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NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Vitamins and Minerals Pharmacology and Therapeutics • Source Session/Topic 15 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 15: Pharmacodynamics of Vitamins and Minerals 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 Vitamins and Minerals Drugs Describe drug interactions associated with Vitamins and Minerals Describe side effects of Vitamins and Minerals Describe contraindications of Vitamins and Minerals 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 Vitamins and Mechanism of Action of Vitamins and 2 2 45 minutes 45 minutes Buzzing Minerals Drugs Minerals Drugs Buzzing Minerals Drugs Minerals Drugs 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Vitamins Drug Interactions Associated With Vitamins 3 3 20 minutes 20 minutes brainstorming and Minerals and Minerals brainstorming and Minerals and Minerals 4 4 20 minutes 20 minutes Presentation Side Effects of Vitamins and Minerals Side Effects of Vitamins and Minerals 5 5 20 minutes 20 minutes Presentation/ Contraindications of Vitamins and Minerals Contraindications of Vitamins and Minerals 5 5 20 minutes 20 minutes Brainstorming Contraindications of Vitamins and Minerals Contraindications of Vitamins and Minerals 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 122 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 Vitamins and Minerals (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do Vitamins and Minerals 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 Vitamins and minerals have different mechanisms of action as discussed below: Vitamin D o The two major forms of vitamin D replacements are vitamin D2 and vitamin D3. o Vitamin D is an important regulator of calcium and phosphate homeostasis and bone metabolism. It works in conjunction with PTH. The overall effect of vitamin D is to increase serum calcium concentrations. These effects are mediated via the following: o Increased calcium absorption from the intestine o Regulation of bone resorption and formation. This occurs via stimulation of both osteoblastic and osteoclastic processes. Osteoblasts form bone, and osteoclasts dissolve bone. o Increased calcium reabsorption in the distal renal tubules o Vitamin D results in a negative feedback loop and decreases transcription and secretion of PTH. The overall effect of PTH is to increase serum calcium levels, so increased vitamin D inhibits the actions of PTH so that both mechanisms do not drive up calcium levels too high. o Vitamin D is lipophilic (it is one of the fat-soluble vitamins—A, D, E, and K) and thus freely crosses the cytoplasmic membrane. Intracellularly, it binds vitamin D receptors (VDRs) and binds DNA, where it regulates transcription of genes in the intestine, bone, kidney, and parathyroid gland. o Vitamin D also has actions in macrophages and T cells and in proliferation and differentiation of a large number of cells, including cancer cells. PST 05104 Pharmacology & Therapeutics 123 NTA Level 5 Semester 1 Facilitator Guide Through these actions, it has immunomodulating and potentially, anticancer actions. Also, these actions are the basis of the mechanism whereby it is effective in psoriasis. Vitamin B1 (Thiamine) Thiamine is used in the treatment of beriberi and other states of thiamine deficiency, or in their prevention. Such conditions include alcoholic neuritis, Wernicke‘s encephalopathy and the neuritis of pregnancy, as well as chronic diarrhoeal states and after intestinal resection. Thiamine (in the form of thiamine pyrophosphate) is required for carbohydrate metabolism, as it is a coenzyme for decarboxylases and transketolases. Vitamin B6 (Pyridoxine) Pyridoxine hydrochloride is given to patients at risk (e.g. alcoholics) during long-term therapy with isoniazid to prevent peripheral neuropathy, and in deficiency states. Pyridoxine is also used to treat certain uncommon inborn errors of metabolism, including primary hyperoxaluria. Vitamin B6 occurs naturally in three forms, namely pyridoxine, pyridoxal and pyridoxamine. All three forms are converted in the body into pyridoxal phosphate, which is an essential cofactor in several metabolic reactions, including decarboxylation, transamination and other steps in amino acid metabolism. Vitamin B3 (Niacin and Nicotinic Acid) Niacin is used to treat and prevent pellagra. Nicotinic acid (or nicotinic acid analogues may be used to treat dyslipidaemia, but hypolipidaemic dosing is limited by vasodilatation/flushing. Niacin is vital metabolic role is as a component of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Vitamin B12 Vitamin B12 is an organic molecule with an attached cobalt atom. Linked to the cobalt atom may be a cyanide (cyanocobalamin), hydroxyl (hydroxocobalamin) or methyl (methylcobalamin) group. These forms are interconvertible. Vitamin B12 is needed for normal erythropoiesis and for neuronal integrity. It is a cofactor needed for the isomerization of methylmalonyl coenzyme A to succinyl coenzyme A, and for the conversion of homocysteine into methionine (which also utilizes 5-methyltetrahydrofolate). Vitamin B12 is also involved in the control of folate metabolism, and B12 and folate are required for intracellular nucleoside synthesis. Vitamin C (Ascorbic Acid) Ascorbic acid is used in the prophylaxis and treatment of scurvy. The reducing properties of ascorbate may be used in the treatment of methaemoglobinaemia. In PST 05104 Pharmacology

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Immunosuppressive Agents Pharmacology and Therapeutics • Source Session/Topic 14 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 14: Pharmacodynamics of Immunosuppressive Agents 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 Immunosuppressive agents Describe drug interactions associated with Immunosuppressive agents Describe side effects of Immunosuppressive agents Describe contraindications of Immunosuppressive agents 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 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 Immunosuppressive Mechanism of Action of Immunosuppressive 2 2 45 minutes 45 minutes Buzzing Agents Agents Buzzing Agents Agents 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Drug Interactions Associated With 3 3 20 minutes 20 minutes brainstorming Immunosuppressive Agents Immunosuppressive Agents brainstorming Immunosuppressive Agents Immunosuppressive Agents 4 4 20 minutes 20 minutes Presentation Side Effects of Immunosuppressive Agents Side Effects of Immunosuppressive Agents 5 5 20 minutes 20 minutes Presentation/ Contraindications of Immunosuppressive Contraindications of Immunosuppressive 5 5 20 minutes 20 minutes Brainstorming Agents Agents Brainstorming Agents Agents 6 6 05 minutes 05 minutes Presentation Key Points Key Points 7 7 05 minutes 05 minutes Presentation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics 114 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 Immunosuppressive Agents (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do Immunosuppressive Agents 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 Calcineurin inhibitors Ciclosporin o It inhibits the production of interleukin-2 (IL-2) and other cytokines by activated lymphocytes through its binding to a cytosolic protein cyclophilin. This conjugate subsequently interacts with a Ca2+–calmodulin dependent Calcineurin complex and inhibits its phosphorylase activity. o This impairs access to the nucleus of the cytosolic component of the transcription promoter nuclear factor of activated T cells (NF-ATc), which in turn reduces the transcription of messenger RNA for IL-2, other pro-inflammatory lymphokines and IL-2 receptors. Tacrolimus o Tacrolimus (FK506) is another calcineurin inhibitor with the same mechanism of action to ciclosporin. o It is more potent than ciclosporin and often used in patients who are refractory to ciclosporin. PST 05104 Pharmacology & Therapeutics 115 NTA Level 5 Semester 1 Facilitator Guide Target of Rapamycin (mTOR) Inhibitors Sirolimus, o mTOR (mammalian target of rapamycin) is a serine-threonine protein kinase activated by several growth factors after receptor binding. o Sirolimus binds a protein called FKBP 12 (FKBP stands for FK506 binding protein) in the cytoplasm. The drug-protein complex then binds and inhibits mTOR. o Inhibition of mTOR blocks cell-cycle progression at the G1 → S phase transition. o mTOR regulates important functions of the cell, including proliferation, angiogenesis (blood vessel formation), cell survival, protein synthesis, and transcription. It is recognized as a key point in many cellular functions. Glucocorticosteroids Prednisolone and others o inhibits expression of pro-inflammatory cytokines IL-2, 3 and 6, TNF, GM-CSF and IFN-γ; o inhibits production of adhesion molecules – ICAM-1,E-selectin and vascortin – leading to reduced vascular permeability o reduces synthesis of arachidonic acid metabolites (prostaglandins, leukotrienes) and reduces histamine release Anti-Proliferative Immunosuppressants Azathioprine o Azathioprine is a prodrug and is converted to 6-mercaptopurine (6-MP) by the liver. Mycophenolate Mofetil o In vivo the active entity, mycophenolic acid, inhibits inosine monophosphate dehydrogenase (a pivotal enzyme in purine synthesis). Hence, it suppresses proliferation both of T and B lymphocytes. o In addition, mycophenolic acid inhibits the production of pro-inflammatory cytokines. Monoclonal Antibodies Anti-CD3 Antibody (Muromonab-CD3) o Anti-CD3 antibodies bind CD3 protein, blocking antigen binding to the T-cell antigen–recognition complex, and decreasing the number of circulating CD3-positive lymphocytes. o In addition, binding of anti-CD3 to its receptor causes cytokine release. The overall effect is to reduce T-cell activation in acute solid-organ graft rejection. Polyclonal Antibodies Antilymphocyte Globulin The major effect is probably to prevent antigen from accessing the antigen-recognition site on the T-helper cells. PST 05104 Pharmacology & Therapeutics 116 NTA Level 5 Semester 1 Facilitator Guide STEP 3: Drug Interactions Associated with Immunosuppressive Agents (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are drug interactions associated with Immunosuppressive agents? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below Calcineurin inhibitors Ciclosporin o These include allopurinol, cimetidine, ketoconazole (and other azoles), erythromycin, diltiazem (and other calcium channel blockers), anabolic steroids, norethisterone and other inhibitors of cytochrome P450 3A4, which reduce the hepatic clearance of ciclosporin leading to increased toxicity. o Phenytoin and rifampicin increase hepatic clearance, thus reducing plasma concentrations. o Concomitant use of nephrotoxic agents such as aminoglycosides, vancomycin and amphotericin increases nephrotoxicity. o Concomitant use of ACE inhibitors increases the risk of hyperkalaemia. Tacrolimus o The drug–drug interaction profile of tacrolimus is similar to that of ciclosporin, but it may cause more neurotoxicity and nephrotoxicity. Target of Rapamycin (mTOR) Inhibitors Sirolimus o Although sirolimus is not nephrotoxic alone, coadministration with a calcineurin inhibitor (another drug used for renal transplants) results in greater kidney damage than with a calcineurin inhibitor alone. Therefore there is some interaction with calcineurin inhibitors that potentiates the renal damage induced by the calcineurin inhibitor, and the two drugs should not be coadministered.

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Antineoplastic Drugs Pharmacology and Therapeutics • Source Session/Topic 13 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 13: Pharmacodynamics of Antineoplastic 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 Antineoplastic Drugs Describe drug interactions associated with Antineoplastic Drugs Describe side effects of Antineoplastic Drugs Describe contraindications of Antineoplastic 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 Antineoplastic Drugs Mechanism of Action of Antineoplastic Drugs 2 2 45 minutes 45 minutes Buzzing Mechanism of Action of Antineoplastic Drugs Mechanism of Action of Antineoplastic Drugs Buzzing 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Drug Interactions Associated With 3 3 20 minutes 20 minutes brainstorming Antineoplastic Drugs Antineoplastic Drugs brainstorming Antineoplastic Drugs Antineoplastic Drugs 4 4 20 minutes 20 minutes Presentation Side Effects of Antineoplastic Drugs Side Effects of Antineoplastic Drugs 5 5 20 minutes 20 minutes Presentation/ Contraindications of Antineoplastic Drugs Contraindications of Antineoplastic Drugs 5 5 20 minutes 20 minutes Brainstorming Contraindications of Antineoplastic Drugs Contraindications of Antineoplastic 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 105 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 Antineoplastic Drugs (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do Antineoplastic 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 Alkylating Agents In general, Alkylating agents are particularly effective when cells are dividing rapidly, but are not phase-specific. They combine with DNA and thus damage malignant and dividing normal cells. If a tumour is sensitive to one alkylating agent, it is usually sensitive to another, but cross-resistance does not necessarily occur. The alkylating agents transfer alkyl (chemical) groups to DNA. DNA alkylation in the nucleus leads to the death of the cell. Once in the cell, the alkylating agents undergo a structural rearrangement that results in the formation of an unstable intermediate, an ethylene immonium ion. This ion either directly, or via another intermediate, a carbonium ion, transfers alkyl groups to nucleic acids such as guanine or to other cellular constituents. Alkylation of guanine or other bases results in abnormal base pairing as well as the excision of these bases, which in turn leads to strand breakage. The connection between DNA alkylation and death of the cancer cell has not been established; however, one of the likely mechanisms is damage to DNA that is sufficient to activate proapoptotic proteins such as p53, leading to cell death. Mustine (Mechlorethamine) Mustine forms highly reactive ethyleneimine ions that alkylate and cross-link guanine bases in DNA and alkylate other macromolecules, including proteins. PST 05104 Pharmacology & Therapeutics 106 NTA Level 5 Semester 1 Facilitator Guide Cyclophosphamide It is an inactive prodrug given orally or intravenously. Nitrosoureas: Carmustine, lomustine, semustine, bendamustine Nitrosoureas have an additional mechanism of action. Nitrosoureas undergo another reaction, referred to as carbamoylation, with lysine residues of proteins. The product of this reaction is referred to as a carbamoylated protein, and this process appears to limit the ability of the cancer cell to repair DNA. This unique mechanism of action limits cross-resistance between nitrosoureas and other members of this class. Procarbazine It is an inactive prodrug given orally or intravenously Platinum compounds Cisplatin, Carboplatin etc o Platinum compound cytotoxicity results from selective inhibition of tumour DNA synthesis by the formation of intra- and inter-strand cross-links at guanine residues in the nucleic acid backbone. o This unwinds and shortens the DNA helix. Antifolate analogues antimetabolites Methotrexate o Folic acid is required in the synthesis of thymidylate (a pyrimidine) and of purine nucleotides and thus for DNA synthesis. o Methotrexate is a very slowly reversible competitive inhibitor of dihydrofolate reductase (DHFR). o The affinity of DHFR for methotrexate is 100 000 times greater than that for dihydrofolate. o Thus, methotrexate prevents nucleic acid synthesis and causes cell death. Folinic acid circumvents this biosynthetic block and thus non-competitively antagonizes the effect of methotrexate. Pyrimidine antimetabolites 5-Fluorouracil o 5-Fluorouracil is a prodrug that is activated by anabolic phosphorylation to form: 5-fluorouridine monophosphate, which is incorporated into RNA, inhibiting its function and its polyadenylation. o The anabolic phosphorylation also forms 5-fluorodeoxyuridylate, which binds strongly to thymidylate synthetase and inhibits DNA synthesis. PST 05104 Pharmacology & Therapeutics 107 NTA Level 5 Semester 1 Facilitator Guide Incorporation of 5-fluorouracil itself into DNA causes mismatching and faulty mRNA transcripts. Purine antimetabolites 6-Mercaptopurine (6-MP) o 6-MP requires transformation by intracellular enzymes to 6-thioguanine which inhibits purine synthesis. Cytotoxic Antibiotics (Anthracyclines ) Doxorubicin o Cytotoxic actions of anthracyclines lead to apoptosis through intercalation between adjacent base pairs in DNA, leading, to fragmentation of DNA and inhibition of DNA repair, enhanced by DNA topoisomerase II inhibition. Camptothecins (Topoisomerase I inhibitors) o Camptothecins act during the S-phase of the cell cycle. DNA topoisomerase I is necessary for unwinding DNA for replication and RNA transcription. o Camptothecins stabilize the DNA topoisomerase I–DNA complex. Cell killing is most likely via induction of apoptosis (programmed cell death). Etoposide and Teniposide (Topoisomerase

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Drugs Acting Locally on the Skin Pharmacology and Therapeutics • Source Session/Topic 12 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 12: Pharmacodynamics of Drugs Acting Locally on the Skin 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 acting locally on the skin Describe drug interactions associated with Drugs acting locally on the skin Describe side effects of Drugs acting locally on the skin Describe contraindications of Drugs acting locally on the skin 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 Acting Mechanism of Action of Drugs Acting 2 2 45 minutes 45 minutes Buzzing Locally on The Skin Locally on The Skin Buzzing Locally on The Skin Locally on The Skin 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Drugs Drug Interactions Associated With Drugs 3 3 20 minutes 20 minutes brainstorming Acting Locally on The Skin Acting Locally on The Skin brainstorming Acting Locally on The Skin Acting Locally on The Skin 4 4 20 minutes 20 minutes Presentation Side Effects of Drugs Acting Locally on The Side Effects of Drugs Acting Locally on The 4 4 20 minutes 20 minutes Presentation Skin Skin Skin Skin 5 5 20 minutes 20 minutes Presentation/ Contraindications of Drugs Acting Locally on Contraindications of Drugs Acting Locally on 5 5 20 minutes 20 minutes Brainstorming the Skin the Skin Brainstorming the Skin the Skin 6 6 05 minutes 05 minutes Presentation Key Points Key Points 7 7 05 minutes 05 minutes Presentation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics 98 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 Acting Locally on the Skin (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes What are the mechanisms of actions of drugs acting locally on the skin ? 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 These drugs includes antibacterial/antibiotics, ant protozoans, antifungal and anti-viral The following are the mechanism of action of Anti-infective drugs Antibacterial/antibiotics Some widely used topical antibiotics are bacitracin, neomycin, gentamycin, mupirocin and polymyxins. Mechanism of action of antibacterial/antibiotics is either inhibiting bacterial growth (bacteriostatic) or kills bacteria (bactericidal) or can have both actions depending on its concentration (e.g Clindamycin and erythromycin in treatment of acne) Aminoglycosides act by interfering bacteria protein synthesis. Mupirocin act by inhibiting protein and RNA synthesis by binding reversibly to sub unit 50s of bacteria ribosome or disrupt synthesis of peptidoglycan layer of bacterial cell wall. It also inhibits bacterial isoleucyl-tRNA synthetase. Polymyxins binds to lipopolysaccharide on outer cell wall of Gram Negative Bacteria leading to permeability change in cell envelope hence leakage of cell content. Polymyxins are only active against gram negative bacteria (P. aeruginosa, E. coli, K. pneumoniae). Antifungal Antifungal drugs may be fungicidal (able to destroy fungi) or fungistatic (able to slow or retard the multiplication of fungi) PST 05104 Pharmacology & Therapeutics 99 NTA Level 5 Semester 1 Facilitator Guide Azoles (Ketoconazole, Clotrimazole and miconazole nitrate) acts by inhibits the biosynthesis of plasma membrane by preventing synthesis of ergosterol and other steroids which results to damage of fungal cell wall membranes and loss of essential intracellular elements. Terbinafine Hydrochloride: binds with squalene epoxidase enzyme and hinders biosynthetic pathway of ergosterone and results to growth and it is associated with high intracellular squalene concentrations which interfere with fungal membrane function and cell wall synthesis causes death of fungi. Antiviral Commonly agents are: acyclovir, famciclovir and valacyclovir Acyclovir works by lowering the ability of the herpes virus to multiply, it acts as specific inhibitor of herpesvirus DNA polymerase (HSV), type 1 and 2 and varicella zoster virus. This selectivity is due to the ability of these viruses to code for a viral thymidine kinase capable of phosphorylating acyclovir to monophosphate (this capability is absent in uninfected cells) Ant protozoans Mechanism of action of ant protozoans differ significantly with drug to drug e.g Paramomycin (antibacteria drug but also it is antiprotozoal agent) interfere with metabolic processes (glycolysis and fatty acid oxidation) or by interfering with reproduction and larval physiology or interfering with muscular physiology of parasites (e,g in treatment of leishmaniasis). Corticosteroids: Used for their Antinflammatory action Details on glucocorticosteroids is found on pharmacology of Antinflammatory drugs STEP 3: Drug Interactions Associated with Drugs Acting Locally on the Skin (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are drug interactions associated with drugs acting locally on the skin? 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 100 NTA Level 5 Semester 1 Facilitator Guide Most of drugs for treating skin infection do not show significant drug interactions because of minimal systemic absorption of these drugs hence systemic drug interactions are unlikely. Drug interactions can result only when the skin barrier is destroyed hence systemic absorption. Antibiotics/antibacterial o For example oral metronidazole has been reported to potentiate the anticoagulant effect of warfarin and coumarin anticoagulants resulting in a prolongation of prothrombin but the

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Analgesics, Antipyretics and Anti-inflammatory Drugs Pharmacology and Therapeutics • Source Session/Topic 11 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 11: Pharmacodynamics of Analgesics, Antipyretics and Anti-inflammatory 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 analgesics, antipyretics and anti-inflammatory drugs Describe drug interactions associated with analgesics, antipyretics and anti-inflammatory drugs Describe side effects of analgesics, antipyretics and anti-inflammatory drugs Describe contraindications of analgesics, antipyretics and anti-inflammatory 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 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 89 89 NTA Level 5 Semester 1 Facilitator Guide NTA Level 5 Semester 1 Facilitator Guide 2 45 minutes Presentation/ Mechanism of Action of Analgesics, 2 45 minutes Buzzing Antipyretics and Anti-Inflammatory Drugs Buzzing Antipyretics and Anti-Inflammatory Drugs Presentation/ Drug Interactions Associated With 3 20 minutes Presentation/ Analgesics, Antipyretics and Anti- 3 20 minutes brainstorming Analgesics, Antipyretics and Anti- brainstorming Inflammatory Drugs Inflammatory Drugs 4 20 minutes Presentation Side Effects of Analgesics, Antipyretics and 4 20 minutes Presentation Anti-Inflammatory Drugs Anti-Inflammatory Drugs 5 20 minutes Presentation/ Contraindications of Analgesics, Antipyretics 5 20 minutes Brainstorming and Anti-Inflammatory Drugs Brainstorming and Anti-Inflammatory Drugs 6 05 minutes Presentation Key Points 7 05 minutes Presentation Evaluation PST 05104 Pharmacology & Therapeutics 90 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 Analgesics, Antipyretics and Anti-Inflammatory Drugs (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes What are the mechanisms of actions of analgesics, antipyretics and anti-Inflammatory drugs? 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 Anti-inflammatory, Antipyretic, Analgesics have different mechanisms of action: Non-Steroidal Anti-Inflammatory Drugs o Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin biosynthesis by inhibiting cyclo-oxygenase (COX). o This is the basis of most of their therapeutic, as well as their undesired actions. COX is a key enzyme in the synthesis of prostaglandins and thromboxanes, important mediators of the erythema, oedema, pain and fever of inflammation. o There are two main isoforms of the enzyme, namely a constitutive form (COX-1) that is present in platelets, stomach, kidneys and other tissues, and an inducible form, (COX-2), that is expressed in inflamed tissues as a result of stimulation by cytokines and is also present to a lesser extent in healthy organs, including the kidneys. Drugs like Aspirin inhibits cyclooxygenase activity, it diminishes the formation of prostaglandins and thus modulates those aspects of inflammation in which prostaglandins act as mediators. Acetaminophen, although a useful analgesic and antipyretic, has weak anti-inflammatory activity and is therefore not useful in the treatment of inflammation such as that seen with rheumatoid arthritis. PST 05104 Pharmacology & Therapeutics 91 NTA Level 5 Semester 1 Facilitator Guide Analgesic action Prostaglandin E2 (PGE2) is thought to sensitize the nerve endings to the action of bradykinin, histamine, and other chemical mediators released locally by the inflammatory process. Thus, by decreasing PGE2 synthesis, aspirin and other NSAIDs repress the sensation of pain. NSAIDs are superior to opioids in the management of pain in which inflammation is involved; combinations of opioids and NSAlDs are effective in, treating pain in malignancy. Antipyretic action Fever occurs when the set-point of the anterior hypothalamic thermoregulatory centre is elevated. This can be caused by PGE2 synthesis, stimulated when an endogenous fever-producing agent (pyrogen) such as a cytokine is released from white cells that are activated by infection, hypersensitivity, malignancy, or inflammation. The salicylates and other NSAIDs lower body temperature in patients with fever by impeding PGE2 synthesis and release. They reset the "thermostat" toward normal and rapidly lower the body temperature of febrile patients by increasing heat dissipation as a result of peripheral vasodilation and sweating. These drugs have no effect on normal body temperature. Glucocorticosteroids Prednisolone and others o These agents lack antipyretic and analgesic activity. o They only have anti-inflammatory activity. o Inhibits expression of pro-inflammatory cytokines IL-2, 3 and 6, TNF, GM-CSF and IFN-γ; o Inhibits production of adhesion molecules – ICAM-1,E-selectin and vascortin – leading to reduced vascular permeability. o Reduces synthesis of arachidonic acid metabolites (prostaglandins, leukotrienes) and reduces histamine release. Other (Slow Acting) Anti-Inflammatory Agents Gold Compounds, Chloroquine and hydroxychloroquine, penicillamine o In contrast to the NSAlDs drugs described earlier, remittive (remission inducing) arthritis drugs are slow-acting. o They do not act by inhibiting cyclooxygenase and have no analgesic or primary anti-inflammatory activity. o These drugs are used primarily for rheumatic disorders, especially in cases where the inflammation does not respond to cyclooxygenase inhibitors. PST 05104 Pharmacology & Therapeutics 92 NTA Level 5 Semester 1 Facilitator Guide They slow the course of the disease and may also induce a remission, preventing further destruction of the joints and involved tissues. Gold compounds: like the other drugs in this group, cannot repair existing damage. Rather, they can only prevent further injury. o The currently available gold preparations are gold sodium thiomalate, aurothioglucose, and auranofin. It is believed that gold salts are taken up by macrophages and suppress phagocytosis and

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Antiemetics and Drugs for Peptic Ulcer Disease Pharmacology and Therapeutics • Source Session/Topic 10 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 10: Pharmacodynamics of Antiemetics and Drugs for Peptic Ulcer 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 Antiemetics and Drugs for Peptic Ulcer Describe drug interactions associated with Antiemetics and Drugs for Peptic Ulcer Disease Describe side effects of Antiemetics and Drugs for Peptic Ulcer Disease Describe contraindications of Antiemetics and Drugs for Peptic Ulcer 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 40 minutes 40 minutes Presentation/ Mechanism of Action of Antiemetics and Mechanism of Action of Antiemetics and Mechanism of Action of Antiemetics and 2 2 40 minutes 40 minutes Buzzing Drugs for Peptic Ulcer Disease Drugs for Peptic Ulcer Disease Drugs for Peptic Ulcer Disease Buzzing Drugs for Peptic Ulcer Disease Drugs for Peptic Ulcer Disease Drugs for Peptic Ulcer Disease Presentation/ Drug Interactions Associated With Drug Interactions Associated With Drug Interactions Associated With 3 3 20 minutes 20 minutes Presentation/ Antiemetics and Drugs for Peptic Ulcer Antiemetics and Drugs for Peptic Ulcer Antiemetics and Drugs for Peptic Ulcer 3 3 20 minutes 20 minutes brainstorming Antiemetics and Drugs for Peptic Ulcer Antiemetics and Drugs for Peptic Ulcer Antiemetics and Drugs for Peptic Ulcer brainstorming Disease Disease Disease Disease Disease Disease 4 4 20 minutes 20 minutes Presentation Side Effects of Antiemetics and Drugs for Side Effects of Antiemetics and Drugs for Side Effects of Antiemetics and Drugs for 4 4 20 minutes 20 minutes Presentation Peptic Ulcer Disease Peptic Ulcer Disease Peptic Ulcer Disease Peptic Ulcer Disease Peptic Ulcer Disease Peptic Ulcer Disease 5 5 20 minutes 20 minutes Presentation/ Contraindications of Antiemetics and Drugs Contraindications of Antiemetics and Drugs Contraindications of Antiemetics and Drugs 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 79 79 79 NTA Level 5 Semester 1 Facilitator Guide NTA Level 5 Semester 1 Facilitator Guide Brainstorming for Peptic Ulcer Disease 6 05 minutes Presentation Key Points 7 05 minutes Presentation Evaluation 8 05 minutes Presentation Take Home Assignment 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 Antiemetics and Drugs for Peptic Ulcer Disease (40 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes What are the mechanisms of action of antiemetic and drugs for peptic ulcers? 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 following are the mechanism of action for drugs for treating Peptic Ulceration; Antiacids o Antacids have a number of actions which include neutralizing gastric acid and thus relieving associated pain and nausea, reducing delivery of acid into the duodenum following a meal, and inactivation of the proteolytic enzyme pepsin by raising the gastric pH above 4–5. o In addition, it is thought that antacid may increase lower oesophageal sphincter tone and reduce oesophageal pressure. H2-Receptor antagonists o H2-receptors stimulate gastric acid secretion and are also present in human heart, blood vessels and uterus (and probably brain). PST 05104 Pharmacology & Therapeutics 80 NTA Level 5 Semester 1 Facilitator Guide Competitive H2-receptor antagonists when used in clinical use block/inhibit gastric acid secretion. Prostaglandin Analogues Misoprostol is a synthetic analogue of prostaglandin E1 which inhibits gastric acid secretion, causes vasodilatation in the submucosa and stimulates the production of protective mucus. Proton Pump Inhibitors The proton-pump inhibitors inhibit gastric acid by blocking the H+/K+-adenosine triphosphatase enzyme system (the proton pump) of the gastric parietal cell. Examples are omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole. Bismuth chelate (a mucosal protective agent) Colloidal tripotassium dicitratobismuthate precipitates at acid pH to form a layer over the mucosal surface and ulcer base, where it combines with the proteins of the ulcer exudate. This coat is protective against acid and pepsin digestion. It also stimulates mucus production and may chelate with pepsin, thus speeding ulcer healing. It has a direct toxic effect on H. pylori and may be used as part of triple therapy. Sucralfate (a mucosal protective agent) Sucralfate is used in the management of benign gastric and duodenal ulceration and chronic gastritis. Its action is entirely local, with minimal if any systemic absorption. It is a basic aluminium salt of sucrose octasulphate which, in the presence of acid, becomes a sticky adherent paste that retains antacid efficacy. This material coats the floor of ulcer craters, exerting its acid-neutralizing properties locally, unlike conventional antacid gels which form a diffusely distributed antacid dispersion. In addition it binds to pepsin and bile salts and prevents their contact with the ulcer base. Mechanism of action of Antiemetics REFER Students to Handout 10.1: Pharmacodynamics of drugs for thyroid disorders and reproductive function STEP 3: Drug Interactions Associated with Drugs for Peptic Ulcer Disease (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are drug interactions associated with antiemetics and drugs for peptic ulcer disease? PST 05104 Pharmacology & Therapeutics 81 NTA Level 5 Semester 1 Facilitator Guide ALLOW few students

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Drugs Acting on Respiratory System Pharmacology and Therapeutics • Source Session/Topic 9 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 9: Pharmacodynamics of Drugs Acting on Respiratory System 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 acting on Respiratory System Describe drug interactions associated with Drugs acting on Respiratory System Describe side effects of Drugs acting on Respiratory System Describe contraindications of Drugs acting on Respiratory System Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD projector Handout 9.1: Pharmacodynamics of drugs for cough, cold and allegy PST 05104 Pharmacology & Therapeutics 68 NTA Level 5 Semester 1 Facilitator Guide 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 40 minutes 40 minutes Presentation/ Mechanism of Action of Drugs acting on Mechanism of Action of Drugs acting on 2 2 40 minutes 40 minutes Buzzing Respiratory System Respiratory System Buzzing Respiratory System Respiratory System 3 3 25 minutes 25 minutes Presentation/ Drug Interactions Associated With Drugs Drug Interactions Associated With Drugs 3 3 25 minutes 25 minutes brainstorming acting on Respiratory System acting on Respiratory System brainstorming acting on Respiratory System acting on Respiratory System 4 4 20 minutes 20 minutes Presentation Side Effects of Drugs acting on Respiratory Side Effects of Drugs acting on Respiratory 4 4 20 minutes 20 minutes Presentation System System System System 5 5 20 minutes 20 minutes Presentation/ Contraindications of Drugs acting on Contraindications of Drugs acting on 5 5 20 minutes 20 minutes Brainstorming Respiratory System Respiratory System Brainstorming Respiratory System Respiratory System 6 6 05 minutes 05 minutes Presentation Key Points Key Points 7 7 05 minutes 05 minutes Presentation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics 69 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 acting on Respiratory System (40 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes What are the mechanisms of action of Drugs acting on respiratory system? 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 following are the mechanisms of drugs used to treat Asthma and chronic obstructive pulmonary disease (COPD); Beta 2 (β2)-Agonists o β-2- Agonists (e.g. salbutamol and the long-acting β2-agonist salmeterol) are used to treat the symptoms of bronchospasm in asthma (both in an acute attack and as maintenance therapy) and o Intravenous salbutamol is also used in obstetric practice to inhibit premature labour). o Agonists occupying β2-adrenoceptors increase cyclic adenosine monophosphate (cAMP) by stimulating adenylyl cyclase via stimulatory G-proteins. o Cyclic AMP phosphorylates a cascade of enzymes. o This causes a wide variety of effects including: Relaxation of smooth muscle including bronchial, uterine and vascular; inhibition of release of inflammatory mediators; increased mucociliary clearance; increase in heart rate, force of myocardial Muscarinic Receptor Antagonists o There is increased parasympathetic activity in patients with reversible airways obstruction, resulting in bronchoconstriction through the effects of acetylcholine on the muscarinic (M2, M3) receptors in the bronchi. PST 05104 Pharmacology & Therapeutics 70 NTA Level 5 Semester 1 Facilitator Guide The final common pathway is via a membrane-bound G-protein which when stimulated leads to a fall in cAMP and increased intracellular calcium, with consequent bronchoconstriction. Antimuscarinic drugs block muscarinic receptors in the airways leading to bronchodilation. Methylxanthines It is not clear exactly how theophylline produces bronchodilation. Its pharmacological actions include the following: Relaxation of airway smooth muscle and inhibition of mediator release (e.g. from mast cells). Theophylline raises intracellular cAMP by inhibiting phosphodiesterase. However, phosphodiesterase inhibition is modest at therapeutic concentrations of theophylline Antagonism of adenosine (a potent bronchoconstrictor) at A2-receptors; Anti-inflammatory activity on T-lymphocytes by reducing release of platelet-activating factor (PAF). Glucocorticosteroids Glucocorticosteroids are used in the treatment of asthma and in severe exacerbations of COPD because of their potent anti-inflammatory effect. This involves interaction with an intracellular glucocorticosteroids receptor that in turn interacts with nuclear DNA, altering the transcription of many genes and thus the synthesis of pro-inflammatory cytokines, β2-adrenoceptors, tachykinin-degrading enzymes and lipocortin (an inhibitor of phospholipase A2, reducing free arachidonic acid and thus leukotriene synthesis). They are used both in maintenance therapy (prophylaxis) and in the treatment of the acute severe attack. Mast Cell Stabilizers (Cromoglicate and Nedocromil) The degranulation of mast cells and eosinophils is an important step in the response to an allergen. Degranulation leads to release of a variety of proinflammatory factors, including histamine, leukotrienes, and various cytokines. These factors then act on tissues to elicit the classic signs of an allergic reaction. Mast cell stabilizers work by preventing this degranulation from occurring. The mechanism by which they accomplish this is still not confirmed. Mast cell stabilizers have a variety of other actions that may contribute to their efficacy. They suppress the actions of chemotactic factors on eosinophils, neutrophils, and monocytes, and they may reduce movement of leukocytes in asthmatic airways. PST 05104 Pharmacology & Therapeutics 71 NTA Level 5 Semester 1 Facilitator Guide Leukotriene Modulators o Leukotriene B4 is a powerful chemo-attractant (eosinophils and neutrophils) and increases vascular permeability producing mucosal oedema. o Leukotrienes C4, D4 and E4 (cysteinyl leukotrienes) are potent spasmogens and pro-inflammatory substances (‗SRS-A‘). o Leukotriene modulators fall into two classes, namely leukotriene receptor antagonists and 5-lipoxygenase inhibitors. o Leukotriene C4 and D4 antagonists:

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Drugs Acting on Endocrine System Pharmacology and Therapeutics • Source Session/Topic 8 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 8: Pharmacodynamics of Drugs Acting on Endocrine System 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 Acting on Endocrine System Describe drug interactions associated with Drugs Acting on Endocrine System Describe side effects of Drugs Acting on Endocrine System Describe contraindications of Drugs Acting on Endocrine System Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD Projector Handout 8.1: Pharmacodynamics of drugs for thyroid disorders and reproductive function 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 Acting on Mechanism of Action of Drugs Acting on 2 2 45 minutes 45 minutes Buzzing Endocrine System Endocrine System Buzzing Endocrine System Endocrine System 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Drugs Drug Interactions Associated With Drugs 3 3 20 minutes 20 minutes brainstorming Acting on Endocrine System Acting on Endocrine System brainstorming Acting on Endocrine System Acting on Endocrine System 4 4 20 minutes 20 minutes Presentation Side Effects of Drugs Acting on Endocrine Side Effects of Drugs Acting on Endocrine 4 4 20 minutes 20 minutes Presentation System System System System 5 5 20 minutes 20 minutes Presentation/ Contraindications of Drugs Acting on Contraindications of Drugs Acting on 5 5 20 minutes 20 minutes Brainstorming Endocrine System Endocrine System Brainstorming Endocrine System Endocrine System 6 6 05 minutes 05 minutes Presentation Key Points Key Points 7 7 05 minutes 05 minutes Presentation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics 57 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 Acting on Endocrine System (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes What asre the mechanisms of action of Drugs Acting on Endocrine system? 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 Diabetes Mellitus Insulins Insulin acts by binding to transmembrane glycoprotein receptors. Receptor occupancy results in: Activation of insulin-dependent glucose transport processes (in adipose tissue and muscle) via a transporter known as ‗Glut-4‘; Inhibition of adenylyl cyclase-dependent metabolism (lipolysis, proteolysis, glycogenolysis); Intracellular accumulation of potassium and phosphate, which is linked to glucose transport in some tissues. Secondary effects include increased cellular amino acid uptake, increased DNA and RNA synthesis and increased oxidative phosphorylation. Biguanides (Metformin) Mechanism remains uncertain. Effects of metformin include: Reduced glucose absorption from the gut Facilitation of glucose entry into muscle by a non-insulin responsive mechanism Inhibition of gluconeogenesis in the liver Suppression of oxidative glucose metabolism and enhanced anaerobic glycolysis. PST 05104 Pharmacology & Therapeutics 58 NTA Level 5 Semester 1 Facilitator Guide Sulphonylureas (tolbutamide, glibenclamide, gliclazide) and Related Drugs The hypoglycaemic effect of these drugs depends on the presence of functioning B cells. Sulphonylureas, like glucose, depolarize B cells and release insulin. They do this by binding to sulphonylurea receptors (SUR) and blocking ATP-dependent potassium channels (KATP); the resulting depolarization activates voltage-sensitive Ca2+ channels, in turn causing entry of Ca2+ ions and insulin secretion. Thiazolidinediones (rosiglitazone and pioglitazone) Glitazones bind to the peroxisome-proliferating activator receptor γ (PPARγ), a nuclear receptor found mainly in adipocytes and also in hepatocytes and myocytes. It works slowly, increasing the sensitivity to insulin possibly via effects of circulating fatty acids on glucose metabolism. Acarbose Acarbose is a reversible competitive inhibitor of intestinal α-glucoside hydrolases and delays the absorption of starch and sucrose, but does not affect the absorption of ingested glucose. The postprandial glycaemic rise after a meal containing complex carbohydrates is reduced and its peak is delayed. Mechanism of action of drugs for treatment of thyroid disorders and reproductive function REFER Students to Handout 8.1: Pharmacodynamics of drugs for thyroid disorders and reproductive function STEP 3: Drug Interactions Associated with Drugs Acting on Endocrine System (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are drug interactions associated with drugs acting on endocrine system occur? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below Biguanides (Metformin etc) o Other oral hypoglycaemic drugs are additive with metformin. o Ethanol predisposes to metformin-related lactic acidosis. PST 05104 Pharmacology & Therapeutics 59 NTA Level 5 Semester 1 Facilitator Guide Sulphonylureas (tolbutamide, glibenclamide, gliclazide) and Related Drugs o Monoamine oxidase inhibitors potentiate the activity of sulphonylureas by an unknown mechanism. o Several drugs (e.g. glucocorticosteroids, growth hormone) antagonize the hypoglycaemic effects of sulphonylureas by virtue of their actions on insulin release or sensitivity. Thiazolidinediones (rosiglitazone and pioglitazone) o Glitazones are additive with other oral hypoglycaemic drugs. o They potentiate insulin, but this combination is contraindicated in some countries because of concerns that it might increase the risk of heart failure. o Pioglitazone is an inducer of CYP3A and may cause treatment failure with concomitantly administered drugs which are CYP3A substrates (e.g. reproductive steroids). STEP 4: Side Effects of Drugs Acting on Endocrine System (20 minutes) The following are the dise effects of drugs for treatment of Diabetes Mellitus; Insulin: Hypoglycemia, Headache, Allergic reactions, Flu like symptoms, Weight gain, Hypokalemia, Lipoatrophy, Itching, Rash , Injection site reaction Chlorpropamide:

NTA Level 5 • Semester 1 • PST05104 Enzyme Inhibitors and Inducers Pharmacology and Therapeutics • Source Session/Topic 7 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 7: Enzyme Inhibitors and Inducers Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe Enzyme induction Describe Enzyme inhibition Describe role of enzyme induction and inhibition 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 Activity/ Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning Tasks Introduction, Learning Tasks 2 2 30 minutes 30 minutes Presentation/ Enzyme Inducers Enzyme Inducers 2 2 30 minutes 30 minutes Buzzing Enzyme Inducers Enzyme Inducers Buzzing Presentation/ 3 3 45 minutes 45 minutes Small Group Enzyme Inhibitors Enzyme Inhibitors Discussion 4 4 30 minutes 30 minutes Presentation Clinical Importance of Enzyme Induction and Clinical Importance of Enzyme Induction and 4 4 30 minutes 30 minutes Brainstorming Inhibition Inhibition Brainstorming Inhibition Inhibition 5 5 05 minutes 05 minutes Presentation Key Points Key Points 6 6 05 minutes 05 minutes Presentation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics 52 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: Description of Enzyme Induction (30 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How does enzyme induction occur? 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 As discussed in the earlier session on metabolism of drugs, Cytochrome P-450 Enzymes Cytochrome (CYP450) enzymes are responsible for metabolism of endogenous or exogenous substrates. There are at least 40 CYP450 enzymes but the most common isozymes are 3A4, 2D6, 2C9 and 2C19, and 1A2. Clinically significant drug interactions arise from either induction or inhibition of these enzymes. Enzyme induction: A number of drugs increase the activity of microsomal oxidase and conjugating systems when administered repeatedly. The effect is referred to as induction and is the result of increased synthesis of microsomal enzymes An inducer stimulates increased production of a CYP450 enzyme. Enzyme induction can increase drug toxicity and may reduce drug effectiveness (drug interaction). Drugs which induce cytochrome P450 enzyme system significantly include: o Rifampicin, ethanol and Carbamazepine o Drinks and herbal plants may also induce the cytochrome 450 isoenzyme a good example being St. John‘s wort and nicotine (smoking). PST 05104 Pharmacology & Therapeutics 53 NTA Level 5 Semester 1 Facilitator Guide STEP 3: Enzyme Inhibition (45Minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: How does enzyme inhibition occur? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below Inhibition of a CYP450 enzyme will result in increased levels of a substrate (drug) that is metabolized by that enzyme. Inhibition may be either competitive or allosteric: Competitive inhibition Two drugs are metabolized by the same enzyme system, and one of the drugs binds more readily to the enzyme, resulting in the inhibition of metabolism of the other drug. Example: Erythromycin and atorvastatin are both metabolized by CYP3A4. o Erythromycin is also a CYP3A4 inhibitor; therefore it inhibits the metabolism of atorvastatin. Allosteric (non-competitive) inhibition A drug inhibits an enzyme that it itself is not metabolized by. This inhibition occurs at an allosteric site (i.e., not at the site where the substrates bind). Drugs which inhibit cytochrome P450 enzyme system significantly include: Cimetidine, Omeprazole, Quinolone antibiotics, Amiodarone, Antipsychotics, Antihistamines, Antifungal drugs, Fluvastatin, Isoniazid, Macrolide antibiotics Drinks and herbal plants may also inhibit the cytochrome 450 isoenzyme a good example being grapefruit juice and red wine. PST 05104 Pharmacology & Therapeutics 54 NTA Level 5 Semester 1 Facilitator Guide STEP 4: Clinical Importance of Enzyme Induction (30minutes) Enzyme inhibition: It may lead to drug-drug interaction due to increased plasma concentration of active drug (substrate) which its metabolism has been inhibited resulting in increased biologic activity (or toxicity) of the drug. Prodrugs require metabolic enzymes for transformation to an active (or more active) metabolite. Therefore enzyme inhibitor would lead to a reduction in levels of active drug, in turn reducing the biologic activity of the drug. Enzyme induction It may lead to drug-drug interaction whereby the plasma concentration of active drug (substrate) which its metabolism has been increased will be sub-optimal, which might result in reduced biologic activity of the drug, perhaps leading to therapeutic failure. However, for drugs having toxic metabolites, enzyme induction may exacerbate metabolite-mediated toxicity because more and more toxic metabolited will be formed. For prodrug enzyme induction may accelerate the formation of active drug, , leading to an exaggerated effect and toxicity STEP 5: Key Points (5 minutes) Induction or inhibition of metabolizing enzyme has a clinical importance. Concomitant administration of known significant inducers or inhibitors with other drugs may result to drug interactions The most common isozymes most likely to be inhibited or induced are 3A4, 2D6, 2C9 2C19 and 1A2. STEP 6: Evaluation (5 minutes) What types of drugs are known to be enzyme inducers? What is the importance of enzyme inhibition? What is the consequence of enzyme induction on a pro drug? PST 05104 Pharmacology & Therapeutics 55 NTA Level 5 Semester 1 Facilitator Guide References Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education. Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier. Tripathi,

NTA Level 5 • Semester 1 • PST05104 Agonists, Antagonists and Dose Response Relationship Pharmacology and Therapeutics • Source Session/Topic 6 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 6: Agonists, Antagonists and Dose Response Relationship Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe Agonist and antagonist effects Describe dose response relationship Explain on factors modifying drug response 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 Presentation/ Description Of Agonist and Antagonist Description Of Agonist and Antagonist 2 2 30 minutes 30 minutes Presentation/ Effects Effects 2 2 30 minutes 30 minutes Brainstorming Effects Effects Brainstorming Presentation 3 3 45 minutes 45 minutes Small Group Description of Dose Response Relationship Description of Dose Response Relationship Discussion 4 4 30 minutes 30 minutes Presentation/ Explanation on Factors Modifying Drug Explanation on Factors Modifying Drug 4 4 30 minutes 30 minutes Brainstorming Responses Responses Brainstorming Responses Responses 5 5 05 minutes 05 minutes Presentation Key Points Key Points 6 6 05 minutes 05 minutes Presentation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics 44 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: Effect of Agonist and Antagonist (30minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What is the meaning of agonist and antagonist? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below Drugs are categorized based on their intrinsic activity at a given receptor: Agonist : o Agonists (sometimes called full agonists) produce maximum activation of the receptor and elicit a maximum response from the tissue. o They are assigned an intrinsic activity of 1. o Agonists activate receptors for endogenous mediators – example salbutamol is an agonist at β2-adrenoceptors, the consequent effect may be excitatory (e.g. increased heart rate) or inhibitory (e.g. relaxation of airway smooth muscle). o Agonists at nicotinic acetylcholine receptors (e.g. suxamethonium) exert an inhibitory effect (neuromuscular blockade) by causing long-lasting depolarization at the neuromuscular junction, and hence inactivation of the voltage- dependent sodium channels that initiate the action potential. Partial Agonist o A partial agonist is a drug that displays efficacy that is intermediate between that of an agonist and an antagonist o Partial agonist produces a lower response at full receptor occupancy than full agonists o Partial agonists also produce concentration –effect curves that resemble those observed with full agonists PST 05104 Pharmacology & Therapeutics 45 NTA Level 5 Semester 1 Facilitator Guide Inverse Agonist : o Inverse agonists inhibit rather than activate the receptor. o This phenomenon is evident with receptors that exhibit baseline (ongoing or constitutive) activity in the absence of agonist binding. o In these cases, binding of the inverse agonist reduces the baseline activity of the receptor, which in turn elicits an effect opposite that of binding of the agonist. o Inverse agonists and antagonists will elicit similar effects because both types of drugs will reverse the effects of endogenous ligands. Antagonist: o Antagonists bind but produce no activation of the receptor and therefore block responses from the tissue. o They are assigned an intrinsic activity of 0. There are two types of antagonism; Competitive antagonists o Antagonist combines with the same receptor as an endogenous agonist (e.g. ranitidine at histamine H2-receptors), but fail to activate it. o When combined with the receptor, they prevent access of the endogenous mediator. o The complex between competitive antagonist and receptor is reversible. o Provided that the dose of agonist is increased sufficiently, a maximal effect can still be obtained, i.e. the antagonism is surmountable. o β-Adrenoceptor antagonists are examples of reversible competitive antagonists. Non-competitive antagonist: o Bind irreversibly to agonist binding site o The effect is equivalent to removing receptors from the system PST 05104 Pharmacology & Therapeutics 46 NTA Level 5 Semester 1 Facilitator Guide The effect of one drug can be reduced in the presence of another in other ways: Chemical antagonism Pharmacokinetic antagonism Block of receptor-effector linkage Physiological antagonism Chemical antagonism It refers to the uncommon situation where the two substances combine in solution; as a result, the effect of the active drug is lost. o Eg 1→ chelating agent dimercaprol that bind to heavy metals and thus reduce their toxicity o Eg 2 → the neutralising antibody infliximab which has an anti-inflammatory action due to its ability to sequester the inflammatory cytokine, tumour necrosis factor Pharmacokinetic antagonism PK antagonism occurs when: o The rate of elimination of the active drug is increased (e.g. the anticoagulant effect of warfarin is ↓ when given together with phenobarbital, o The rate of absorption of the active drug from the Git is reduced, o The rate of renal excretion may be increased. Physiological antagonism Physiological antagonism occurs when two drugs whose opposing actions in the body tend to cancel each other. For example, histamine acts on receptors of the parietal cells of the gastric mucosa to stimulate acid secretion, while omeprazole blocks this effect by inhibiting the proton pump; STEP 3: Dose – Response Relationship (45minutes) There are two types of Dose –response relationships, which are best, represented in curves: Graded dose-response curve Quantal dose-response curve (all or none). Graded dose-response curve In this type, response is gradual There is Gradual increase in response by increasing the dose (continuous response). Lowering of blood pressure, heart rate, blood glucose level, cholesterol Curve is usually sigmoid in shape PST 05104 Pharmacology