Central Nervous System Pharmacology

At the end of this course, students should be able to: 1. explain the role of COX and PGs in inflammation, pain and fever; 2. identify the role of PGs in homeostatic regulation of gastric function, kidney function, vasoconstriction and platelet activation; 3. describe basic pharmacology of the different classes of NSAIDs; 4. discuss the rationale behind use of low-dose aspirin as prophylactic in CV disease; 5. describe mechanism of salicylate toxicity caused by aspirin and its treatment; 6. explain mechanism of acetaminophen poisoning and its treatment; 7. illustrate the opioid system and its role in pain transduction; 8. describe pharmacology of narcotic analgesics and antagonists; and 9. discuss opioid-induced tolerance, physical dependence, addiction and pseudo-addiction.

Pain and Analgesics. Narcotic analgesics opioid system. Receptors, endogenous ligands, signal transduction pathways, role in pain. Concept of opioid-induced tolerance, physical dependence, addiction and pseudo-addiction. Basic pharmacology of narcotic analgesics (morphine, pethidine, methadone and congeners), narcotic antagonists, full and partial antagonists (nalorphine, levallorphan, naloxone). Non-Steroidal Anti-Inflammatory drugs (NSAIDs). Role of cyclo-oxygenase and prostaglandins in aetiology of inflammation, pain and fever, role of prostaglandins in homeostatic regulation of gastric function, kidney function, vasoconstriction and platelet activation. Basic pharmacology of NSAIDs (aspirin and salicylates, traditional NSAIDs, COX-2 inhibitors, acetaminophen). Rationale behind unique indication for low-dose aspirin as prophylactic treatment in development of CV disease. Pharmacokinetics of aspirin and the mechanism that lead to the development of salicylate toxicity. Mechanism underlying acetaminophen poisoning and its treatment. Epilepsy and Antiepileptic Drugs. Different types of seizures. Seizure types as determinants of specific antiepileptic drugs used in management. Spectrum of action of most commonly used drugs. Selection process of an epileptic drug for a given seizure type, based on its mechanism of action efficacy, clinical pharmacokinetics (ease of use), drug-drug interaction potential, tolerability (common side effects), serious toxicity (idiosyncratic reactions). Role of co-morbidities in the selection of an epileptic drug. Antidepressants Primary sites of action of the different classes of antidepressants, Tricyclic antidepressants, TCAs, (imipramine, amitriptyline, clomipramine, desipramine, doxepin). Selective-serotonin reuptake inhibitors, SSRIs, (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), Noradrenaline/serotonin reuptake inhibitors, SNRIs, (Venlafaxine, desvenlafaxine, nefazodone), monoamine oxidase inhibitors, MAOIs, (Irreversible, phenelzine, tranylcypromine and selegiline and reversible such as moclobemide). Adverse side effects of the different classes with respect to use in certain population (elderly, pregnancy), Pharmacological sites of actions that contribute to the acute or chronic side effects of these drugs. Proposed mechanism underlying the delayed therapeutic effects. Considerations in using irreversible MAOIs, their potential adverse effects and the important considerations in switching between MAOIs and SSRIs or other antidepressants. Antipsychotic drugs, the four well-defined dopamine systems in the brain as they relate to antipsychotic drug action and side effects. Distinction between the typical (chlorpromazine, haloperidol) and atypical antipsychotics (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone); difference in mechanism of action between the typical antipsychotics, atypical antipsychotics and the partial agonist, aripiprazole, common and rare side effects associated with use of both low potency and high potency antipsychotics as well as the second-generation antipsychotics. Sedative-Hypnotic Drugs used in treating anxiety and sleep disorders. Sleep and wakefulness. Structural aspects of GABAA receptor and the receptor. components (binding sites) mediating 232 the effects of drugs that modulate GABAA receptor activity. Differences between benzodiazepines with respect to time of onset, potency, metabolism and elimination half-lives. Similarities and differences between the benzodiazepines and the barbiturates in producing sedative-hypnotic effects. Factors to consider in choosing the most appropriate drug for specific clinical situations and/or individuals. Characteristics of benzodiazepines and other sedative-hypnotics that contribute to different degrees of abuse liability and withdrawal symptoms. Target sites or putative mechanisms of non-benzodiazepine drugs that can be used to treat sleep disorders, Barbiturates, bromides, cyclic ethers, paraldehyde, carbamic acid esters (meprobamate), chloral derivatives (chloral hydrate) piperazine dienes (glutethimide, methyprylon) alcohols. Target sites of action for SSRIs and strategy for using SSRIs in combination with benzodiazepines in the treatment of anxiety. Bipolar affective disorder and drugs used in management. Target sites of action for lithium, its pharmacokinetics, adverse effects and considerations in its use. Sites of action, adverse effects and considerations in using anticonvulsants (carbamazepine, lamotrigine, valproate) and the atypical antipsychotics (aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone) to treat bipolar disorder. Potential risks of birth defects with use of lithium, valproate, carbamazepine and lamotrigine in pregnant women. Parkinson’s disease and drugs used in management. Pathophysiology of Parkinson’s disease and its presentation; functional circuitry of the nigrostriatal system. Major classes of drugs used in management and the timeline for their use, indications, mechanism of action, adverse effects and contraindications. Types and mechanisms of alternative treatments. Local Anaesthetics. Mechanism by which local anaesthetics block nerve conduction, how their physiochemical properties (esters and amides) influence their pharmacodynamics and pharmacokinetics. The side effects that may occur with their use and why they occur. Unique characteristics and the common clinical use for each prototypical local anaesthetic. Common uses with emphasis on spinal and epidural anaesthesia, commonly caused severe complications of their use. General anaesthetics. Definition of general anaesthesia and how it is achieved, stages of anaesthesia. Pharmacokinetics of inhalational anaesthetics. Blood, gas coefficient, ventilation rate and pulmonary blood flow influence on the onset (and termination) of action of inhalational anaesthetics, influence of tissue blood flow on the tension of anaesthetic gas in that tissue, definition of minimum alveolar concentration (MAC) and what information it provides on a volatile anaesthetic. Pharmacokinetic properties of the ultra-short-acting hypnotics and how they make this class of drugs popular general anaesthetic drugs. Advantages and disadvantages of clinically used inhaled and intravenously administered general anaesthetics, when they should be used, their contraindications. Concept that inhalational and intravenous anaesthetics cause varying degrees of respiratory depression with exception of ketamine. Use of anaesthetics in persons already taking drugs such as neuromuscular blocking drugs and CNS stimulants.