Pharmaceutical Sciences Notes

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

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

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

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

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

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