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AGENTS ACTING ON THE CENTRAL NERVOUS SYSTEM

AGENTS ACTING ON THE CENTRAL NERVOUS SYSTEM. Liu Juntian ( 刘俊田 ) (Pharmacol Dept, Med School of XJTU). CHAPTER 13 General consideration. 1.composition of nervous system (1)central and peripheral nervous systems (2)neuron and synapse *. 2.function of CNS: regulating body functions.

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AGENTS ACTING ON THE CENTRAL NERVOUS SYSTEM

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  1. AGENTS ACTING ON THE CENTRAL NERVOUS SYSTEM Liu Juntian (刘俊田) (Pharmacol Dept, Med School of XJTU)

  2. CHAPTER 13 General consideration 1.composition of nervous system (1)central and peripheral nervous systems (2)neuron and synapse*

  3. 2.function of CNS: regulating body functions. 3.activity of neuron(conduction of nervous impulse) (1)AP: sodium, calcium, kalium, chloride ion channel: voltage-gated, ligand-gated (2) neurotransmitter: ①NA, ACh, DA, GABA, glutamate, glycine, 5HT, histamine, opioid peptides, tachykinins (excitatory/ inhibitory). ②biosynthesis, storage, release, degradation, reuptake.*

  4. (3)receptor *

  5. (4)conduction of impulse cross synapse: presynaptic neuron release neurotransmitter synaptic cleft neurotransmitter interacts with receptor neurotransmitter-receptor complex initiates a sequence of events (open ion channel) modulate the electrical activity of the postsynaptic neuron (depolarization/ hyperpolarization). *

  6. 4.mechanism of drugs on CNS (1)axon: slow/block axonal electrical conduction e.g. antiepileptics anaesthetics (2)synapse: most drugs ①affect transmitter: synthesis, storage, release, reuptake. e.g. antidepressants ②affect receptor: activation/inhibition(block) e.g. benzodiazepines, antipsychotics ③directly act on ion channels e.g. phenytoin

  7. 5.BBB (1)structure barrier between blood and brain cell; 3 parts barrier between blood and cerebrospinal fluid barrier between brain cell and cerebrospinal fluid. endothelial cells (2)function: restrict passage of polar compounds and macromolecules from blood into brain (3)Pharmacological significance: prerequisite e.g. penicillin/SD----meningitis

  8. CHAPTER 14 Sedative-Hypnotics 【classification】 1. benzodiazepines. 2. barbiturates. 3.other agents: e.g. chloral hydrate. 【general use】 anxiety, insomnia, convulsion, epilepsy etc.

  9. Benzodiazepines 【classification】 1.short-acting triazolam (t1/22~4h) 2.intermediate-acting chlordiazepoxide (t1/2 5~10h) oxazepam (t1/2 5~10h) 3.long-acting diazepam (t1/2 30~60h) flurazepam (t1/2 50~100h)

  10. 【pharmacokinetics】 • Benzodiazepines are lipophilic and are rapidly and completely absorbed after oral administration and are distributed throughout body. • Most benzodiazepines are metabolized by hepatic microsomal metabolizing system to compounds that are also active. • The benzodiazepines are excreted in urine asglucuronides or oxidized metabolites.

  11. 【mechanism of action】 There are benzodiazepine receptors (BZR1, BZR2) in CNS, which are separate from but adjacent to receptor for GABAA. Benzodiazepines activate BZR promote GABA binding to GABAA receptors The binding opens Cl— channel Cl— influx to neurons The influx causes a small hyperpolarization inhibits formation of action potentials inhibitory effect on neuronal conduction.*

  12. 【pharmacologic effects and uses】 antianxiety small dose sedation hypnosis anticonvulsion respiratory depression large dose DOSE, ADMINISTRATION

  13. 【pharmacologic effects and therapeutic uses】 1. antianxiety (1) effect All sedative-hypnotic drugs are capable of relieving anxiety at sedative doses, but benzodiazepines exert antianxiety action at the lowest effective doses that do not cause sedation. (2) use anxiety states: restlessness worry stress phobia states common drug: chlordiazepoxide, diazepam P.O./small dose

  14. 2. sedation(calming effect) use: • general anaesthesis • tracheoscopy examination electric defibrillation (temporary loss of memory, i.v.) common drug: diazepam P.O. / i.v. /small dose

  15. 3. hypnosis (1) effect to reduce awaking times, to prolong sleep time to shorten sleep latency. (2) use insomnia, especially insomnia with anxiety common drug: flurazepam, temazepam, triazolam, P.O./middle dose

  16. 4. anticonvulsant effect (1) effect to inhibit development and spread of epileptiform activity in CNS. (2)use: convulsion and status epilepticus, injection/large dose. (3) common drug: ①clonazepam for chronic treatment of epilepsy; ②diazepam for terminating grand mal epileptic seizures and status epilepticus; ③chlordiazepoxide, clorazepate, diazepam and oxazepam for alcohol withdrawal.

  17. 5. muscle relaxation (1) effect inhibitory effects on polysynaptic reflexes and internuncial transmission in CNS, leading to muscle relaxation (2) use relaxing muscle spasm induced by cerebral palsy common drug: diazepam injection/large dose

  18. 【adverse effects】 Benzodiazepines have a low toxicity and wide margin of safety (therapeutic index). 1. central inhibitory effect dizziness, asthenia, drowsiness. 2. tolerance, dependence and addiction. 3. acute toxication flumazenil--competitively BZR blocker.

  19. Barbiturates 【history】 【classification】 1. ultra-short-acting thiopental (action of duration：0.25h) 2. short-acting secobarbital (action of duration：2~3h) 3.intermediate-acting pentobarbital and amobarbital (action of duration：3~6h) 4. long-acting phenobarbital (action of duration：6~8h)

  20. 【pharmacokinetics】 • Duration of action depends on rate of metabolic degradation, degree of lipid solubility, extent of binding to serum proteins. Ultra-short-acting barbiturates are highly lipid-soluble, whereas long- acting barbiturates are lowly lipid-soluble. • redistribution: e.g. thiopental. • excretion via kidney. Alkalinization of urine profoundly promotes excretion of barbiturates.

  21. 【mechanism of action】 ①to enhance effects of GABA. ②to interfere with sodium and potassium transport across cell membrane that leads to inhibition of mesencephalic reticular activating system. ③todirectly activate chloride channel, to prolong opening time of chloride channel, to increase influx of Cl- to enlarge membrane potential in large dose.

  22. 【pharmacologic effects】 1. to depress CNS at all levels sedation small dose hypnosis anticonvulsion anesthesia respiratory depression depression of vasomotor center large dose

  23. 2.to augment action of other CNS depressants 3.to shorten amount of time in REMS 4.induce hepatic microsomal drug-metabolizing enzymes clinical significance: (1) to increase degradation of the barbiturates, ultimately leading to barbiturate tolerance. (2)to increase inactivation and decreased action of other compounds in drug interaction.

  24. 【therapeutic uses】 DOSE, ADMINISTRATION 1.sedation and hypnosis: intermediate and long-acting barbiturates P.O. small dose disadvantages: ① narrow therapeutic-to-toxic dosage range; ② suppressing REMS; ③ tolerance ; ④ high potential for physical dependence and abuse ⑤ drug interaction secondary to microsomal enzyme induction.

  25. 2. Anticonvulsion phenobarbital, pentobarbital or amobarbital injection large dose 3. Antiepileptism phenobarbital for epileptism in infant and children injection large dose 4. intravenous anesthetics or intravenous adjunct to surgical anesthetics thiopental intravenous injection large dose

  26. 5.cerebral edema, cerebral infarction Barbiturates, especially in anesthetic doses, significantly decrease oxygen utilization by brain, which may be of value in lessening cerebral edema caused by surgery or trauma and in protecting against cerebral infarction duration cerebral ischemia. 6. Hyperbilirubinemia (jaundice) and kernicterus in the neonate.

  27. 【adverse effects】 1.CNS depressant effects • Oversedation • nightmare. 2. dependence: physiologic and psychological dependence. Withdrawal of barbiturates may result in grand mal seizures, severe tremors, vivid hallucinations, and psychoses. Abrupt withdrawal should be avoided.

  28. 3. acute barbiturate overdosage (1) clinical menifestations coma, diminished reflexes, severe respiratory depression, cardiovascular collapse, renal failure. (2) treatments ① supporting respiration and circulation; ② alkalizing gastric juice, body fluids and urine(sodium bicarbonate), ③ diuresis.

  29. Differentiation of barbiturates with benzodiazepines benzodiazepines barbiturates 1. antianxiety: dose lower than same dose as one for sedation. for sedation. 2. shortening REMS : weak obvious 3. central muscular have no 4. anaesthesis: no have 5. hepatic micro- no have some induction: 6. margin of safety: wide narrow 7. depression of weak strong respiration:

  30. Chloral hydrate 1. a relatively safe hypnotic drug, inducing sleep in a half hour and lasting about 6 hours. 2. relatvely small reduction in REM sleep. 3. use: children and the elderly with insomania, most effective for 1-3 nights. 4. bad-tasting and irritating to the gastro- intestinal tract, administered by enema in children. 5. addiction can occur.

  31. Paraldehyde 1. CNS depressant activity of paraldehyde resembles that of alcohol, chloral hydrate and barbiturates. 2. use exclusively for patients undergoing withdrawal from alcohol and for patients with hepatic or renal failure.

  32. Summary for this chapter 1. main effects 2. main uses 3.main adverse reactions central inhibition dependence toxic effects 4.common drugs 5.dose and administration

  33. CHAPTER 15 Agents used in the treatment of seizures 1.etiology (1) primary epilepsy: inherited abnormality. (2) secondary epilepsy: such as brain tumors, head injury, hypoglycemia, meningeal infection, rapid withdrawal of alcohol from an alcoholic. 2.pathogenesis sudden, excessive and abnormal discharge of cerebral neurons which diffuses to local or whole brain in short time over-excitement.

  34. 3. clinic manifestation regional or whole brain dysfunction: • motor • vegetative and mental episodes • loss of consciousness etc.

  35. 4. classification (1)generalized ①grand mal epilepsy (tonic-clonic) epilepticism (status epilepticus) ②absence epilepsy(petit mal) ③ myoclonic epilepsy ④febrile seizures (2)Partial ①Simple partial ②Complex partial *

  36. 5.treatment (1) primary epilepsy antiepileptic drugs (2) secondary epilepsy antiepileptic drugs + against primary cause Mechanisms of action of drugs: • Inhibiting sodium influx • Potentiating GABA-neuronal function

  37. Phenytoin 【pharmacokinetics】 • high concentrations in brain, • high plasma albumin binding, • half-life: 24 hours. 【mechanism of action】 to decrease Na+ conductance in neurons to stabilize nervous cellular membranes to reduce the influx of calcium ions during depolarization suppresses high-frequency repetitive firing halts seizure activity.

  38. 【pharmacologic effects】 1.antiepileptic effect effective for tonic-clonic and partial seizures 2. Anti-peripheral neuralgia 3. antiarrhythmia

  39. 【therapeutic uses】 1. epilepsy. • highly effective for all partial seizures, tonic-clonic seizures and status epilepticus. • not effective for absence seizure. 2. peripheroneural pain. trigeminal neuralgia, glossopharyngeal neuralgia and sciatic neuralgia etc.. 3. arrhythmia (see antiarrhythmic drugs)

  40. 【adverse effects】 1. gastrointestinal irritation administration with or after meal. 2. depression of CNS 3. blood dyscrasias 4.cardiovascular collapse (arrhythmia, calcium antagonism) 5. gingival hyperplasia 6. hepatitis in the long administration 7. allergic reaction 8. fetal malformation 9. to induce the P-450 system

  41. Barbiturates 1.characteristics (1)mechanism of action is unknown but involves potentiation of inhibitory effects of GABA neurons. (2)dose required for antiepileptic action is lower than dose that causes pronounced CNS depression for the patient. More selectivity in anticonvulsant action than in sedative effect. 2.use (1) 50% effective rate for simple partial seizure. (2) not effective for complex partial seizure. (3) first-choice drug for epilepticism in infant and children. (4) effective for recurrent tonic-clonic seizures, especially inpatients who do not respond to diazepam plus phenytoin.

  42. Benzodiazepines Intravenous diazepam is used for epilepticism in adults. Clonazepam is used for absence and myoclonic seizure in children.

  43. Carbamazepine 1.The actions and mechanism are similar to those of phenytoin. • highly effective for all partial seizure as first-choice drug, • highly effective for tonic-clonic seizures, • effective for trigeminal neuralgia etc.. 2.More adverse effects, especially serious liver toxicity.

  44. Ethosuximide 1.effective for absence seizure, no effective for other seizures. 2.more adverse effects. • Stevens- Johnson syndrome in sensitive individuals • Urticarria • leukopenia, aplastic anemia and thrombocytopenia

  45. Sodium valproate • most effective for myoclonic seizure to reduce incidence and severity of tonic-clonic seizures, • effective for absence seizure but second choice because of its hepatotoxicity. Other new agents: gabapenitin in 1993 lamotrigine in 1994 tiagabine in 1998*

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