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NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Anticoagulants Pharmacology and Therapeutics • Source Session/Topic 35 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 35: Pharmacodynamics of Anticoagulants Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe mechanism of action of Anticoagulants Describe drug interactions associated with Anticoagulants Describe side effects of Anticoagulants Describe contraindications of Anticoagulants Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD projector SESSION OVERVIEW Step Time Activity/ Content Step Time Activity/ Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning tasks Introduction, Learning tasks Introduction, Learning tasks 2 2 40 minutes 40 minutes Presentation/ Mechanism of Action of Anticoagulants Mechanism of Action of Anticoagulants Mechanism of Action of Anticoagulants 2 2 40 minutes 40 minutes Buzzing Mechanism of Action of Anticoagulants Mechanism of Action of Anticoagulants Mechanism of Action of Anticoagulants Buzzing 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated with Drug Interactions Associated with Drug Interactions Associated with 3 3 20 minutes 20 minutes brainstorming Anticoagulants Anticoagulants Anticoagulants brainstorming Anticoagulants Anticoagulants Anticoagulants 4 4 20 minutes 20 minutes Presentation Side Effects of Anticoagulants Side Effects of Anticoagulants Side Effects of Anticoagulants PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics 277 277 277 NTA Level 5 Semester 1 Facilitator Guide NTA Level 5 Semester 1 Facilitator Guide 5 15 minutes Presentation/ Contraindications of Anticoagulants 5 15 minutes Brainstorming Contraindications of Anticoagulants Brainstorming 6 05 minutes Presentation Key Points 7 05 minutes Presentation Evaluation 8 10 minutes Presentation Assignment PST 05104 Pharmacology & Therapeutics 278 NTA Level 5 Semester 1 Facilitator Guide SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Mechanism of Action of Anticoagulants (40 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do Anticoagulants produce their pharmacological effects? ALLOW few pairs to respond and let other pairs add on points not mentioned WRITE their response on the flip chart/board CLARIFY and SUMMARIZE by using the content below Anticoagulants Heparins: o Heparin is a sulphated acidic mucopolysaccharide that is widely distributed in the body. o The unfractionated preparation is extracted from the lung or intestine of ox or pig, and is a mixture of polymers of varying molecular weights. o Since the structure is variable, the dosage is expressed in terms of units of biological activity. o Low-molecular-weight heparins (LMWH) are fragments or short synthetic sequences of heparin with much more predictable pharmacological effects, and monitoring of their anticoagulant effect is seldom needed. o They have largely replaced unfractionated heparin in therapy. Unfractionated Heparin(UFH) o Unfractionated heparin has been replaced by LMWH for most indications, but remains important for patients with impaired or rapidly changing renal function. o Treatment is monitored by measuring the activated partial thromboplastin time (APTT) four to six hours after starting treatment and then every six hours, until two consecutive readings are within the target range, and thereafter at least daily. o Dose adjustments are made to keep the APTT ratio (i.e. the ratio between the value for the patient and the value of a control) in the range 1.5–2.5. o Mechanism: PST 05104 Pharmacology & Therapeutics 279 NTA Level 5 Semester 1 Facilitator Guide The main action of heparin is on the coagulation cascade. It works by binding to antithrombin III, a naturally occurring inhibitor of thrombin and other serine proteases (factors IXa, Xa, XIa and XIIa), and enormously potentiating its inhibitory action. A lower concentration is required to inhibit factor Xa and the other factors early in the cascade than is needed to antagonize the action of thrombin, providing the rationale for low-dose heparin in prophylaxis. o As an antithrombin drug, it inhibits platelet activation by thrombin Low Molecular Weight Heparins (LMWH) Low-molecular-weight heparins (LMWH) preferentially inhibit factor Xa. They do not prolong the APTT, and monitoring (which requires sophisticated factor Xa assays) is not needed in routine clinical practice, because their pharmacokinetics are more predictable(less protein binding and first-order kinetics) than those of unfractionated. LMWH (e.g. enoxaparin and dalteparin) are at least as safe and effective as unfractionated products, except in patients with renal impairment. Thrombocytopenia and related thrombotic events and antiheparin antibodies are less common than with unfractionated preparations. Once-daily dosage makes them convenient, and patients can administer them at home, reducing hospitalization. However, LMWH are eliminated solely by renal excretion, unlike unfractionated heparin; as a consequence, unfractionated heparin should be used rather than low-molecular-weight preparations in patients with significant renal dysfunction. Mechanism: as discussed on UFH Direct Factor Xa Inhibitors: Rivaroxaban: Direct factor Xa inhibitors are agents that inhibit clotting by inhibiting a specific component of the coagulation cascade. Factor Xa converts prothrombin to thrombin (factor IIa). Thrombin is an enzyme that catalyses the final step in the coagulation cascade, the conversion of fibrinogen to fibrin. Fibrin is a fibrous protein that forms a mesh, providing structural rigidity to a clot. The mesh is created by the cross-linking of fibrin, and this cross-linking step is facilitated by factor XIII. In addition to converting fibrinogen to fibrin, thrombin also activates factor XIII; thus thrombin not only catalyses the creation of the key component of the clot, it also facilitates the provision of structural rigidity to the clot. Thrombin also activates factors V, VIII, and XI, therefore amplifying the coagulation cascade. In addition, thrombin activates platelets, leading to their aggregation. Direct factor Xa

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Antihypertensive Drugs Pharmacology and Therapeutics • Source Session/Topic 34 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 34: Pharmacodynamics of Antihypertensive Drugs Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe mechanism of action of Antihypertensive Drugs Describe drug interactions associated with Antihypertensive Drugs Describe side effects of Antihypertensive Drugs Describe contraindications of Antihypertensive Drugs Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD projector SESSION OVERVIEW Step Time Activity/ Content Step Time Activity/ Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning Tasks Introduction, Learning Tasks 2 2 45 minutes 45 minutes Presentation/ Mechanism of Action of Antihypertensive Mechanism of Action of Antihypertensive 2 2 45 minutes 45 minutes Buzzing Drugs Drugs Buzzing Drugs Drugs 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Drug Interactions Associated With 3 3 20 minutes 20 minutes brainstorming Antihypertensive Drugs Antihypertensive Drugs brainstorming Antihypertensive Drugs Antihypertensive Drugs 4 4 20 minutes 20 minutes Presentation Side Effects of Antihypertensive Drugs Side Effects of Antihypertensive Drugs 5 5 20 minutes 20 minutes Presentation/ Contraindications of Antihypertensive Drugs Contraindications of Antihypertensive Drugs 5 5 20 minutes 20 minutes Brainstorming Contraindications of Antihypertensive Drugs Contraindications of Antihypertensive Drugs Brainstorming 6 6 05 minutes 05 minutes Presentation Key Points Key Points 7 7 05 minutes 05 minutes Presentation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics 268 NTA Level 5 Semester 1 Facilitator Guide SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Mechanism of Action of Antihypertensive Drugs (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do antihypertensive drugs produce their pharmacological effects? ALLOW few pairs to respond and let other pairs add on points not mentioned WRITE their response on the flip chart/board CLARIFY and SUMMARIZE by using the content below Angiotensin-Converting Enzyme Inhibitors(ACEI) o These drugs block the enzyme that cleaves angiotensin I to form the potent vasoconstrictor, angiotensin II. o ACEI lower blood pressure by reducing angiotensin II and perhaps also by increasing vasodilator peptides, such as bradykinin by diminishing their inactivation. o Angiotensin II causes aldosterone secretion from the zona glomerulosa of the adrenal cortex and inhibition of this contributes to the antihypertensive effect of ACE inhibitors because of decreased sodium and water retention. Beta blockers o Β-Adrenoceptor antagonists reduce cardiac output (via negative chronotropic and negative inotropic effects on the heart). o These drugs also inhibit renin secretion and some have additional central actions reducing sympathetic outflow from the central nervous system (CNS). Angiotensin receptor blockers o Most of the effects of angiotensin II, including vasoconstriction and aldosterone release, are mediated by the angiotensin II subtype 1 (AT1) receptor. o These drugs block the AT1 receptors thus blocking Angiotensin II actions/effects. Calcium Channel blockers o Calcium-channel blockers inhibit Ca2+ influx through voltage-dependent L-type calcium channels. o Cytoplasmic Ca2+ concentrations control the contractile state of actomyosin. PST 05104 Pharmacology & Therapeutics 269 NTA Level 5 Semester 1 Facilitator Guide Calcium-channel blockers therefore relax arteriolar smooth muscle, reduce peripheral vascular resistance and lower arterial blood pressure. Diuretics o Thiazide Diuretics: Thiazide diuretics inhibit reabsorption of sodium and chloride ions in the proximal part of the distal convoluted tubule. o Excessive salt intake or a low glomerular filtration rate interferes with their antihypertensive effect. Natriuresis is therefore probably important in determining their hypotensive action. α-Adrenoceptor antagonists There are two main types of α-adrenoceptor, α1- and α2. Noradrenaline activates α1-receptors on vascular smooth muscle, causing tonic vasoconstriction. α1-Antagonists cause vasodilatation by blocking this tonic action of noradrenaline hence α1-Adrenoceptor antagonist‘s lower blood pressure. Prazosin, doxazosin and other alpha 1 receptor blockers decrease peripheral vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and venous smooth muscle. These drugs cause only minimal changes in cardiac output, renal blood flow, and glomerular filtration rate. Centrally acting drugs Methyldopa: after uptake into central neurones and methyldopa is metabolised to a false transmitter (α-methylnoradrenaline) which is an α2-adrenoceptor agonist. Activating central α2-adrenoceptors by the false transmitter inhibits sympathetic outflow from the CNS. Moxonidine is another centrally acting drug: it acts on imidazoline receptors and is said to be better tolerated than methyldopa. Other vasodilators Minoxidil: works via a sulphate metabolite which activates potassium channels. This relaxes vascular smooth muscle, reducing peripheral vascular resistance and lowering blood pressure. Nitroprusside: It is a rapid acting inorganic nitrate which degrades to NO relaxes blood vessels hence reduced blood pressure. PST 05104 Pharmacology & Therapeutics 270 NTA Level 5 Semester 1 Facilitator Guide STEP 3: Drug Interactions Associated with Antihypertensive Drugs (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What drug interactions associated with antihypertensives drugs? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below Angiotensin Converting Enzyme Inhibitors o ACEI interaction with Diuretics: o Diuretic treatment increases plasma renin activity and the consequent activation of angiotensin II and aldosterone thus limiting efficacy of ACEIs. o ACE inhibition interrupts the loop and thus enhances the hypotensive efficacy of diuretics, as well as reducing thiazide-induced hypokalaemia. o Conversely, ACEI have a potentially adverse interaction with potassium-sparing diuretics and potassium supplements, leading to hyperkalaemia, especially in patients with renal impairment. o As with other antihypertensive drugs, NSAIDs increase blood pressure in patients treated with ACE inhibitors. Beta Blockers o Pharmacokinetic interactions: o β-adrenoceptor antagonists inhibit drug metabolism indirectly by decreasing hepatic blood flow secondary to decreased cardiac output. o This causes accumulation

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Drugs for Heart Failure Pharmacology and Therapeutics • Source Session/Topic 33 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 33: Pharmacodynamics of Drugs for Heart Failure Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe mechanism of action of drugs for heart failure Describe drug interactions associated with drugs for heart failure Describe side effects of drugs for heart failure Describe contraindications of drugs for heart failure Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD projector SESSION OVERVIEW Step Time Activity/ Content Step Time Activity/ Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning Tasks Introduction, Learning Tasks 2 2 45 minutes 45 minutes Presentation/ Mechanism of Action of Drugs for Heart Mechanism of Action of Drugs for Heart 2 2 45 minutes 45 minutes Buzzing Failure Failure Buzzing Failure Failure 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated Drugs for Heart Drug Interactions Associated Drugs for Heart 3 3 20 minutes 20 minutes brainstorming Failure Failure brainstorming Failure Failure 4 4 20 minutes 20 minutes Presentation Side Effects of Drugs for Heart Failure Side Effects of Drugs for Heart Failure 5 5 20 minutes 20 minutes Presentation/ Contraindications of Drugs for Heart Failure Contraindications of Drugs for Heart Failure 5 5 20 minutes 20 minutes Brainstorming Contraindications of Drugs for Heart Failure Contraindications of Drugs for Heart Failure Brainstorming 6 6 05 minutes 05 minutes Presentation Key Points Key Points 7 7 05 minutes 05 minutes Presentation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics 261 NTA Level 5 Semester 1 Facilitator Guide SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Mechanism of Action of Drugs for Heart Failure (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do Drugs for Heart Failure produce their pharmacological effects? ALLOW few pairs to respond and let other pairs add on points not mentioned WRITE their response on the flip chart/board CLARIFY and SUMMARIZE by using the content below Drugs for Heart Failure Diuretics o In Chronic heart failure: a diuretic is used to control symptomatic oedema and dyspnoea in patients with heart failure. o For more information on adverse effects, interactions , contraindications and mechanism refer a session on Pharmacodynamics of drugs acting on urinal genital system o Spironolactone improves survival in patients with cardiac failure and counters diuretic-induced hypokalaemia. o Diuretic-induced hypokalaemia increases the toxicity of digoxin. Conversely, spironolactone and other K+-retaining diuretics (e.g. amiloride, triamterene) can cause severe hyperkalaemia, especially if given with ACEI or sartans to patients with renal impairment. o It is therefore important to monitor plasma K+ during treatment with all diuretic therapy. Angiotensin-Converting Enzyme Inhibitors For more information on adverse effects, interactions , contraindications and mechanism refer a session on Pharmacodynamics of drugs acting on urinal genital system (session ) and Pharmacodynamics of Antihypertensive drugs(session ) When symptoms are mild, diuretics can be temporarily discontinued a day or two before starting an ACEI, reducing the likelihood of first-dose hypotension. PST 05104 Pharmacology & Therapeutics 262 NTA Level 5 Semester 1 Facilitator Guide Angiotensin Receptor Antagonists, Sartans o For more information on adverse effects, interactions, contraindications and mechanism refer a session on Pharmacodynamics of Pharmacodynamics of Antihypertensive drugs (session). o As in hypertension, the pharmacodynamics of sartans are similar to those of ACEI apart from a lower incidence of some adverse effects, including, particularly, dry Inotropic action: Through the action of Na/K/ATP ion pump blockade, the following sequence of ionic events occurs: o ↓ Na exits the cell o ↑ Intracellular Na o ↓ Na electrochemical gradient for Na-Ca exchanger o ↓ Ca exits the cell o ↑ Intracellular Ca o The increase in intracellular calcium results in increased contractility, SV, and CO. o In heart failure, sympathetic tone is increased as a compensatory mechanism to increase CO. o Digoxin increases contractility and hence SV and CO, therefore reducing the need for sympathetic compensation cough. Thus digoxin reduces the sympathetic tone in heart failure Beta blockers o For more information on adverse effects, interactions , contraindications and mechanism refer a session on Pharmacodynamics of Antihypertensives o Beta-blockers are negative inotropes and so intuitively would be expected to worsen heart failure. o There is, however, a rationale for their use in terms of antagonizing counter regulatory sympathetic activation and several randomized controlled trials have demonstrated improved survival when a β-adrenoceptor antagonist is added to other drugs, including an ACEI. Beta1-Adrenergic Agonists: Dobutamine ,Dopamine, Amrinone and Milrinone o Improves cardiac performance by their positive inotropic effects and vasodilatation ((β-2), minimum effects on HR by dobutamine) Increase in intracellular cAMP → results in the entry of Ca2+ into the myocardial cells increases, thus enhancing contraction Diminished effects after long-time infusions and possible worsening upon withdrawal o Ibopamine which is a pro-drug and has actions at β-1, β-2, D1 and D2 is not preferred because of the non-selectivity hence increased toxicity. Glucagon o Glucagon increases cyclic AMP thus increasing myocardial contraction hence used in acute cardiac dysfunction due to overdose of β-blockers Inhibitors of Phosphodiesterase III o Inhibitors of phosphodiesterase III which is specific to the heart and responsible for degradation of cyclic AMP thus increases myocardial contractility are also used. PST 05104 Pharmacology & Therapeutics 263 NTA Level 5 Semester 1 Facilitator Guide STEP 3: Drug Interactions Associated with Drugs for Heart Failure (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are drug interactions associated with drugs for heart failure? ALLOW

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Antidepressants Pharmacology and Therapeutics • Source Session/Topic 32 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 32: Pharmacodynamics of Antidepressants Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Explain pathophysiology of depression Describe mechanism of action of Antidepressants Describe drug interactions associated with Antidepressants Describe side effects of Antidepressants Describe contraindications of Antidepressants Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD projector SESSION OVERVIEW Step Time Activity/ Content Step Time Activity/ Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning tasks Introduction, Learning tasks Introduction, Learning tasks 2 2 20 minutes 20 minutes Presentation Pathophysiology of depression Pathophysiology of depression Pathophysiology of depression 3 3 45 minutes 45 minutes Presentation/ Mechanism of Action of Antidepressants Mechanism of Action of Antidepressants Mechanism of Action of Antidepressants 3 3 45 minutes 45 minutes Buzzing Mechanism of Action of Antidepressants Mechanism of Action of Antidepressants Mechanism of Action of Antidepressants Buzzing 4 4 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Drug Interactions Associated With Drug Interactions Associated With 4 4 20 minutes 20 minutes brainstorming Antidepressants Antidepressants Antidepressants brainstorming Antidepressants Antidepressants Antidepressants 5 5 10 minutes 10 minutes Presentation Side Effects of Antidepressants Side Effects of Antidepressants Side Effects of Antidepressants PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics 251 251 251 NTA Level 5 Semester 1 Facilitator Guide NTA Level 5 Semester 1 Facilitator Guide 6 10 minutes Presentation/ Contraindications of Antidepressants 6 10 minutes Brainstorming Contraindications of Antidepressants Brainstorming 7 05 minutes Presentation Key Points 8 05 minutes Presentation Evaluation PST 05104 Pharmacology & Therapeutics 252 NTA Level 5 Semester 1 Facilitator Guide SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Pathophysiology of Depression (20 minutes) Monoamine theory of depression suggest that depression is due to a cerebral deficiency of monoamines particularly noradrenaline (NA), 5-hydroxytryptamine (5HT) and methyltyrosine. The following actions of drugs support the above theory: Reserpine -depletes neuronal stores of noradrenaline (NA) and 5-hydroxytryptamine (5HT) and α-methyltyrosine, which inhibits NA synthesis causing depression, Tricyclic antidepressants (TCA) of the amitriptyline type (which raise the synaptic concentration of NA and 5HT) are antidepressant and Monoamine oxidase inhibitors (MAOIs, which increase total brain NA and 5HT) are antidepressant. Another theory of depression is the serotonin-only hypothesis. o This theory emphasizes the role of 5HT and downplays that of NA in the causation of depression, and is backed by the effectiveness of the selective serotonin reuptake inhibitors, or SSRI class of drugs, in the treatment of depression. STEP 3: Mechanism of Action of Antidepressants (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do antidepressants produce their pharmacological effects? ALLOW few pairs to respond and let other pairs add on points not mentioned WRITE their response on the flip chart/board CLARIFY and SUMMARIZE by using the content below Tricyclic Antidepressants (TCAs) Examples include amitriptyline, desipramine, imipramine, nortriptyline, clomipramine, trimipramine, doxepin, maprotiline PST 05104 Pharmacology & Therapeutics 253 NTA Level 5 Semester 1 Facilitator Guide The monoamine hypothesis suggests that depression is caused by a deficiency of synaptic neurotransmitters such as serotonin (5-HT), NA, and dopamine. Serotonin, in particular, is associated with mood. Normally, 5-HT and NA are released from presynaptic vesicles into the synaptic cleft, where they travel to postsynaptic receptors. Once released from these postsynaptic receptors, 5-HT and NA are removed from the synaptic cleft by reuptake transporters located on the presynapse. The TCAs inhibit the reuptake of serotonin (5-HT) and NA into the presynaptic cell body, increasing the amount of 5-HT and NA available to bind to postsynaptic receptors. TCAs antagonize other receptors: muscarinic, histamine (H1), adrenergic (α1) receptors. This accounts for their extensive list of side effects. Selective Serotonin Reuptake Inhibitors (SSRIs) Examples include fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram and escitalopram. The monoamine hypothesis suggests that depression is caused by a deficiency of synaptic neurotransmitters such as serotonin (5-HT), norepinephrine, and dopamine. Serotonin, in particular, is associated with mood. Normally, 5-HT is released from presynaptic vesicles into the synaptic cleft, where it travels to postsynaptic receptors. Once released from these postsynaptic receptors, 5-HT is removed from the synaptic cleft by reuptake transporters located on the presynapse. Once it is taken up presynaptically, it is degraded. SSRIs bind to this reuptake transporter, preventing the removal of 5-HT and leading to increased 5-HT available to bind to postsynaptic receptors. Serotonin-Noradrenaline Reuptake Inhibitors (SNRIs) Examples include venlafaxine, desvenlafaxine, duloxetine and milnacipran Once released from these postsynaptic receptors, 5-HT and NA are removed from the synaptic cleft by reuptake transporters located on the presynapse. Once they are taken up presynaptically, they are degraded. SNRIs bind to these reuptake transporters, preventing the removal of 5-HT and NA and leading to increased availability to bind to postsynaptic receptors. Venlafaxine has much higher affinity for the serotonin reuptake transporter, and at low doses acts more like an SSRI. It is not until higher doses are used that it also blocks noradrenaline reuptake. o Conversely, milnacipran blocks serotonin and noradrenaline reuptake equally, whereas the other agents in this class fall somewhere between these two. PST 05104 Pharmacology & Therapeutics 254 NTA Level 5 Semester 1 Facilitator Guide Monoamine oxidase Inhibitors (MAOIs) Examples include :Selective to MAO-B: Selegiline, rasagiline, Selective to MAO-A: Moclobemide and Nonselective inhibitors: phenelzine and tranylcypromine o MAO degrades catecholamines, serotonin, and

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Drugs Used in Parkinson's Disease Pharmacology and Therapeutics • Source Session/Topic 31 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 31: Pharmacodynamics of Drugs Used in Parkinson's Disease Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe mechanism of action of Drugs Used in Parkinson's Disease Describe drug interactions associated with Drugs Used in Parkinson's Disease Describe side effects of Drugs Used in Parkinson's Disease Describe contraindications of Drugs Used in Parkinson's Disease Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD projector SESSION OVERVIEW Step Time Activity/ Content Step Time Activity/ Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning Tasks Introduction, Learning Tasks Introduction, Learning Tasks 2 2 45 minutes 45 minutes Presentation/ Mechanism of Action of Drugs Used in Mechanism of Action of Drugs Used in Mechanism of Action of Drugs Used in 2 2 45 minutes 45 minutes Buzzing Parkinson's Disease Parkinson's Disease Parkinson's Disease Buzzing Parkinson's Disease Parkinson's Disease Parkinson's Disease 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Drugs Drug Interactions Associated With Drugs Drug Interactions Associated With Drugs 3 3 20 minutes 20 minutes brainstorming Used in Parkinson's Disease Used in Parkinson's Disease Used in Parkinson's Disease brainstorming Used in Parkinson's Disease Used in Parkinson's Disease Used in Parkinson's Disease 4 4 20 minutes 20 minutes Presentation Adverse Effects of Drugs Used in Parkinson's Adverse Effects of Drugs Used in Parkinson's Adverse Effects of Drugs Used in Parkinson's 4 4 20 minutes 20 minutes Presentation Disease Disease Disease Disease Disease Disease 5 5 20 minutes 20 minutes Presentation/ Contraindications of Drugs Used in Contraindications of Drugs Used in Contraindications of Drugs Used in 5 5 20 minutes 20 minutes Brainstorming Parkinson's Disease Parkinson's Disease Parkinson's Disease Brainstorming Parkinson's Disease Parkinson's Disease Parkinson's Disease PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics 242 242 242 NTA Level 5 Semester 1 Facilitator Guide NTA Level 5 Semester 1 Facilitator Guide 6 05 minutes Presentation Key Points 7 05 minutes Presentation Evaluation PST 05104 Pharmacology & Therapeutics 243 NTA Level 5 Semester 1 Facilitator Guide SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning objectives and clarify ASK students if they have any questions before continuing. STEP 2: Mechanism of Action of Drugs Used in Parkinson's Disease (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do drugs Used in Parkinson's Disease produce their pharmacological effects? ALLOW few pairs to respond and let other pairs add on points not mentioned WRITE their response on the flip chart/board CLARIFY and SUMMARIZE by using the content below Parkinsonism is a progressive neurologic disorder of muscle movement, characterized by tremors, muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural and gait abnormalities. The cause of Parkinson's disease is unknown for most patients. The disease is correlated with a reduction in the activity of inhibitory dopaminergic neurons in the substantia nigra and corpus striatum parts-of the brain's basal ganglia system that are responsible for motor control. Mechanisms of drugs used for treatment of Parkinsonism are: Dopamine Precussors; Levodopa o Levodopa is a metabolic precursor of dopamine. o Cross blood brain barrier as it is readily taken up by the amino transport systems. o It restores dopamine levels in the extrapyramidal centers (substantia nigra) that atrophy in parkinsonism. o Required in high doses because the drug is decarboxylated to dopamine in the periphery by L-aromatic amino acid decarboxylase enzyme. o Since Parkinsonism results from insufficient dopamine in specific regions of the brain, attempts have been made to replenish the dopamine deficiency. Dopamine itself PST 05104 Pharmacology & Therapeutics 244 NTA Level 5 Semester 1 Facilitator Guide does not cross the blood-brain barrier, but its immediate precursor levodopa is readily transported into the CNS and is converted to dopamine in the brain Actions: Levodopa decreases rigidity, tremors and other symptoms of parkinsonism. Carbidopa The effects of levodopa on the CNS can be greatly enhanced by coadministering carbidopa, a dopamine decarboxylase inhibitor that does not cross the blood-brain barrier. Carbidopa diminishes the metabolism of levodopa in the GI tract and peripheral tissues; thus, it increases the availability of levodopa to the CNS. The addition of carbidopa lowers the dose of levodopa needed by 4- to 5- fold and, consequently, decreases the severity of the side effects of peripherally formed dopamine. Catechol-O-Methyl Transferase (COMT) Inhibitors: Entacapone and tolcapone COMT inhibitors increase the amount of dopamine available to the CNS. COMT is one of the two major enzymes involved in the metabolism of catecholamines (epinephrine, norepinephrine, and dopamine). Thus one of the ways COMT inhibitors increase dopamine is by inhibiting its breakdown. Monoamine oxidase B inhibitors (MAO B) Inhibitors: Selegiline and Rasagiline Selectively inhibit MAO-B which metabolizes dopamine more efficiently than NE and 5-HT. The net effect is an increase in brain dopamine levels. These drugs can be used in conjunction with L-dopa. Because selegiline and rasagiline selectively inhibit MAO-B, they are much less likely to produce a hypertensive reaction with cheese or other sources of tyramine than non-selective MAOIs, such as phenelzine. Dopamine Agonists: Bromocriptine The absorption and extent of first-pass metabolism of bromocriptine is highly variable, leading to wide fluctuations in plasma concentrations and variability in dose response. Dopamine agonists bind to dopamine receptors to produce actions similar to dopamine. The dopamine agonists used in Parkinson‘s disease have longer durations

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Antipsychotic Drugs Pharmacology and Therapeutics • Source Session/Topic 30 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 30: Pharmacodynamics of Antipsychotic Drugs Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe mechanism of action of Antipsychotic Drugs Explain the dopamine theory of schizophrenia Describe drug interactions associated with Antipsychotic Drugs Describe side effects of Antipsychotic Drugs Describe contraindications of Antipsychotic Drugs Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD projector SESSION OVERVIEW Step Time Activity/ Content Step Time Activity/ Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning Tasks Introduction, Learning Tasks Introduction, Learning Tasks 2 2 15 minutes 15 minutes Presentation/ Dopamine Theory of Schizophrenia Dopamine Theory of Schizophrenia Dopamine Theory of Schizophrenia 2 2 15 minutes 15 minutes Buzzing Dopamine Theory of Schizophrenia Dopamine Theory of Schizophrenia Dopamine Theory of Schizophrenia Buzzing 3 3 40 minutes 40 minutes Presentation Mechanism of Action of Antipsychotic Drugs Mechanism of Action of Antipsychotic Drugs Mechanism of Action of Antipsychotic Drugs 4 4 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Drug Interactions Associated With Drug Interactions Associated With 4 4 20 minutes 20 minutes brainstorming Antipsychotic Drugs Antipsychotic Drugs Antipsychotic Drugs brainstorming Antipsychotic Drugs Antipsychotic Drugs Antipsychotic Drugs 5 5 20 minutes 20 minutes Presentation Side Effects of Antipsychotic Drugs Side Effects of Antipsychotic Drugs Side Effects of Antipsychotic Drugs 6 6 10 minutes 10 minutes Presentation/ Contraindications of Antipsychotic Drugs Contraindications of Antipsychotic Drugs Contraindications of Antipsychotic Drugs 6 6 10 minutes 10 minutes Brainstorming Contraindications of Antipsychotic Drugs Contraindications of Antipsychotic Drugs Contraindications of Antipsychotic Drugs Brainstorming 7 7 05 minutes 05 minutes Presentation Key Points Key Points Key Points 8 8 05 minutes 05 minutes Presentation Evaluation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics 233 233 233 NTA Level 5 Semester 1 Facilitator Guide NTA Level 5 Semester 1 Facilitator Guide SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Dopamine Theory of Schizophrenia (15 minutes) Pathophysiology of Schizophrenia Dopamine theory o Schizophrenia is due to neurochemical disorder, this concept is advanced by the dopamine theory of schizophrenia which gives evidence that schizophrenia is mainly due to excess levels of dopamine in the CNS. o Evidence supporting dopamine theory is shown below: o There is excess dopamine activity in the mesolimbic system in schizophrenia. o Antipsychotic potency is often proportional to D2-blocking potency. o Amphetamine (which increases dopamine release) can produce acute psychosis that is indistinguishable from acute schizophrenia (positive symptoms). o D2 agonists (bromocriptine and apomorphine) aggravate schizophrenia in schizophrenic patients. o There is an increase in D2 and D4 receptors on PET in schizophrenic patients. o L-Dopa can cause hallucinations and acute psychotic reactions and paranoia, but does not cause all the features of these conditions. o The majority of antipsychotics block dopamine receptors in the forebrain. o However, about 30% of patients with schizophrenia respond inadequately to conventional dopamine D2 receptor antagonists. o This indicates that there are other neurotransmitters involved apart from dopamine. o 5-Hydroxytryptamine is also implicated in schizophrenia. o Glutamine hypoactivity, GABA hypoactivity and α-adrenergic hyperactivity are also potential neurochemical targets. STEP 3: Mechanism of Action of Antipsychotic Drugs (40 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do antipsychotics produce their pharmacological effects? ALLOW few pairs to respond and let other pairs add on points not mentioned WRITE their response on the flip chart/board CLARIFY and SUMMARIZE by using the content below PST 05104 Pharmacology & Therapeutics 234 NTA Level 5 Semester 1 Facilitator Guide Conventional/Typical Antipsychotic drugs (First generation antipsychotics) Phenothiazine: o Include chlorpromazine, thioridazine, fluphenazine, perphenazine, trifluoperazine, pipotiazine, pericyazine, prochlorperazine o Conventional antipsychotics are antagonists at dopamine D2 receptors. It is the antagonism of D2 receptors in the mesolimbic pathway that is thought to alleviate the positive symptoms of schizophrenia. o Blockade of D2 receptors in other pathways is believed to result in many of the side effects of typical antipsychotics. o The effect on D1 receptors is variable. Blockade of the D2 receptors induces extrapyramidal effects. o Repeated administration causes an increase in D2-receptor sensitivity due to an increase in abundance of these receptors. o This appears to underlie the tardive dyskinesias that are caused by prolonged use of the conventional antipsychotic drugs. o The choice of conventional drugs is largely determined by the demands of the clinical situation, in particular the degree of sedation needed and the patient‘s susceptibility to extrapyramidal toxicity and hypotension. o First-generation antipsychotics antagonize numerous other receptors, including adrenergic and cholinergic as well as histamine H1 receptors. o Although it is still unclear to what extent, if any, antagonism of these receptors contributes to the efficacy of antipsychotics, they have a clear role in mediating many of the side effects associated with these agents. Butyrophenones : o Include Haloperidol, droperidol o Butyrophenones are antagonists at dopamine D2 receptors. It is the antagonism of D2 receptors in the mesolimbic pathway that is thought to alleviate the positive symptoms of schizophrenia. Blockade of D2 receptors in other pathways is believed to result in many of the side effects of typical antipsychotics. o Other actions are similar to phenothiazines. Thioxanthenes: o Include Flupenthixol, thiothixene, zuclopenthixol o Thioxanthenes are antagonists at dopamine D2 receptors. It is the antagonism of D2 receptors in

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Hypnotics and Anxiolytics Pharmacology and Therapeutics • Source Session/Topic 29 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 29: Pharmacodynamics of Hypnotics and Anxiolytics Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe mechanism of action of Hypnotics and Anxiolytics Describe drug interactions associated with Hypnotics and Anxiolytics Describe side effects of Hypnotics and Anxiolytics Describe contraindications of Hypnotics and Anxiolytics Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD projector SESSION OVERVIEW Step Time Activity/ Content Step Time Activity/ Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning Tasks Introduction, Learning Tasks Introduction, Learning Tasks 2 2 45 minutes 45 minutes Presentation/ Mechanism of Action of Hypnotics and Mechanism of Action of Hypnotics and Mechanism of Action of Hypnotics and 2 2 45 minutes 45 minutes Buzzing Anxiolytics Anxiolytics Anxiolytics Buzzing Anxiolytics Anxiolytics Anxiolytics 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Hypnotics Drug Interactions Associated With Hypnotics Drug Interactions Associated With Hypnotics 3 3 20 minutes 20 minutes brainstorming and Anxiolytics and Anxiolytics and Anxiolytics brainstorming and Anxiolytics and Anxiolytics and Anxiolytics 4 4 20 minutes 20 minutes Presentation Side Effects of Hypnotics and Anxiolytics Side Effects of Hypnotics and Anxiolytics Side Effects of Hypnotics and Anxiolytics 5 5 20 minutes 20 minutes Presentation/ Contraindications of Hypnotics and Contraindications of Hypnotics and Contraindications of Hypnotics and 5 5 20 minutes 20 minutes Brainstorming Anxiolytics Anxiolytics Anxiolytics Brainstorming Anxiolytics Anxiolytics Anxiolytics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics 225 225 225 NTA Level 5 Semester 1 Facilitator Guide NTA Level 5 Semester 1 Facilitator Guide 6 05 minutes Presentation Key Points 7 05 minutes Presentation Evaluation PST 05104 Pharmacology & Therapeutics 226 NTA Level 5 Semester 1 Facilitator Guide SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Mechanism of Action of Hypnotics and Anxiolytics (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do hypnotics and anxiolytics produce their pharmacological effects? ALLOW few pairs to respond and let other pairs add on points not mentioned WRITE their response on the flip chart/board CLARIFY and SUMMARIZE by using the content below Hypnotics and Anxiolytics The distinction between hypnotics and anxiolytics is rather arbitrary, and the same classes of drugs are used for both purposes. Compounds with a short half-life tend to be used as hypnotics, because they cause less ‗hangover‘ effects; longer half-life drugs tend to be used as anxiolytics, since a longer duration of action is generally desirable in this setting. Benzodiazepines o These drugs are anxiolytic, anticonvulsant muscle relaxants that induce sleepiness; they remain drugs of choice for the pharmacological treatment of insomnia and anxiety. o Clonazepam is believed to be more anticonvulsant than other members of the group at equi-sedating doses. o Benzodiazepines target the GABA receptors (GABA is the major inhibitory neurotransmitter in the CNS). Binding of BZDs to this BZD binding site at GABA enhances the effects of GABA at the GABAA receptor. o Binding of GABA triggers the opening the Cl- channel resulting in hyperpolarization pushing the postsynaptic neuron further from the threshold. This result to an increase in suppressing action potential generation thus increased hyperpolarization-induced neuronal inhibition. o The clinical effects of BZDs correlate well with GABA receptor binding affinity. o BZDs are unable to activate the GABAA receptor on their own; therefore BZDs have no pharmacologic effects on the Cl− channel when GABA is absent. PST 05104 Pharmacology & Therapeutics 227 NTA Level 5 Semester 1 Facilitator Guide The Actions of BDZ are: Reduction of anxiety: At low doses, the benzodiazepines are anxiolytic. They are thought to reduce anxiety by selectively inhibiting neuronal circuits in the limbic system of the brain. Sedative and hypnotic actions: All of the benzodiazepines used to treat anxiety have some sedative properties. At higher doses, certain benzodiazepines produce hypnosis (artificially-produced sleep). Anticonvulsant action: Several of the benzodiazepines have anticonvulsant activity and are used to treat epilepsy and other seizure disorders. Muscle relaxant effect: The benzodiazepines relax the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord. Zolpidem o Although the hypnotic zolpidem is not a benzodiazepine, it acts on a subset of the benzodiazepine receptor family. o The difference with BDZ: Zolpidem has no anticonvulsant or muscle relaxing properties. It shows no withdrawal effects, exhibits minimal rebound insomnia and little or no tolerance occurs with prolonged use. Buspirone o Buspirone is useful in the treatment of generalized anxiety disorders and has an efficacy comparable to the benzodiazepines. o The actions of buspirone appear to be mediated by serotonin (5-HTlA) receptors, although other receptors could be involved, since buspirone displays some affinity for DA2 doparnine receptors and 5-HT2 serotonin receptors. The mode of action thus differs from that of the benzodiazepines. o Difference with BDZ: Buspirone lacks anticonvulsant and muscle-relaxant properties of the benzodiazepines and causes only minimal sedation. o Dependence is unlikely. o Buspirone has the disadvantage of a slow onset of action. Hydroxyzine o Hydroxyzine is an antihistamine with antiemetic activity. o It has a low tendency for habituation; thus it is useful for patients with anxiety, who have a history of drug abuse. It is also often used for sedation prior to dental procedures or surgery. Barbiturates o Barbiturates have been used as mild sedatives to

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Anticonvulsants Pharmacology and Therapeutics • Source Session/Topic 28 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 28: Pharmacodynamics of Anticonvulsants Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe mechanism of action of Anticonvulsants Describe drug interactions associated with Anticonvulsants Describe side effects of Anticonvulsants Describe contraindications of Anticonvulsants Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and projector SESSION OVERVIEW Step Time Activity/ Content Step Time Activity/ Content Step Time Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning Tasks Introduction, Learning Tasks Introduction, Learning Tasks 2 2 45 minutes 45 minutes Presentation/ Mechanism of Action of Anticonvulsants Mechanism of Action of Anticonvulsants Mechanism of Action of Anticonvulsants 2 2 45 minutes 45 minutes Buzzing Mechanism of Action of Anticonvulsants Mechanism of Action of Anticonvulsants Mechanism of Action of Anticonvulsants Buzzing 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Drug Interactions Associated With Drug Interactions Associated With 3 3 20 minutes 20 minutes brainstorming Anticonvulsants Anticonvulsants Anticonvulsants brainstorming Anticonvulsants Anticonvulsants Anticonvulsants 4 4 20 minutes 20 minutes Presentation Adverse Effects of Anticonvulsants Adverse Effects of Anticonvulsants Adverse Effects of Anticonvulsants 5 5 20 minutes 20 minutes Presentation/ Contraindications of Anticonvulsants Contraindications of Anticonvulsants Contraindications of Anticonvulsants 5 5 20 minutes 20 minutes Brainstorming Contraindications of Anticonvulsants Contraindications of Anticonvulsants Contraindications of Anticonvulsants Brainstorming 6 6 05 minutes 05 minutes Presentation Key Points Key Points Key Points 7 7 05 minutes 05 minutes Presentation Evaluation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics 218 218 218 NTA Level 5 Semester 1 Facilitator Guide NTA Level 5 Semester 1 Facilitator Guide SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Mechanism of Action of Anticonvulsants Drugs (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do drugs acting on the CNS produce their pharmacological effects? ALLOW few pairs to respond and let other pairs add on points not mentioned WRITE their response on the flip chart/board CLARIFY and SUMMARIZE by using the content below Anticonvulsants Sodium channel blockers (Phenytoin, Carbamazepine,) o Carbamazepine stabilizes the inactive form of the Na+ channel, which slows the rate of channel recovery from the inactivated state. This increases the threshold for action potentials and prevents repetitive firing. o Carbamazepine and other Na+ channel blockers bind to the Na+ channel when it is open. Because rapidly firing neurons, such as those found in seizure disorders are open a greater percentage of the time, these drugs tend to be selective for abnormal electrical activity found in a seizure focus and do not suppress normal neuronal activity. This is referred to as use-dependent blockade and is essential for limiting the toxicity of these agents. o Valproic acid may also reduce reduces the propagation of abnormal electrical discharge in the brain. It may enhance GABA action at inhibitory synapses. Calcium channel blockers (Ethosuximide) o Ethosuximide is used clinically for its selective effect on absence seizures. The mechanism of action is due to inhibition of T-type calcium channels, which may play a role in generating the 3/second firing rhythm in thalamic relay neurons that is characteristic of absence seizures Barbiturates: (Phenobarbital, Secobarbital, pentobarbital, mephobarbital, butabarbital, amobarbital) PST 05104 Pharmacology & Therapeutics 219 NTA Level 5 Semester 1 Facilitator Guide Binding of GABA to GABA A receptors leads to the opening of the chloride (Cl−) channel, facilitating Cl− influx and cellular hyperpolarization (making the inside more negative). Hyperpolarization of a cell decreases the probability that the cell can be subsequently depolarized by other incoming excitatory signals; this will have a net inhibitory effect. Barbiturates increase the binding of GABA to GABA A receptors and increase the influx of Cl− into the neuron, resulting in hyperpolarization and decreased neuronal activity. Barbiturates also potentiate the binding of benzodiazepines to GABAA receptors. The overall net effect of this binding is a global reduction in CNS activity; barbiturates are CNS depressants. GABA-transaminase inhibition (vigabatrin ) Vigabatrin inhibit transaminase enzyme thus preventing the metabolism of GABA to its metabolites resulting to an increase in GABA concentration. GABA-reuptake inhibitors (Tiagabine ) Tiagabine Inhibits GABA transporter (GAT-1) hence reducing reuptake of GABA by neurons and glial cells. γ-Aminobutyric acid (GABA) Analogues (Gabapentin, Pregabalin) GABA analogues are primarily used in the treatment of seizures and management of neuropathic pain. The structure of gabapentin is derived from GABA; therefore it has long been thought of as simply a GABA agonist. However, gabapentin does not appear to bind to GABA receptors. Instead, it may promote the release of GABA. Benzodiazepines BDZ like Diazepam (Valium), lorazepam, clonazepam, clorazepate have anticonvulsant activity. Not all BDZ are used as anticonvulsants. These drugs increases the frequency of GABAA-activated Cl- channel opening as discussed in Pharmacodynamics of Hypnotics and Anxiolytics STEP 3: Drug Interactions Associated with Anticonvulsants (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are drug interactions associated with anticonvulsants? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below PST 05104 Pharmacology & Therapeutics 220 NTA Level 5 Semester 1 Facilitator Guide The following are drug interactions of Anticonvulsants Sodium channel blockers (Phenytoin, Carbamazepine, Valproate ) o Carbamazepine: should not be combined with monoamine oxidase inhibitors. It is a potent enzyme inducer and,

NTA Level 5 • Semester 1 • PST05104 Management of Acute Poisoning Pharmacology and Therapeutics • Source Session/Topic 27 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 27: Management of Acute Poisoning Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe approaches/measures in management of acute poisoning Describe management of specific drug overdoses/poisoning of clinical importance Describe management of overdoses/poisoning of other chemicals of clinical importance Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD projector Handout 27.1: Management of Specific Drug Overdoses/Poisoning of Clinical Importance SESSION OVERVIEW Step Time Activity/ Content Step Time Activity/ Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning Tasks Introduction, Learning Tasks Introduction, Learning Tasks 2 2 60 minutes 60 minutes Presentation/ Approaches/Measures in Management of Approaches/Measures in Management of Approaches/Measures in Management of 2 2 60 minutes 60 minutes Buzzing Acute Poisoning Acute Poisoning Acute Poisoning Buzzing Acute Poisoning Acute Poisoning Acute Poisoning 3 3 25 minutes 25 minutes Presentation/ Management of Specific Drug Management of Specific Drug Management of Specific Drug 3 3 25 minutes 25 minutes brainstorming Overdoses/Poisoning of Clinical Importance Overdoses/Poisoning of Clinical Importance Overdoses/Poisoning of Clinical Importance brainstorming Overdoses/Poisoning of Clinical Importance Overdoses/Poisoning of Clinical Importance Overdoses/Poisoning of Clinical Importance 4 4 20 minutes 20 minutes Presentation Management of Overdoses/Poisoning of Other Management of Overdoses/Poisoning of Other Management of Overdoses/Poisoning of Other 4 4 20 minutes 20 minutes Presentation Chemicals of Clinical Importance Chemicals of Clinical Importance Chemicals of Clinical Importance Chemicals of Clinical Importance Chemicals of Clinical Importance Chemicals of Clinical Importance 6 6 05 minutes 05 minutes Presentation Key Points Key Points Key Points 7 7 05 minutes 05 minutes Presentation Evaluation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics 208 208 208 NTA Level 5 Semester 1 Facilitator Guide NTA Level 5 Semester 1 Facilitator Guide SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning objectives and clarify ASK students if they have any questions before continuing. STEP 2: Approaches/Measures in Management of Acute Poisoning (60minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes What are approaches in management of poisoned/overdosed patients? ALLOW few pairs to respond and let other pairs add on points not mentioned WRITE their response on the flip chart/board CLARIFY and SUMMARIZE by using the content below Supportive Therapy In general involves maintaining of the airways flow, proper breathing, adequate circulation. After an initial assessment of vital signs and instigation of appropriate resuscitation, repeated observations are necessary, as drugs may continue to be absorbed with a subsequent increase in plasma concentration. In the unconscious patient, repeated measurements of cardiovascular function, including blood pressure, urine output and (if possible) continuous electrocardiographic (ECG) monitoring should be performed. Plasma electrolytes and acid-base balance should be measured. Hypotension is the most common cardiovascular complication of poisoning. o Hypotension can usually be managed with intravenous colloid. o If this is inadequate, positive inotropic agents (e.g. dobutamine) may be considered. o If dysrhythmias occur any hypoxia or hypokalaemia should be corrected, but anti- dysrhythmic drugs should only be administered in life-threatening situations. Prevention of Further Absorption Emesis: o Replaced by lavage/charcoal o Syrup of ipecacuanha is no longer recommended in the management of poisoning. o Contraindicated in corrosive poisonings/aspiration risk. PST 05104 Pharmacology & Therapeutics 209 NTA Level 5 Semester 1 Facilitator Guide Gastric Lavage: o Technique involves placing of patient in left lateral head down position if not intubated. o Then Insertion of a soft lubricated tube through mouth or nose into stomach. o Aspirate and save contents and then lavage repeatedly with 50-100ml of fluid until returns are clear . o Use luke warm water or saline. o Gastric aspiration and lavage should only be performed if the patient presents within one hour of ingestion of a potentially fatal overdose. o If there is any suppression of the gag reflex, a cuffed endotracheal tube is mandatory. o Gastric lavage is unpleasant and is potentially hazardous. o Indications: Removal of gastric contents (within the first hour). Examination of gastric contents is important. o Contraindications: Do not do if patient comatose unless intubated. Also do not use if corrosives are ingested Activated Charcoal: o Adsorbs almost all drugs and poisons. Poorly adsorbed substances are Lithium, Potassium, alcohol, iron, cyanide. Metal salts, alcohols and solvents are not adsorbed by activated charcoal. o To be effective, large amounts of charcoal are required, typically ten times the amount of poison ingested, and again timing is critical, with maximum effectiveness being obtained soon after ingestion. Its effectiveness is due to its large surface area (1000m2/g). Binding of charcoal to the drug is by non-specific adsorption. o The use of repeated doses of activated charcoal may be indicated after ingestion of sustained-release medications or drugs with a relatively small volume of distribution, and prolonged elimination half-life (e.g. salicylates, quinine, dapsone, carbamazepine, barbiturates or theophylline). o The rationale is that these drugs will diffuse passively from the bloodstream if charcoal is present in sufficient amounts in the gut or to trap drug that has been eliminated in bile from being re-absorbed. o Whole bowel irrigation using non-absorbable polyethylene o Contraindications: Comatose or obtunded unless given by gastric tube or intubated as drinking charcoal can cause emesis. Ileus or intestinal obstruction (delays expulsion of charcoal). Corrosive poisonings where endoscopy is planned. Oral charcoal may also inactivate any oral antidote (e.g. methionine). Whole Bowel Irrigation : o Cleanses the GI

NTA Level 5 • Semester 1 • PST05104 Introduction to Toxicology Pharmacology and Therapeutics • Source Session/Topic 26 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 26: Introduction to Toxicology Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Define terms used in toxicology Describe broad areas/branches of toxicology Describe mechanisms of toxicology Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD projector SESSION OVERVIEW Activity/ Step Time Activity/ Content Step Time Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning Tasks Introduction, Learning Tasks Introduction, Learning Tasks 2 2 50 minutes 50 minutes Presentation/ Definition of Terms Used in Toxicology Definition of Terms Used in Toxicology Definition of Terms Used in Toxicology 2 2 50 minutes 50 minutes Buzzing Definition of Terms Used in Toxicology Definition of Terms Used in Toxicology Definition of Terms Used in Toxicology Buzzing 3 3 30 minutes 30 minutes Presentation/ Description of Broad Areas/Branches of Broad Areas/Branches of 3 3 30 minutes 30 minutes brainstorming Toxicology brainstorming Toxicology 4 4 25 minutes 25 minutes Presentation Description of Mechanisms of Toxicology Mechanisms of Toxicology 5 5 05 minutes 05 minutes Presentation Key Points 6 6 05 minutes 05 minutes Presentation Evaluation PST 05104 Pharmacology & Therapeutics 202 NTA Level 5 Semester 1 Facilitator Guide SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Definition of Terms Used in Toxicology (50 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes What is toxicology? ALLOW few pairs to respond and let other pairs add on points not mentioned WRITE their response on the flip chart/board CLARIFY and SUMMARIZE by using the content below The followings are common terms/definitions used in toxicology Toxicology: o The science that investigates the adverse effects of chemicals on health. o The field of toxicology is a broad-based multidisciplinary science that examines the harmful effects of substances on living organisms, including humans. Poison: o Is any substance that may disrupt biologic function and potentially kill an organism. Toxin: o Toxin, by strict definition, is a poison of biologic origin that does not have the ability to replicate. o However, the term toxin has been used more loosely. o For example, environmental toxin has been used to describe toxic substances of nonbiologic origin. Venom: o Is a toxin that is injected into the victim by some means (e.g., bee sting, snake bite). Toxicant: o Is a general term that refers to any harmful substance and is generally interchangeable with poison. PST 05104 Pharmacology & Therapeutics 203 NTA Level 5 Semester 1 Facilitator Guide Toxicodynamics: Refers to the general concepts of pharmacodynamics (interaction with molecular targets and mechanisms of effects) as applied to interactions and mechanisms that generate toxic effects. Toxicokinetics: o Refers to the general concepts of pharmacokinetics (absorption, distribution, biotransformation, and elimination) as applied to toxic substances. Toxicity: o Is the ability of a chemical to damage an organ system, to disrupt a biochemical process, or to disturb an enzyme system. Paracelsus theory: ―All things are toxic and there is nothing without poisonous qualities: it is only the dose which makes something a poison‖ STEP 3: Broad Areas/Branches of Toxicology (30 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are branches of toxicology? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below The field of toxicology is a broad-based multidisciplinary science that examines the harmful effects of substances on living organisms, including humans and has several major subdivisions as listed below: Descriptive toxicology: o Focuses on toxicity testing with the intent of defining the degree of risk associated with substances. Environmental toxicology: o Involves the detection and understanding of environmental pollutants and their effects on humans and other organisms. Forensic toxicology: Is primarily concerned with detection and quantification of toxic substances for legal purposes. Mechanistic toxicology: Is focused on determining the mechanisms by which substances exert toxic effects. Regulatory toxicology: PST 05104 Pharmacology & Therapeutics 204 NTA Level 5 Semester 1 Facilitator Guide Uses toxicologic data to establish policies regarding exposure limits for toxic substances. Medical or clinical toxicology: Focuses on the diagnosis and treatment of toxic effects in humans. STEP 4: Mechanisms of Toxicology (25 minutes) Mechanisms of toxicity can be classified as follows: Physical: o The physical presence of the toxicant triggers reactions that are harmful (e.g., asbestos fibers in the lung). Chemical: o Toxicants react chemically with the tissues or body fluids such as blood to produce harmful effects (e.g., strong acids or bases cause burns). Pharmacologic: o Toxicants interact with endogenous pharmacologic pathways, resulting in inhibition or overstimulation (e.g., botulinum toxin inhibits release of acetylcholine to cause paralysis). Biochemical: o Toxicant reacts biochemically with cellular constituents to produce cellular damage (e.g., venom of many snakes contains phospholipases that destroy cell membranes). Genomic (genotoxic): o Toxicant alters the genetic material of the cell, resulting in disruption of function. Genotoxic substances may be mutagenic or carcinogenic. Mutagenic (carcinogenic): o Toxicants alter DNA structure or function sufficiently to cause mutations (benzene) or initiate and promote the development of cancers (polycyclic aromatic hydrocarbons such as benzo[a]pyrene, found in cigarette smoke). Immunologic: o Toxicant may trigger an immune response that leads to cellular damage (e.g., penicillin-induced hemolytic anemia) or conversely suppresses the immune system, causing an increased susceptibility to infection (e.g., procainamide-induced agranulocytosis). Teratogenic: o Toxicant alters foetal development, resulting in birth defects (e.g., phenytoin is associated with development of cleft lip). PST 05104 Pharmacology & Therapeutics 205 NTA Level 5