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NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Antiviral Drugs Pharmacology and Therapeutics • Source Session/Topic 25 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 25: Pharmacodynamics of Antiviral 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 Antiviral Drugs Describe drug interactions associated with Antiviral Drugs Describe side effects of Antiviral Drugs Describe contraindications of Antiviral 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 Antiviral Drugs Mechanism of Action of Antiviral Drugs 2 2 45 minutes 45 minutes Buzzing Mechanism of Action of Antiviral Drugs Mechanism of Action of Antiviral Drugs Buzzing 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Antiviral Drug Interactions Associated With Antiviral 3 3 20 minutes 20 minutes brainstorming Drugs Drugs brainstorming Drugs Drugs 4 4 20 minutes 20 minutes Presentation Side Effects of Drugs for Antiviral Drugs Side Effects of Drugs for Antiviral Drugs 5 5 20 minutes 20 minutes Presentation/ Contraindications of Antiviral Drugs Contraindications of Antiviral Drugs 5 5 20 minutes 20 minutes Brainstorming Contraindications of Antiviral Drugs Contraindications of Antiviral 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 193 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 Antiviral Drugs (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do Antiviral 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 Anti-HIV Drugs Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs): Zidovudine(ZDV), lamivudine (3-TC), stavudine (d4T), didanosine(ddI), emtricitabine (FTC) and abacavir (ABC). o Anti retroviral drugs targets several steps which are involved in the replication of HIV. o The virus must fuse to the host cell, uncoat, enter and be transcribed by reverse transcriptase, become incorporated into the host genome, and be transcribed to viral RNA, which is then translated into polyproteins. o Reverse transcriptase is an enzyme that transcribes viral RNA into viral DNA (hence the term reverse). o The parent drug, ZDV, enters virally infected cells by diffusion and undergoes phosphorylation first to its monophosphate (ZDV-MP) then to the diphosphate (ZDV-DP), the rate-limiting step, and finally to the triphosphate (ZDV-TP). o ZDV-TP is a competitive inhibitor of the HIV-1 reverse transcriptase and when incorporated into nascent viral DNA causes chain termination. o Human cells lack reverse transcriptase and human nuclear DNA polymerases are much less sensitive (by at least 100-fold) to inhibition by ZDV-TP, thus producing a selective effect on viral replication. o This mechanism of action is common to all anti-HIV nucleoside analogues. PST 05104 Pharmacology & Therapeutics 194 NTA Level 5 Semester 1 Facilitator Guide Non -Nucleoside Analogue Reverse Transcriptase Inhibitors (nNRTIs): nevirapine, delavirdine, efavirenz and Second-generation: etravirine o Reverse transcriptase is an enzyme that transcribes viral RNA into viral DNA (hence the term reverse). o The nNRTIs bind to a site distant from the active site of the reverse transcriptase, and induce a conformational change in the enzyme. o This conformational change greatly reduces the activity of the enzyme. o Unlike the NRTIs, the nNRTIs have no activity against DNA polymerase. o Also, because the binding of nNRTIs to the reverse transcriptase is very specific, nNRTIs act specifically on the HIV-1 strain and lack activity against HIV-2. o Conversely, the NRTIs indirectly inhibit reverse transcriptase and are therefore not specific for HIV-1. Protease Inhibitors: Saquinavir, indinavir, nelfinavir, ritonavir, atazanavir, fosamprenavir, amprenavir, lopinavir and darunavir o Several steps are involved in the replication of HIV. The virus must fuse to the host cell, uncoat, enter and be transcribed by reverse transcriptase, become incorporated into the host genome, and be transcribed to viral RNA, which is then translated into polyproteins. o These polyproteins are then cleaved into smaller viral proteins by proteases as they are released from the cell. o This process is called viral maturation. o These smaller viral proteins perform important functions, either structural or acting as enzymes such as reverse transcriptase, integrase, or protease itself. o Protease inhibitors bind to these proteases and prevent them from performing this important step in viral maturation. o This results in the production of immature, non-infectious virus particles. o The selective toxicity of the protease inhibitors is based on structural differences between human proteases and viral proteases. Integrase Inhibitors: o Integrase inhibitors are a newer class of drugs for HIV infection that inhibit HIV by preventing the virus from incorporating its DNA into the host genome. o The integrase enzyme incorporates viral DNA into the host genome. o Specifically, integrase binds to viral DNA and joins it with host DNA. The divalent cations in the catalytic core of integrase enable it to form covalent bonds with DNA. o This is followed by cellular repair activities that seal the viral DNA into the chromosome. o Integrase inhibitors prevent the formation of covalent bonds with host DNA. This prevents incorporation of HIV into the host genome. PST 05104 Pharmacology & Therapeutics 195 NTA Level 5 Semester 1 Facilitator Guide Fusion Inhibitors: enfuvirtide ibalizumab o Enfuvirtide mimics the HIV machinery required to fuse to the CD4

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Drugs for Amoebiasis Pharmacology and Therapeutics • Source Session/Topic 24 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 24: Pharmacodynamics of Drugs for Amoebiasis Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe mechanism of action of Drugs for Amoebiasis Describe drug interactions associated with Drugs for Amoebiasis Describe side effects of Drugs for Amoebiasis Describe contraindications of Drugs for Amoebiasis Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD projector SESSION OVERVIEW Step Time Activity/ Content Step Time Activity/ Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning Tasks Introduction, Learning Tasks 2 2 45 minutes 45 minutes Presentation/ Mechanism of Action of Drugs for Mechanism of Action of Drugs for 2 2 45 minutes 45 minutes Buzzing Amoebiasis Amoebiasis Buzzing Amoebiasis Amoebiasis 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Drugs for Drug Interactions Associated With Drugs for 3 3 20 minutes 20 minutes brainstorming Amoebiasis Amoebiasis brainstorming Amoebiasis Amoebiasis 4 4 20 minutes 20 minutes Presentation Side Effects of Drugs for Amoebiasis Side Effects of Drugs for Amoebiasis 5 5 20 minutes 20 minutes Presentation/ Contraindications of Drugs for Amoebiasis Contraindications of Drugs for Amoebiasis 5 5 20 minutes 20 minutes Brainstorming Contraindications of Drugs for Amoebiasis Contraindications of Drugs for Amoebiasis 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 188 NTA Level 5 Semester 1 Facilitator Guide SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Mechanism of Action of Drugs for Amoebiasis (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do Drugs for Amoebiasis 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 Tissue Amoebicides Nitroimidazoles amoebicides (Metronidazole, tinidazole and ornidazole). Nitroimidazoles are chemically reduced by ferredoxin and the reduction products are responsible for killing the parasite. Entamoeba lacks a functional Krebs cycle and oxidative phosphorylation Metronidazole is a prodrug. The nitrogen group must be reduced (addition of electron) before the chemical obtains its anti-infective function. It is reduced by a nitro reductase enzyme called a ferredoxin (an iron- and sulfur-containing enzyme). The extra nitrogen side chain is reduced in this reaction. With aerobic bacteria the electron transport chain does not require these special enzymes because oxygen is the terminal electron acceptor; therefore the prodrug is not converted to the active form of the drug. However, with anaerobic bacteria, with which oxygen is absent, these special enzymes are present. Therefore metronidazole is not activated with aerobic bacteria but is particularly effective against anaerobic bacteria. Reduction of the prodrug metronidazole results in the production of toxic products (hydroxylamine) and other free radicals that damage DNA. Their bactericidal, activity is limited to anaerobic bacteria and protozoa. Metronidazole kills trophozoites of E. histolytica in intestine and tissue but does not eradicate cysts from intestines. PST 05104 Pharmacology & Therapeutics 189 NTA Level 5 Semester 1 Facilitator Guide Emetines (Emetine and dihydroemetine). o The drugs cause an irreversible block of protein synthesis by inhibiting movement of the ribosome along messenger RNA. o They have a direct lethal action to trophozoites. Chloroquine o Is active principally against amoeba in the liver Luminal Amoebicides Dichloracetamides (Diloxanide furoate, clefamide, teclozan, etofanide) o Mechanism is still unknown Halogenated hydroxyquinolines ( Iodoquinol, Clioquinol) Mechanism is unknown Luminal amoebicide; acts primarily in bowel lumen since it is poorly absorbed. Since active only against intraluminal form of amoebiasis, used to eradicate cysts of E. histolytica after treatment of invasive disease. Antibiotics Tetracyclines– these affect luminal amoebae indirectly- tetracyclines inhibit the bacterial associates of amoebae (E.histolytica). Paromomycin- an effective directly acting amoebicide Erythromycin has direct amoebicidal action but cannot be used alone. STEP 3: Drug Interactions Associated with Drugs for Amoebiasis (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are drug interactions associated with drugs for amoebiasis? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below Nitroimidazoles amoebicides (Metronidazole, tinidazole and ornidazole). Metronidazole elimination is accelerated by simultaneous use of phenytoin and phenobarbital which are CYP450 enzyme inducers. Metronidazole clearance is decreased by cimetidine which is an enzyme inhibitor. PST 05104 Pharmacology & Therapeutics 190 NTA Level 5 Semester 1 Facilitator Guide Metronidazole potentiates coumarin type of anticoagulants. Metronidazole can have a disulfuram-like effect: ingestion with alcohol can lead to severe nausea and vomiting. This results from inhibition of the enzyme acetaldehyde dehydrogenase, leading to increased levels of acetaldehyde, which are toxic. STEP 4: Side Effects of Drugs for Amoebiasis (20 minutes) The following areSide and adverse effects; Metronidazole o Metallic taste: common, harmless o CNS toxicity: rare, manifests as ataxia, encephalopathy, or seizure. STEP 5: Contraindications of Drugs for Amoebiasis (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are the contraindications of drugs for amoebiasis? ALLOW few students to respond? WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below Contraindications include; Metronidazole o Ethanol: Metronidazole can have a disulfuram-like effect: ingestion with alcohol can lead to severe nausea and vomiting. o This results from inhibition of the enzyme acetaldehyde dehydrogenase, leading to increased levels of acetaldehyde, which are toxic. o Pregnancy (first trimester in particular): Metronidazole causes tumour growth

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Aminoglycosides Pharmacology and Therapeutics • Source Session/Topic 23 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 23: Pharmacodynamics of Aminoglycosides 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 Aminoglycosides Describe drug interactions associated with Aminoglycosides Describe side effects of Aminoglycosides Describe contraindications of Aminoglycosides 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 Aminoglycosides Mechanism of Action of Aminoglycosides 2 2 45 minutes 45 minutes Buzzing Mechanism of Action of Aminoglycosides Mechanism of Action of Aminoglycosides Buzzing 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Drug Interactions Associated With 3 3 20 minutes 20 minutes brainstorming Aminoglycosides Aminoglycosides brainstorming Aminoglycosides Aminoglycosides 4 4 20 minutes 20 minutes Presentation Side Effects of Aminoglycosides Side Effects of Aminoglycosides 5 5 20 minutes 20 minutes Presentation/ Contraindications of Aminoglycosides Contraindications of Aminoglycosides 5 5 20 minutes 20 minutes Brainstorming Contraindications of Aminoglycosides Contraindications of Aminoglycosides 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 182 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 Aminoglycosides (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do Aminoglycosides 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 Aminoglycosides include Tobramycin, amikacin, neomycin, streptomycin, kanamycin and Paromomycin. Aminoglycosides are protein synthesis inhibitors. They irreversibly bind the 30S ribosomal subunit (RSU). At low concentrations they cause misreading of the mRNA by ribosomes, leading to synthesis of proteins with incorrect amino acid sequences. Recent experimental studies show that the initial site of action is the outer bacterial membrane. The cationic antibiotic molecules create fissures and pores in the outer cell membrane, resulting in leakage of intracellular contents and enhanced antibiotic uptake. Aminoglycosides are particularly effective against gram-negative bacteria. Many other protein synthesis inhibitors are bacteriostatic (only inhibit replication of bacteria versus killing bacteria). The action of aminoglycosides on the outer bacterial membrane, in addition to its protein synthesis inhibition, is thought to be the reason that aminoglycosides are bactericidal. Mechanisms of Resistance: Three mechanisms of resistance have been recognized: Ribosome alteration, Decreased permeability and inactivation by aminoglycoside modifying enzymes. The third mechanism is of most clinical importance, because the genes encoding aminoglycoside-modifying enzymes can be disseminated by plasmids, which are segments of DNA that are outside of the chromosome. PST 05104 Pharmacology & Therapeutics 183 NTA Level 5 Semester 1 Facilitator Guide Amikacin is particularly effective when used against bacteria that are resistant to other aminoglycosides, because its chemical structure makes it less susceptible to inactivating enzymes. STEP 3: Drug Interactions Associated with Aminoglycosides Drugs (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are drug interactions associated with aminoglycosides drugs? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below Drud Interaction of aminoglycoside; o Concurrent use with: loop diuretics eg, furosemide, ethacrynic acid o Other nephrotoxic antimicrobial agents eg, vancomycin or amphotericin) potentiates nephrotoxicity o The above drugs should be should be avoided if possible when using aminoglycosides STEP 4: Side Effects of Aminoglycosides (20 minutes) Aminoglycosides have the following side effects; Ototoxicity (damage to the inner ear): o Occurs in about 10% of patients. o Is caused by inhibition of human mitochondrial ribosomes, damaging the hair cells of the inner ear. o Symptoms can include the following: Decreased hearing, tinnitus (ringing in the ear) vertigo (a spinning type of dizziness) Nephrotoxicity: o Occurs in up to 10% of patients and in up to 25% of patients who are critically ill. o Drug accumulates in proximal tubule cells, leading to mitochondrial poisoning and cell membrane disruptions. o If the serum creatinine starts to rise during administration, then there must be a very high suspicion that kidney damage secondary to the aminoglycoside is occurring. PST 05104 Pharmacology & Therapeutics 184 NTA Level 5 Semester 1 Facilitator Guide The aminoglycoside should be immediately stopped. Nephrotoxicity is usually mild and reversible if the drug is stopped. Neuromuscular blockade: occurs because of a reduction in acetylcholine release. These drugs do not paralyze patients, but under anesthesia in patients who are already receiving a neuromuscular blocking drug (such as rocuronium or vecuronium), the duration of blockade can be longer than normal. Hypersensitivity reactions: skin rash, fever, eosinophilia and anaphylactic shock can be seen though infrequently. The special attention should be paid to the anaphylactic shock caused by streptomycin. STEP 5: Contraindications of Aminoglycosides Drugs (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are the contraindications of Aminoglycosides? ALLOW few students to respond? WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below The following are the contraindications of Aminoglycosides; Renal dysfunction: Patients starting with poor functioning kidneys can experience a further decline in kidney function if exposed to aminoglycosides. Serum levels of aminoglycosides must be monitored. Peak and trough levels help determine required doses. Doses must be adjusted according

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Fluoroquinolones Pharmacology and Therapeutics • Source Session/Topic 22 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 22: Pharmacodynamics of Fluoroquinolones 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 Fluoroquinolones Describe drug interactions associated with Fluoroquinolones Describe side effects of Fluoroquinolones Describe contraindications of Fluoroquinolones 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 05 Presentation Introduction, Learning Tasks Introduction, Learning Tasks 1 1 minutes minutes Presentation Introduction, Learning Tasks Introduction, Learning Tasks minutes minutes 2 2 45 45 Presentation/ Mechanism of Action of Fluoroquinolones Mechanism of Action of Fluoroquinolones 2 2 minutes minutes Buzzing Mechanism of Action of Fluoroquinolones Mechanism of Action of Fluoroquinolones minutes minutes Buzzing 3 3 20 20 Presentation/ Drug Interactions Associated With Drug Interactions Associated With 3 3 minutes minutes brainstorming Fluoroquinolones Fluoroquinolones minutes minutes brainstorming Fluoroquinolones Fluoroquinolones 4 4 20 20 Presentation Side Effects of Fluoroquinolones Side Effects of Fluoroquinolones 4 4 minutes minutes Presentation Side Effects of Fluoroquinolones Side Effects of Fluoroquinolones minutes minutes 5 5 20 20 Presentation/ Contraindications of Fluoroquinolones Contraindications of Fluoroquinolones 5 5 minutes minutes Brainstorming Contraindications of Fluoroquinolones Contraindications of Fluoroquinolones minutes minutes Brainstorming 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 176 176 NTA Level 5 Semester 1 Facilitator Guide NTA Level 5 Semester 1 Facilitator Guide 6 05 Presentation Key Points 6 minutes Presentation Key Points minutes 7 05 Presentation Evaluation 7 minutes Presentation Evaluation minutes PST 05104 Pharmacology & Therapeutics 177 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 Fluoroquinolones (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How do Fluoroquinolones 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 Fluoroquinolones DNA is normally supercoiled. Supercoiled DNA is under too much tension to be separated, so an extra step is required before replication and transcription can occur. DNA gyrase relaxes supercoiled DNA by cutting it, allowing rotation to occur, and then reattaching it. Fluoroquinolones bind to and inhibit DNA gyrase (also called topoisomerase II) and topoisomerase IV. Fluoroquinolones inhibit DNA gyrase in gram-negative organisms and topoisomerase IV in gram-positive organisms. The fluoroquinolones inhibit DNA gyrase after the cutting step, preventing reattachment from occurring. o At high doses this leads to the release of these broken segments of DNA. o It is thought that the accumulation of these DNA fragments leads to cell death, accounting for the bactericidal action of fluoroquinolones. Fluoroquinolones can enter human cells easily and therefore are often used to treat intracellular pathogens. Originally, quinolones were mainly effective against gram-negative bacteria, but newer agents are useful against gram-positive cocci as well. Mechanism of resistance: o Mutations in the genes that encode type II topoisomerase result in the enzyme not being inhibited by the fluoroquinolone. PST 05104 Pharmacology & Therapeutics 178 NTA Level 5 Semester 1 Facilitator Guide Alterations in membrane porins or efflux pumps that actively pump the drug out of the bacterial cell result in lower drug levels inside the bacteria. STEP 3: Drug Interactions Associated with Fluoroquinolones (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are drug interactions associated with fluoroquinolones drugs? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below The following are drug interaction associated with Fluoroquinolones; With NSAIDS, fluoroquinolones may potentiate CNS toxicity and cause seizures. With theophylline, they will increase theophylline levels and increase risk of theophylline toxicity. STEP 4: Side Effects of Fluoroquinolones (20 minutes) Fluoroquinolones have the following side effects: Most fluoroquinolones are cleared renally, and dose adjustment may be required in patients with renal impairment. Tendon ruptures (Achilles, shoulder); occur rarely. The mechanism of this complication is not well understood. Gatifloxacin: hyperglycemia Trovafloxacin: acute liver failure and death Temafloxacin: hemolytic anemia Grepafloxacin: long QT syndrome and sudden death Fleroxacin: phototoxicity PST 05104 Pharmacology & Therapeutics 179 NTA Level 5 Semester 1 Facilitator Guide STEP 5: Contraindications of Fluoroquinolones (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are the contraindications of Fluoroquinolones? ALLOW few students to respond? WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below Fluoroquinolones have the following contraindications: Moxifloxacin: is cleared by the liver and therefore contraindicated in patients with hepatic failure. Pregnancy Children: Joint pain (arthralgia) and swelling has occurred, and therefore administration to children is not common. STEP 6: Key Points (5 minutes) More than 30 different fluoroquinolones exist. Some are used for veterinary purposes only. Newer fluoroquinolones have extended spectrum against gram-positive cocci as well. Fluoroquinolones have some significant drug interactions STEP 7: Evaluation (5 minutes) What is the mechanism of action of fluoroquinolones? What are contraindications of ciprofloxacin? What are the side effects of gatifloxacin? PST 05104 Pharmacology & Therapeutics 180 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,

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

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 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 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 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 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