Pharmaceutical Sciences Notes

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 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 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 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 Drugs Acting on Genital-Urinal System Pharmacology and Therapeutics • Source Session/Topic 16 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 16: Pharmacodynamics of Drugs Acting on Genital-Urinal 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 Genital-Urinal System Describe drug interactions associated with Drugs acting on Genital-Urinal System Describe side effects of Drugs acting on Genital-Urinal System Describe contraindications of Drugs acting on Genital-Urinal System 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 on Mechanism of Action of Drugs acting on 2 2 45 minutes 45 minutes Buzzing Genital-Urinal System Genital-Urinal System Buzzing Genital-Urinal System Genital-Urinal 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 Genital-Urinal System acting on Genital-Urinal System brainstorming acting on Genital-Urinal System acting on Genital-Urinal System 4 4 20 minutes 20 minutes Presentation Side Effects of Drugs acting on Genital-Urinal Side Effects of Drugs acting on Genital-Urinal 4 4 20 minutes 20 minutes Presentation System System System System 5 5 20 minutes 20 minutes Presentation/ Contraindications of Drugs acting on Genital- Contraindications of Drugs acting on Genital- 5 5 20 minutes 20 minutes Brainstorming Urinal System Urinal System Brainstorming Urinal System Urinal 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 130 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 Genital-Urinal System (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 genital-urinal system 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 Diuretics Thiazides Diuretics: (Hydrochlorothiazide, chlorothiazide, chlorthalidone) o Thiazide diuretics are used first-line treatment for hypertension, edema and nephrogenic diabetes insipidus (DI) (rare). o Thiazide diuretics inhibit the Na+/Cl− co-transporter channel in the distal tubule of the nephron leading to reduction in Na+ reabsorbed in kidney leading to rise in Na+ lost in urine hence more water lost in urine. o Therefore Na+, Cl− (and water) remain in the lumen of the tubule hence natriuresis and diuresis. o In addition, the actions of the thiazides impact other ions as follows: A passive Na+/H+ exchange occurs at a distal site in the tubule. Na+ gradients drive this exchange. When the Na+/Cl− cotransporter is blocked, the Na+ concentration in the lumen of the tubule is high, this facilitates Na+ reabsorption in exchange for excretion of H+ ions at this distal site. Therefore thiazides create alkalosis by H+ ion loss through a secondary, passive exchange. o Similarly, Na+ is exchanged for K+ at a distal site in the tubule. By enhancing delivery of Na+ to distal sites of the nephron, Na+ is exchanged for K+, leading to enhanced K+ excretion, in a similar manner to the K+ depletion that occurs with loop diuretics. o Thiazides also promote Ca+2 reabsorption through a poorly understood mechanism. PST 05104 Pharmacology & Therapeutics 131 NTA Level 5 Semester 1 Facilitator Guide Owing to the fact they act so distally in the nephron, after much of the Na+ reabsorption has already occurred, thiazides are relatively weak diuretics when compared with loop diuretics. Thiazides are also vasodilators, an effect independent of their diuretic actions. Their antihypertensive effect is probably related mainly to this mechanism and not the diuretic mechanism. Effect on plasma ion concentrations: Decreased Na+, Cl−, K+, Mg+2, Increased Ca+2, Increased HCO3−. (This creates a metabolic alkalosis.) This is a result of H+ ion loss. Remember that the equation will shift left with a loss of H+: i.e H+ + HCO3 – →H2O+CO2 Loop Diuretics: ( furosemide, ethacrynic acid, torsemide, bumetanide ) Loop diuretics are used in management of edema in Heart failure, Nephrotic syndrome and Liver failure. They are also used in acute hypercalcemia. Loop diuretics inhibit the Na+/K+/2Cl− co-transporter channel in the thick ascending limb (Henle‘s loop) of the renal tubule. This results in less Na+ being reabsorbed back into the body. Cl− and K+ also move in the same direction through this ion channel, as does Na+. Therefore Na+, Cl−, and K+ are lost in the urine hence Natriuresis and diuresis. Blockade of the Na+/K+/2Cl− cotransporter has effects on other ions as well as follows: Blockade of the Na+/K+/2Cl− cotransporter interferes with the ability of K+ and Cl-channels to create the positive to negative gradient. Disruption of this electrochemical gradient facilitates excretion of Ca+2 and Mg+2. Normally these divalent cations undergo paracellular reabsorption, repelled by the positively charged tubular lumen and attracted to the negatively charged interstitium. Attenuation of the positive to negative gradient reduces paracellular reabsorption of A passive Na+/H+ exchanger is present at a distal site in the tubule. Na+ gradients drive this exchange. When the Na+/K+/2Cl− channel is blocked, the Na+ concentration in the lumen of the tubule is high, which facilitates the reabsorption of Na+ and excretion of H+ at this distal site. Therefore furosemide creates alkalosis by H+ ion loss through a secondary, passive

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Antihelminthics Pharmacology and Therapeutics • Source Session/Topic 17 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 17: Pharmacodynamics of Antihelminthics 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 Antihelminthics Describe drug interactions associated with Antihelminthics Describe side effects of Antihelminthics Describe contraindications of Antihelminthics 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 Antihelminthics Mechanism of Action of Antihelminthics 2 2 45 minutes 45 minutes Buzzing Mechanism of Action of Antihelminthics Mechanism of Action of Antihelminthics Buzzing 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Drug Interactions Associated With 3 3 20 minutes 20 minutes brainstorming Antihelminthics Antihelminthics brainstorming Antihelminthics Antihelminthics 4 4 20 minutes 20 minutes Presentation Side Effects of Antihelminthics Side Effects of Antihelminthics 5 5 20 minutes 20 minutes Presentation/ Contraindications of Antihelminthics Contraindications of Antihelminthics 5 5 20 minutes 20 minutes Brainstorming Contraindications of Antihelminthics Contraindications of Antihelminthics 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 141 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 Antihelminthics (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do antihelminthics 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 Benzimidazoles Albendazole o Albendazole like other benzimidazoles acts by binding to and interfering with the synthesis of the parasite's microtubules and also by decreasing glucose uptake. Affected parasites are expelled with the feces. o Benzimidazoles have a selective inhibitory action on helminthic microtubular function, being 250-400 times more potent in helminths than in mammalian tissue. The inhibitory concentration is lower Mebendazole Has same mechanism of action with Albendazole discussed above Thiabendazole Has same mechanism of action with Albendazole discussed above Pyrantel pamoate o It acts as a depolarizing neuromuscular blocking agent, causing persistent activation of the parasite‘s nicotinic receptors. o The paralysed worms are then expelled from the intestinal tract of the host. Ivermectin o Ivermectin targets the parasite's y-aminobutyric acid (GABA) receptors. o Chloride efflux is enhanced and hyperpolarization occurs, resulting in paralysis of the worm. Praziquantel PST 05104 Pharmacology & Therapeutics 142 NTA Level 5 Semester 1 Facilitator Guide Praziquantel acts by increasing membrane permeability to ca2+.This causes increased contraction of the musculature and eventually results in paralysis and death of the worm (SPASTIC PARALYSIS). It has been suggested that praziquantel (at slightly high concentrations ) modifies the parasite so that it becomes susceptible to hosts normal immune responses by causing tegumental damage hence worm destruction. It is associated with IL-4 and a type 2 (TH2) response Piperazine Piperazine inhibits neuromuscular transmission in the worm, probably by acting like GABA the inhibitory neurotransmitter on GABA gated chloride channels in the nematode muscle hence flaccid paralysis. The paralysed worms are expelled live Niclosamide Act by inhibiting anaerobic phosphorylation of ADP by the mitochondria of the parasite ,an energy producing process that is dependent on carbon dioxide (co2 ) fixation thus resulting into decreased glucose uptake and glycogen synthesis The scolex and a proximal segment are irreversibly damaged by the drug. The worm separates from the intestinal wall and is expelled. Neither the larvae nor the ova are affected. Oxamoniquine The drug undergoes ATP dependent enzymatic activation to unstable phosphate ester which dissociates to yield a reactive carbocation which then alkylates DNA. Has some anticholinergic effects on the worm. Diethylcarbamazine Modifies parasite membrane so that it becomes susceptible to the host normal immune response. Causes progressive paralysis of the worm due to decreased ATP resulting from prevention of ADP phosphorylation. may also interfere with parasite arachidonate mechanism Levamisole It has nicotinic like action, stimulating and subsequently blocking the neuromuscular junctions. The paralysed worms are then passed in the faeces. The ova are not killed. PST 05104 Pharmacology & Therapeutics 143 NTA Level 5 Semester 1 Facilitator Guide STEP 3: Drug Interactions Associated with Antihelminthics Drugs (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What drug interactions associated with of antihelminthics drugs? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below Antihelminthics do not have significant drug interactions. STEP 4: Side Effects of Antihelminthics (20 minutes) Benzimidazoles: Albendazole and others. o Generally well tolerated. Attributing side effects to drug can be challenging, as many side effects are consistent with the host response to dead or dying parasites rather than the drug itself. o GI side effects may be experienced, although in some cases these may be largely the result of passage of the worm. o Mebendazole only: Serious and Rare: Agranulocytosis, alopecia, and elevated hepatic enzymes have been reported at high doses, although mechanisms have not been established for any of these side effects. Praziquantel o Serious and Rare: CNS effects (seizures, changes in mental status, intracranial hypertension) may occur in the treatment of neurocysticercosis. o These effects are believed to be caused by inflammatory reactions that occur because of the dead parasites. o Corticosteroids may be coadministered with praziquantel

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Antimalarial Drugs Pharmacology and Therapeutics • Source Session/Topic 18 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 18: Pharmacodynamics of Antimalarial 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 antimalarial drugs Describe drug interactions associated with antimalarial drugs Describe side effects of antimalarial drugs Describe contraindications of antimalarial drugs 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 Antimalarial Drugs Mechanism of Action of Antimalarial Drugs 2 2 45 minutes 45 minutes Buzzing Mechanism of Action of Antimalarial Drugs Mechanism of Action of Antimalarial Drugs Buzzing 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Drug Interactions Associated With 3 3 20 minutes 20 minutes brainstorming Antimalarial Drugs Antimalarial Drugs brainstorming Antimalarial Drugs Antimalarial Drugs 4 4 20 minutes 20 minutes Presentation Side Effects of Antimalarial Drugs Side Effects of Antimalarial Drugs 5 5 20 minutes 20 minutes Presentation/ Contraindications of Antimalarial Drugs Contraindications of Antimalarial Drugs 5 5 20 minutes 20 minutes Brainstorming Contraindications of Antimalarial Drugs Contraindications of Antimalarial 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 147 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 Antimalarial Drugs (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do antimalarial 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 The mechanisms of action for Antimalarials are as follows: The 4-Aminoquinolines:chloroquine Chloroquine is still used as antimalarial drugs world-wide, but increasing resistance (especially P. falciparum) has reduced its efficacy. Its uses are now limited to malaria prophylaxis, treatment of rheumatoid arthritis or systemic lupus erythematosis The erythrocyte stages of Plasmodium are sensitive to chloroquine. At this stage of its life cycle, the parasite digests haemoglobin in a food vacuole to provide energy for the parasite. The food vacuole is acidic and the weak base chloroquine is concentrated within it by diffusion ion-trapping. Chloroquine and other 4-aminoquinolines are believed to inhibit the malarial haem polymerase within the food vacuole of the plasmodial parasite, thereby inhibiting the conversion of toxic haemin (ferriprotoporphyrin IX) to haemozoin (a pigment which accumulates in infected cells and is not toxic to the parasite). Ferriprotoporphyrin IX accumulates in the presence of chloroquine and is toxic to the parasite, which is killed by the waste product of its own appetite (‗hoist with its own petard‘). Decreased DNA synthesis: The drug can also decrease DNA synthesis in the parasite by disrupting the tertiary structure of the nucleic acid. PST 05104 Pharmacology & Therapeutics 148 NTA Level 5 Semester 1 Facilitator Guide Mechanisms of Resistance: o The actions of chloroquine and related agents on heme occur at the food vacuole, and the main theory regarding resistance centers around the ability of chloroquine and others to access the food vacuole. o Malaria may limit this through various mutations that either prevent access to the vacuole or pump drug out of the vacuole. o One strategy being investigated to overcome resistance is to inhibit the activity of this efflux pump using another drug . Arylaminoalcohols (4-Aminoquinoline derivatives) o Quinine is the main alkaloid of cinchona bark. o The mechanism of its antimalarial activity remains unclear, but may be similar to that of chloroquine 8-Aminoquinolines (Primaquine) o Primaquine is used to eradicate the hepatic forms of P. vivax or . malariae after standard chloroquine therapy, provided that the risk of re-exposure is low. o It may also be used prophylactically with chloroquine. o It interferes with the organism‘s mitochondrial electron transport chain. o Intermediates are believed to act as oxidants that are responsible for the schizonticidal action as well as for hemolysis and methemoglobinemia encountered as toxicities. Artenusate and Artemether o Artemesinins undergo haem-mediated decomposition of the endoperoxide bridge to yield carbon-centred free radicals. o The involvement of haem explains why they are selectively toxic to malaria parasites. o The resulting carbon-centred free radicals alkylate haem and proteins, particularly in the membranes of the parasite‘s food vacuole and mitochondria, causing rapid death Anti-folates (Dapsone Proguanil, Pyrimethamine) o Combinations of these drugs are taken orally in malaria prophylaxis, but their efficacy in acute malaria treatment is limited due to resistance. o These agents inhibit folate biosynthesis at all stages of the malaria parasite‘s life cycle, acting as competitive inhibitors of the malarial dihydropteroate synthase (dapsone) or the malarial dihydrofolate reductase (proguanil or pyrimethamine). PST 05104 Pharmacology & Therapeutics 149 NTA Level 5 Semester 1 Facilitator Guide STEP 3: Drug Interactions Associated With Antimalarial Drugs (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are drug interactions associated with Antimalarial Drugs? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below Drug interactions include; Arylaminoalcohols (4-Aminoquinoline derivatives) o Retardation of absorption when quinine if taken with aluminium-containing antacids o Potentiation of neuromuscular blocking and elevation of digoxin levels if taken concurrently with quinine. STEP 4: Side Effects of Antimalarial Drugs (20 minutes) The

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Antifungal Drugs Pharmacology and Therapeutics • Source Session/Topic 19 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 19: Pharmacodynamics of Antifungal 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 antifungal drugs Describe drug interactions associated with antifungal drugs Describe side effects of antifungal drugs Describe contraindications of antifungal drugs 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 Antifungal Drugs Mechanism of Action of Antifungal Drugs 2 2 45 minutes 45 minutes Buzzing Mechanism of Action of Antifungal Drugs Mechanism of Action of Antifungal Drugs Buzzing 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Antifungal Drug Interactions Associated With Antifungal 3 3 20 minutes 20 minutes brainstorming Drugs Drugs brainstorming Drugs Drugs 4 4 20 minutes 20 minutes Presentation Side Effects of Antifungal Drugs Side Effects of Antifungal Drugs 5 5 20 minutes 20 minutes Presentation/ Contraindications of Antifungal Drugs Contraindications of Antifungal Drugs 5 5 20 minutes 20 minutes Brainstorming Contraindications of Antifungal Drugs Contraindications of Antifungal 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 154 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 Antifungal Drugs (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do antifungal 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 Polyenes Amphotericin B o Is a polyene macrolide with a hydroxylated hydrophilic surface on one side of the molecule and an unsaturated conjugated lipophilic surface on the other side. o The lipophilic surface has a higher affinity for fungal sterols than for cholesterol in mammalian cell membranes and increases membrane permeability by creating a ‗membrane pore‘ with a hydrophilic centre which causes leakage of small molecules, e.g. glucose and potassium ions. Nystatin o Nystatin works in the same way as amphotericin B, but its greater toxicity precludes systemic use. Azoles (imidazoles and Triazoles) Fluconazole (a triazole) o Imidazoles and Triazoles competitively inhibit lanosterol 14-α-demethylase (a fungal cytochrome-haem P450 enzyme), which is a major enzyme in the pathway that synthesizes ergosterol from squalene. o This disrupts the acyl chains of fungal membrane phospholipids, increasing membrane fluidity and causing membrane leakage and dysfunction of membrane-bound enzymes. PST 05104 Pharmacology & Therapeutics 155 NTA Level 5 Semester 1 Facilitator Guide Triazole drugs work by the same mechanism as imidazoles but have a wider antifungal spectrum and are more specific for fungal CYP450. The imidazoles have considerable specificity/affinity for fungal cytochrome-haem P450 enzymes. Ketoconazole (an imidazole) Mechanism of action is as discussed above Imidazoles are fungistatic at low concentrations and fungicidal at higher concentrations. The imidazoles have considerable specificity/affinity for fungal cytochrome-haem P450 enzymes but less specific when compared to Triazoles. Itraconazole and Voriconazole ( Triazoles) Have a similar mechanism of action to fluconazole Echinocandins Caspofungin and micafungin o Echinocandins are non-competitive inhibitors of 1, 3-β-D glucan synthase, an enzyme necessary for synthesis of a glucose polymer crucial to the structure and integrity of the cell walls of some fungi. o Fungal cells unable to synthesize this polysaccharide cannot maintain their shape and lack adequate rigidity to resist osmotic pressure, which results in fungal cell lysis. Allylamines Terbinafine o Terbinafine acts by inhibiting the enzyme squalene epoxidase, which is involved in fungal ergosterol biosynthesis. Other antifungals Griseofluvin o This drug is concentrated in fungi and binds to tubulin, blocking polymerization of the microtubule, disrupting the mitotic spindle. Flucytosine (5-Fluorocytosine) o This drug is deaminated to 5-fluorouracil in the fungus and converted to an antimetabolite 5-FdUMP. o This inhibits thymidylate synthetase, impairing fungal DNA synthesis. PST 05104 Pharmacology & Therapeutics 156 NTA Level 5 Semester 1 Facilitator Guide STEP 3: Drug Interactions Associated with Antifungal Drugs (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What drug interactions associated with antifungal drugs? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below Azoles (imidazoles and Triazoles) Fluconazole (a triazole) o Fluconazole reduces the metabolism of several drugs by inhibiting CYP3A, including benzodiazepines, calcium channel blockers, ciclosporin, docetaxel and, importantly, warfarin. o The plasma concentrations and toxicity of these drugs will increase during concomitant treatment with fluconazole. o Rifampicin enhances the metabolism of fluconazole. Itraconazole and Voriconazole ( Triazoles) o Drugs which decrease gastric acid (e.g. proton pump inhibitors) reduce the bioavailablity of both agents and drugs that induce hepatic CYP3A decrease systemic drug concentrations. Echinocandins Caspofungin and micafungin o These are minimal compared to the azoles. Ciclosporin increases Caspofungin AUC by 35% and micafungin increases the bioavailability of sirolimus and nifedipine. o The pharmacokinetics of micafungin do not appear to be affected by other drugs; however, micafungin has been shown to increase levels of amphotericin B. o Because of their complementary MOA, these two antifungal agents might be combined. Other antifungals Griseofluvin o Griseofluvin induces hepatic CYP450s and consequently can interact with many drugs. PST 05104 Pharmacology & Therapeutics 157 NTA Level 5 Semester 1 Facilitator

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Penicillins and Cephalosporins Pharmacology and Therapeutics • Source Session/Topic 20 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 20: Pharmacodynamics of Penicillins and Cephalosporins 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 Penicillins and Cephalosporins Describe drug interactions associated with Penicillins and Cephalosporins Describe side effects of Penicillins and Cephalosporins Describe contraindications of Penicillins and Cephalosporins Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and projector Handout 20.1 Important Information on Mechanism of Actions of Penicillins and Cephalosporins 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 Penicillins and Mechanism of Action of Penicillins and 2 2 45 minutes 45 minutes Buzzing Cephalosporins Cephalosporins Buzzing Cephalosporins Cephalosporins 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Penicillins Drug Interactions Associated With Penicillins 3 3 20 minutes 20 minutes brainstorming and Cephalosporins and Cephalosporins brainstorming and Cephalosporins and Cephalosporins 4 4 20 minutes 20 minutes Presentation Side Effects of Penicillins and Cephalosporins Side Effects of Penicillins and Cephalosporins 5 5 20 minutes 20 minutes Presentation/ Contraindications of Penicillins and Contraindications of Penicillins and 5 5 20 minutes 20 minutes Brainstorming Cephalosporins Cephalosporins Brainstorming Cephalosporins Cephalosporins 6 6 05 minutes 05 minutes Presentation Key Points Key Points 7 7 05 minutes 05 minutes Presentation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics 162 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 Penicillins and Cephalosporins (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes • How do Penicillins and Cephalosporins 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 B-lactams Penicillins o The penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation or cross-linkage thus exposing the osmotically less stable membrane. o Cell lysis can then occur, and these drugs are therefore bactericidal. o The efficacy of penicillin antibiotic in causing cell death is related to its size, charge, and hydrophobicity. o These drugs are only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall. o Therefore, Penicillins are inactive against organisms devoid of this structure, such as mycobacteria, protozoa, fungi, and viruses. Cephalosporins o These drugs have the same mode of action as Penicillins. General information for cephalosporins and penicillins: In general two major components are required for β-lactam activity The first is the binding to penicillin-binding proteins. The second is the destruction of the bacterial cell wall. PST 05104 Pharmacology & Therapeutics 163 NTA Level 5 Semester 1 Facilitator Guide All β-lactams (penicillins, carbapenems, and cephalosporins) act through this common sequence of events. o Virtually all bacteria contain penicillin-binding proteins. REFER Students to Handout 20.1: Important Information on Mechanism of Actions of Penicillins and Cephalosporins STEP 3: Drug Interactions Associated with Penicillins and Cephalosporins Drugs (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are drug interactions associated with Penicillins and Cephalosporins drugs? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below B-lactams Penicillins o Probenecid, a uricosuric, competes with penicillin in the organic acid transporter in the kidney and therefore decreases renal clearance of penicillin, thereby prolonging high tissue concentrations and a longer half life. It is coadministered with penicillin. STEP 4: Description of Side Effects of Penicillins and Cephalosporins (20 minutes) B-lactams Penicillins o Hypersensitivity: most commonly only a rash, but can include anaphylaxis o Nausea and vomiting if given orally o Diarrhoea o Stinging in the vein if given intravenously (IV) Cephalosporins o Hematologic: rare cases of bone marrow suppression resulting in a low white blood cell (WBC) count (aka neutropenia or granulocytopenia) o Nephrotoxicity: occasional interstitial nephritis and tubular necrosis PST 05104 Pharmacology & Therapeutics 164 NTA Level 5 Semester 1 Facilitator Guide Pseudomembranous colitis: many antibiotics, including cephalosporins, can wipe out gut flora and permit the bacterium C. difficile to colonize, which causes this condition. STEP 5: Description of Contraindications of Penicillins and Cephalosporins Drugs (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are the contraindications of Penicillins and Cephalosporins drugs? ALLOW few students to respond? WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below B-lactams Penicillins o Hypersensitivity (allergy) o Incidence is as high as 10%. o Anaphylaxis o Cross-reactivity between penicillin allergy and other β-lactam antibiotics (cephalosporins and carbapenems) is around 1% to 10%. o Anaphylaxis to penicillins is an absolute contraindication. o Nonanaphylactic allergy to penicillins is a relative contraindication; however, the cross-reactivity is reported to be 2% to 10%, and cephalosporins have been used frequently in patients with a penicillin allergy. o Side effects (GI upset, nausea) are sometimes called allergies by patients when in fact they are not allergies. Cephalosporins o Anaphylaxis to penicillins is an absolute contraindication. o Nonanaphylactic allergy to penicillins is a relative contraindication; however, the cross-reactivity is reported to be 2% to 10%, and cephalosporins have been used frequently in patients with a penicillin allergy. o Maculopapular rash (flat confluent red rash) o Urticaria (itchy hives) o Eosinophilia (which is common to allergic reactions) PST 05104 Pharmacology &

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Macrolides Pharmacology and Therapeutics • Source Session/Topic 21 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 21: Pharmacodynamics of Macrolides 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 Macrolide Describe drug interactions associated with Macrolides Describe side effects of Macrolides Describe contraindications of Macrolides 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 45 minutes 45 minutes Presentation/ Mechanism of Action of Macrolides Mechanism of Action of Macrolides Mechanism of Action of Macrolides 2 2 45 minutes 45 minutes Buzzing Mechanism of Action of Macrolides Mechanism of Action of Macrolides Mechanism of Action of Macrolides Buzzing 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Macrolides Drug Interactions Associated With Macrolides Drug Interactions Associated With Macrolides 3 3 20 minutes 20 minutes brainstorming Drug Interactions Associated With Macrolides Drug Interactions Associated With Macrolides Drug Interactions Associated With Macrolides brainstorming 4 4 20 minutes 20 minutes Presentation Side Effects of Macrolides Side Effects of Macrolides Side Effects of Macrolides 5 5 20 minutes 20 minutes Presentation/ Contraindications of Macrolides Contraindications of Macrolides Contraindications of Macrolides 5 5 20 minutes 20 minutes Brainstorming Contraindications of Macrolides Contraindications of Macrolides Contraindications of Macrolides 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 170 170 170 NTA Level 5 Semester 1 Facilitator Guide NTA Level 5 Semester 1 Facilitator Guide PST 05104 Pharmacology & Therapeutics 171 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 Macrolides (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes • How do Macrolides 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 Macrolides The macrolides bind irreversibly to a site on the 50s subunit of the bacterial ribosome, thus inhibiting the translocation steps of protein synthesis. The binding site is either identical to or in close proximity to that for lincomycin, clindamycin, and chloramphenicol. Inhibition of protein synthesis does not typically kill bacteria cells, so these agents are generally bacteriostatic, but in high concentrations they can be bactericidal. Macrolides are phagocytosed by macrophages, which is a benefit because WBCs preferentially travel to sites of infection, thereby theoretically delivering the drug to the site at which it is needed. Mechanisms of Resistance: o Modification of the RSU binding site either by chromosomal mutation or through methylation via methylase greatly decreases the efficacy of macrolides; bacterial methylase can be produced constitutively (all the time) or can be induced. o Reduced intracellular concentrations are found within the bacterium, through either reduced permeability of cell membrane to macrolides or, probably more important, increased efflux of macrolides via active pumps. o A third, and maybe least prominent, method of resistance is through the production of esterases that hydrolyze macrolides; this is more common with gram-negative enteric bacteria (bacteria that colonize the GI tract). PST 05104 Pharmacology & Therapeutics 172 NTA Level 5 Semester 1 Facilitator Guide Cross-resistance is complete among all macrolides; if a bacterium is resistant to one, it will be resistant to all others in this class. STEP 3: Drug Interactions Associated with Macrolides (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are drug interactions associated with Macrolides drugs? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below Macrolides Erythromycin o Erythromycin metabolites inhibit cytochrome P450 enzymes and, thus, increase the serum concentrations of numerous drugs, including theophylline, warfarin, cyclosporine, and methylprednisolone. o Erythromycin also increases serum concentrations of oral digoxin by increasing its bioavailability. o Erythromycin and some antibiotics eliminate a species of intestinal flora that ordinarily inactivates digoxin, thus leading to a greater reabsorption of digoxin from the enterohepatic circulation. o Erythromycin and clarithromycin are significant CYP450 enzyme inhibitors and are metabolized by the liver. Drug interactions with other CYP450 inhibitors should be monitored. Azithromycin o Because it has a 15-member (not 14-member) lactone ring, azithromycin does not inactivate cytochrome P450 enzymes and, therefore, is free of the drug interactions that occur with erythromycin and clarithromycin. o Erythromycin is unstable in gastric acid and therefore must be administered with salts or esters or via enteric-coated tablets when administered orally. o The addition of a methyl group to erythromycin creates clarithromycin, and the addition of methylated nitrogen to erythromycin creates azithromycin; both are stable in gastric acid and very well absorbed orally. o Because of the long duration of action of azithromycin, a 5-day, oral, once-a-day course for most sensitive infections is considered a treatment of adequate duration. PST 05104 Pharmacology & Therapeutics 173 NTA Level 5 Semester 1 Facilitator Guide STEP 4: Side Effects of Macrolides (20 minutes) Macrolides Erythromycin o GI: Significant GI upset because of increased gut motility o Acute cholestatic hepatitis: Likely hypersensitivity-related, this side