesic ladder. (*Adjuvants, e.g. carbamazepine, amitriptyline, diazepam, prednisolone.) (Source: https://www.who.int/cancer/palliative/painladder/ en/) long bones, bullet wound, etc. Opioids are also used to control severe pain in terminal stages of cancer. In renal and biliary colic, atropine is used with morphine to counteract spasmogenic effect of morphine. Opioids are the preferred analgesics in severe painful conditions (WHO analgesic ladder) (Fig. 5.11). Patient controlled analgesia: This allows the patient to control the delivery of s.c., epidural or i.v. analgesic in a safe and effective way through a pump. The patient should inform nurse when he or she takes a dose so that it can be replaced. PHARMACOLOGY FOR MEDICAL GRADUATES 208 2. Preanaesthetic medication: Opioids like morphine and pethidine are used about half an hour before anaesthesia because of their sedative, analgesic and euphoric effects; the dose of anaesthetic required is reduced. 3. Acute pulmonary oedema (cardiac asthma): i.v. morphine relieves breathlessness associated with acute left ventricular failure due to pulmonary oedema by: (a) Reducing preload on heart by peripheral vasodilatation. (b) Shifting blood from pulmonary to systemic circulation. (c) Reducing anxiety, fear and apprehension associated with illness. 4. Postanaesthetic shivering – pethidine is effective. 5. Cough: Codeine and dextromethorphan are used for suppression of dry cough. 6. Diarrhoea: Synthetic opioids such as loperamide and diphenoxylate are used for symptomatic treatment of diarrhoea. Other Opioids The route of administration, uses and important features are represented in Table 5.13. Table 5.13 Important points and uses of other opioids Important adverse effects Opioid Actions and uses Codeine (p.o.) metabolized to morphine Analgesia – less potent than morphine Cough suppressant – more selective for cough centre Constipation Low addiction liability Pethidine (i.m., i.v., s.c.) Synthetic opioid Rapid but short acting No significant antitussive effect Analgesic – less potent than morphine Similar to morphine (urinary retention, constipation less common) Anticholinergic effects – dry mouth, tachycardia Seizures, tremors (due to norpethidine) With SSRI n serotonin syndrome Methadone (p.o., i.m.) µ-Receptor agonist Oral route: well absorbed Long duration of action Repeated dosing: persistent action Substitution therapy in opioid dependence Actions similar to morphine Tolerance, dependence more slowly than morphine Withdrawal symptoms – mild 1 mg methadone substituted for 4 mg of morphine Uses – substitution therapy in opioid dependent subjects; for chronic pain Similar to morphine Tramadol (p.o., i.m., i.v.) µ-Agonist (–) reuptake of 5-HT, NA into neurons Similar to morphine but less marked Haemodynamic effects minimal Uses – mild to moderate pain due to trauma and surgery; cancer pain Similar to morphine Seizures With SSRI n serotonin syndrome Action on smooth muscle Histamine release } Less than morphine 5—DRUGS ACTING ON CENTRAL NERVOUS SYSTEM Table 5.13 209 Important points and uses of other opioids—cont’d Important adverse effects Opioid Actions and uses Fentanyl (i.v., transdermal, epidural) Highly lipid soluble i.v.: peak analgesia in 5 minutes, short duration Similar to morphine but less marked and short acting; except analgesia, respiratory depression (80–100 times more potent than morphine) Few cardiovascular effects Use – as analgesic to supplement anaesthetics; cancer pain; postoperative pain Similar to morphine Buprenorphine (i.m., i.v., sublingual) Thebaine congener Slow onset Longer acting Similar to morphine Analgesia: more potent than morphine Less tolerance, dependence Withdrawal symptoms: milder, longer Uses –