Pharmaceutical Sciences Notes

NTA Level 5 • Semester 1 • PST05104 Drug Distribution Total Session Time: 120 minutes Pharmacology and Therapeutics • Source Session/Topic 2 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 2: Drug Distribution Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe the distribution of drugs in various compartments of the body Describe factors affecting/determining distribution of drugs Describe Volume of distribution Calculate Volume of distribution Explain clinical applications of volume of distribution 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 10 minutes 10 minutes Presentation/ Distribution of Drugs in Various Distribution of Drugs in Various 2 2 10 minutes 10 minutes Buzzing Compartments of the Body Compartments of the Body Buzzing Compartments of the Body Compartments of the Body 3 3 30 minutes 30 minutes Presentation/ Factors Affecting Distribution of Drugs Factors Affecting Distribution of Drugs 3 3 30 minutes 30 minutes Brainstorming Factors Affecting Distribution of Drugs Factors Affecting Distribution of Drugs Brainstorming 4 4 20 minutes 20 minutes Presentation Volume of Distribution Volume of Distribution 4 4 20 minutes 20 minutes Presentation Presentation/ 5 5 30 minutes 30 minutes Small Group Calculation of Volume of Distribution Calculation of Volume of Distribution Discussion 6 6 15minutes 15minutes Presentation Clinical Application of Volume of Clinical Application of Volume of 6 6 15minutes 15minutes Presentation Distribution Distribution Distribution Distribution 7 7 05 minutes 05 minutes Presentation Key Points Key Points 8 8 05 minutes 05 minutes Presentation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics 11 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: Distribution of Drugs in various Compartments of the Body (10 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes What is distribution process of drugs in the body? 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 Once in the systemic circulation drugs will distribute into sections/units called compartments. The following are the compartments for governing drug distribution: o Plasma compartment (Vascular compartment) Drugs with very large molecular weight or those binding extensively to plasma proteins are effectively trapped within the plasma (vascular) compartment because such drugs are too large to move out through the endothelial slit junctions of the capillaries. Extracellular fluid o Observed in drugs with low molecular weights but also hydrophilic, such drugs can move through the endothelial slit junctions of the capillaries into the interstitial fluid. However, these hydrophilic drugs cannot move across the membranes of cells to enter the water phase inside the cell. Total Body Water o Observed in drugs with low molecular weight and are hydrophobic, such drugs can not only move into the interstitium through the slit junctions, but can also move ,through the cell membranes into the intracellular fluid. Other sites o In pregnancy, the foetus may take up drugs and thus increase the volume of distribution. PST 05104 Pharmacology & Therapeutics 12 NTA Level 5 Semester 1 Facilitator Guide STEP 3: Factors Affecting Distribution of Drugs (30Minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are the factors determining distribution of drugs? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below Distribution of drugs in the body is dependent on the following factors: Organ Blood Flow o Organs with high blood flow will have larger amounts of drug delivered to them per unit time. o Organs with high blood flow will experience initial high concentrations of drug, but these high concentrations will diminish as the drug is redistributed throughout the body to sites with lower blood flow. Barriers to diffusion o There are special barriers which restrict drug entry to some organs o Blood Brain Barrier ―BBB‖ is a special case o In general, the BBB restricts the movement of hydrophilic drugs into brain; however, the BBB is ―broken‖ by ischemia and inflammation. o The BBB can be exploited to develop drugs with reduced CNS adverse effects Adipose tissue o Lipophilic drugs will distribute into adipose (fat) tissue. o Distribution of lipophilic drugs into fat may necessitate a larger initial bolus of drug to achieve the desired effect. o Large depots of drug in fat may necessitate a longer period of time for drug to be removed from the body. o The distribution of lipophilic drugs will be different in thin versus obese patients Plasma protein Binding o Drugs bound to protein are pharmacologically inactive. o Only when the protein molecules release the drug can the drug diffuse into the tissues, interact with receptors, and produce a therapeutic effect. o Some drugs are highly bound (> 90%) to plasma proteins. o Acid drugs bind to albumin and basic drugs bind to alpha1-acid glycoprotein. o Binding of drugs by plasma proteins limits the distribution of drugs out of the vascular compartment, necessitating more drug initially to achieve the desired effect PST 05104 Pharmacology & Therapeutics 13 NTA Level 5 Semester 1 Facilitator Guide Displacement of a highly plasma-protein bound drug by another drug may lead to drug-drug interactions because of a rapid increase in the availability of ―free‖ (unbound) drug. Tissue protein binding Some drugs are highly bound to tissue proteins. Binding of drugs by tissue may necessitate a larger initial

NTA Level 5 • Semester 1 • PST05104 Metabolism of Drugs Pharmacology and Therapeutics • Source Session/Topic 3 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 3: Metabolism of Drugs Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe reactions involved in drug metabolism Describe factors affecting drug metabolism Describe first pass effect Describe kinetics of metabolism Explain clinical importance of drug metabolism 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 10 minutes 10 minutes Presentation/ Reactions Involved in Metabolism Reactions Involved in Metabolism 2 2 10 minutes 10 minutes Buzzing Reactions Involved in Metabolism Reactions Involved in Metabolism Buzzing Presentation/ 3 3 45 minutes 45 minutes Small Group Factors Affecting Metabolism Factors Affecting Metabolism Discussion 4 4 20 minutes 20 minutes Presentation First Pass Metabolism First Pass Metabolism 5 5 20 munites 20 munites Presentation Kinetics of Metabolism Kinetics of Metabolism 6 6 10 minutes 10 minutes Presentation Clinical Importance of Metabolism Clinical Importance of Metabolism 7 7 05 minutes 05 minutes Presentation Key Points Key Points 8 8 05 minutes 05 minutes Presentation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics 19 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: Reactions Involved in Drug Metabolism (10 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes What are thereactions involved in drug biotransformation? 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 There are several reactions involved in drug biotransformation. These reactions are grouped into two major groups called Phase 1 and Phase 2. Phase 1 Reaction Phase 1 reactions are catabolic (e.g. oxidation, reduction or hydrolysis), and the products are often more chemically reactive and hence, paradoxically, sometimes more toxic or carcinogenic than the parent drug. Phase 1 reactions often introduce a reactive group, such as hydroxyl, into the molecule, a process known as 'functionalisation'. This group then serves as the point of attack for the conjugating system to attach a substituent such as glucuronide explaining why phase 1 reactions so often precede phase 2 reactions. Phase 1 reactions take place mainly in the liver whereby many hepatic drug-metabolising enzymes, including CYP enzymes are involved. In general phase 1 reactions include hydroxylation, dealkylation, deamination, desulfuration, dechlorination, hydrolysis and reductions reactions PST 05104 Pharmacology & Therapeutics 20 NTA Level 5 Semester 1 Facilitator Guide Phase 2 reactions Most of phase 1 metabolites are more polar hence expected to be readily excreted. However some drugs are not eliminated rapidly require a further reaction involving an addition of an endogenous glucuronic acid, sulfuric acid, amino acid or acetic acid to form a highly polar conjugate for elimination. In general Phase 2 conjugation reactions involves glucuronidation, acetylation, conjugation, sulphation and methylation. Rang and Dale pharmacology seventh edition STEP 3: Factors Affecting Metabolism of Drugs (45Minutes) Activity: Small Group Discussion ( 30 minutes) DIVIDE students into small manageable groups ASK students to discuss on the following question What are factors affecting metabolism of drugs? ALLOW students to discuss for 15 minutes ALLOW few groups to present and the rest to add points not mentioned CLARIFY and SUMMARIZE by using the contents below Drug metabolism is affected by the followings: Genetic factors o Genetic factors influence enzyme levels and expression of activity. There is a great variation in the population how individuals metabolize drugs. o The greater part of this effect is due to Cytochrome P450 polymorphism. PST 05104 Pharmacology & Therapeutics 21 NTA Level 5 Semester 1 Facilitator Guide A few examples of variation on metabolism due to genetics include acetylation of isoniazid and hydroxylation where there are slow and fast metabolizers in the population for the drugs. Diet and environmental factors Cigarette smokers metabolize some drug faster than non-smokers because of enzyme induction Some foods and drinks also affect drug metabolism. For example grape juice decrease metabolism of some drugs because of enzyme inhibition Age and Sex A decreased metabolism of drugs is observed in clinical practice in very young patients due to immature enzymes and very old patients due to deterioration of liver function A variation in metabolism basing on sex difference in human is reported for ethanol, salicylates, some benzodiazepines, oestrogens and propranolol Drug drug interactions Drugs known to be enzyme inducers or enzyme inhibitors can affect metabolism of other drugs when administered concomitantly Diseases Some acute or chronic diseases/conditions decrease greatly hepatic metabolism. Such conditions include alcoholic hepatitis, alcoholic cirrhosis and drug or viral induced hepatitis STEP 4: First Pass Effect (20minutes) Some drugs are extracted so efficiently by the liver or gut wall that the amount reaching the systemic circulation is considerably less than the amount absorbed. This is known as first-pass or presystemic metabolism and reduces bioavailability even when a drug is well absorbed. Presystemic metabolism is important for many therapeutic drugs and is a problem because: o A much larger dose of the drug is needed when it is given orally than when it is given parenterally o Marked individual variations occur in the extent of first-pass metabolism Examples of drugs that undergoes first pass metabolism are as follows; o Aspirin o Metoprolol o Glyceryl trinitrate o Morphine o Isosorbide dinitrate o Propranolol o Levodopa o Salbutamol PST 05104 Pharmacology & Therapeutics 22 NTA Level 5 Semester

NTA Level 5 • Semester 1 • PST05104 Drug Excretion Total Session Time: 120 minutes Pharmacology and Therapeutics • Source Session/Topic 4 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 4: Drug Excretion Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe routes of drug elimination Describe factors affecting renal drug excretion Calculate clearance Describe clinical importance of elimination half life 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 25 minutes 25 minutes Presentation/ Routes of Drug Excretion Routes of Drug Excretion 2 2 25 minutes 25 minutes Buzzing Routes of Drug Excretion Routes of Drug Excretion Buzzing 3 3 40 minutes 40 minutes Presentation/ Factors Affecting Renal Drug Excretion Factors Affecting Renal Drug Excretion 3 3 40 minutes 40 minutes brainstorming Factors Affecting Renal Drug Excretion Factors Affecting Renal Drug Excretion brainstorming 4 4 20 minutes 20 minutes Presentation Calculation of Clearance Calculation of Clearance 5 5 20 minutes 20 minutes Presentation/ Description of Clinical Importance of Description of Clinical Importance of 5 5 20 minutes 20 minutes Brainstorming Elimination Half Life Elimination Half Life Brainstorming Elimination Half Life Elimination Half Life 6 6 05 minutes 05 minutes Presentation Key Points Key Points 7 7 05 minutes 05 minutes Presentation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics 26 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: Routes of Drug Elimination (25 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes What routes are involved in the excretion of drugs? ALLOW few pairs to respond and let other pairs add on points not mentioned WRITE their response on the flip chart/board CLARIFY and SUMMARIZE by using the content below Removal of a drug from the body may occur via a number of routes, the most important being through the kidney into the urine. Other routes include o the bile, o intestine, o sweat o lung, o Milk in breastfeeding mothers. Renal excretion: Most drugs are renally cleared and differ greatly in the rate at which they are excreted by the kidney Some drugs are almost completely cleared renally such as penicillin and others are slowly cleared, eg diazepam Three fundamental processes account for renal drug excretion: o glomerular filtration o active tubular secretion o passive diffusion across tubular epithelium Excretion via Breast Milk Breast milk is a quantitatively relatively minor route of drug excretion. PST 05104 Pharmacology & Therapeutics 27 NTA Level 5 Semester 1 Facilitator Guide Nevertheless, it is clinically important for breastfeeding mothers and their infants. The baby will ingest drugs excreted in the breast milk. Moreover, breast milk has a lower pH than plasma. Accordingly, basic drugs will be concentrated in the breast milk through the phenomenon of ion (pH) trapping. A number of drugs can reach clinically significant concentrations in the breast milk and thereby affect nursing babies. Pulmonary excretion Is important for gaseous lipophilic substances. The gaseous general anaesthetics are the most common example. Drug diffuses from the plasma into the alveolar space and is excreted during expiration. Biliary Excretion: Biliary excretion involves active secretion of drug molecules or their metabolites from hepatocytes into the bile. The bile then transports the drugs to the gut, where the drugs are excreted. The transport process is similar to those described for renal tubular secretion. The efficiency of biliary excretion is quite variable. Enterohepatic cycling. Although many drugs may reach the gut through Biliary Excretion, deconjugating enzymes in the gut and the gut pH causes many drugs to assume nonpolar lipophilic forms that then are promptly reabsorbed by diffusion into the plasma. Drugs that undergo extensive enterohepatic cycling generally have long durations of action e.g Rifampicin STEP 3: Factors Affecting Renal Drug Excretion (40 Minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are the factors affecting renal drug clearance? 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 28 NTA Level 5 Semester 1 Facilitator Guide Renal excretion of a drug is affected by the following factors depending on the mechanism: Glomerular filtration: Molecular weight of a drug Glomerular capillaries allow drug molecules of molecular weight below about 20 000 to pass into the glomerular filtrate. Plasma albumin (molecular weight approximately 68 000) is almost completely impermeant, but most drugs-with the exception of macromolecules such as heparin or biological products can cross the barrier freely. Protein binding If a drug binds to plasma albumin, only free drug is filtered. If, like warfarin, a drug is approximately 98% bound to albumin, the concentration in the filtrate is only 2% of that in plasma, and clearance by filtration is correspondingly reduced. Disease or age Glomerular filtration rate decreases approximately 1% per year and may be significantly compromised in elderly patients. The decline in glomerular filtration rate is accelerated by disease states such as diabetes. For drugs that are eliminated by glomerular filtration, dosages are often adjusted based on the patient‘s glomerular filtration rate. Tubular secretion Secretory mechanisms in the renal tubules actively transport endogenous substances and drug molecules from the plasma in peritubular capillaries to the tubular lumen. Although quite diverse in some characteristics, the tubular transporters can be classified into two major groups: the organic anion transporter (OAT) and the organic cation transporter (OCT) families. Tubular

NTA Level 5 • Semester 1 • PST05104 Drug Receptor Interaction Pharmacology and Therapeutics • Source Session/Topic 5 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 5: Drug Receptor Interaction Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe the drug-receptor interaction Describe the types of receptors Explain the concept of receptor regulation 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 30 minutes 30 minutes Presentation/ Drug-Receptor Interaction Drug-Receptor Interaction 2 2 30 minutes 30 minutes Buzzing Drug-Receptor Interaction Drug-Receptor Interaction Buzzing 3 3 45 minutes 45 minutes Presentation/ Types of Receptor Types of Receptor 3 3 45 minutes 45 minutes brainstorming Types of Receptor Types of Receptor brainstorming 4 4 30 minutes 30 minutes Presentation Concept of Receptor Regulation Concept of Receptor Regulation 5 5 05 minutes 05 minutes Presentation Key Points Key Points 6 6 05 minutes 05 minutes Presentation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics 33 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: Drug-Receptor Interaction (30 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes How does drug interact with receptors? 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 A drug receptor is a specialized target macromolecule, present on the cell surface or intracellularly, that binds a drug and mediates its pharmacologic actions. It describes protein molecules whose function is to recognise and respond to endogenous chemical signals. The term is most often used to describe the target molecules through which soluble physiological mediators-hormones, neurotransmitters, inflammatory mediators, etc.-produce their effects. Examples are acetylcholine receptors, cytokine receptors, steroid receptors, and growth hormone receptors Pharmacological effects, therefore, require, in general, that drug molecules must be 'bound' to particular constituents of cells and tissues in order to produce an effect. Four main kinds of regulatory protein are commonly involved as primary drug targets, namely: o receptors o enzymes o carrier molecules (transporters) o ion channels The function of a cell alters when a drug interacts with a receptor cell. At its most fundamental level, the interaction of drug and receptor follows the law of mass action. PST 05104 Pharmacology & Therapeutics 34 NTA Level 5 Semester 1 Facilitator Guide The law of mass action dictates that: o The combination of drug (also called ligand) and receptor depends on the concentrations of each o The amount of drug-receptor complex formed determines the magnitude of the response o A minimum number of drug receptor complexes must be formed for a response to be initiated (threshold) o As drug concentration increases, the number of drug-receptor complexes increases and drug effect increases o A point will be reached at which all receptors are bound to drug, and therefore no further drug-receptor complexes can be formed and the response does not increase any further (saturation) Law of Mass Action Applied to Drugs: Drug +Receptor ↔ Drug-Receptor Complex →Effect Occupation of a receptor by a drug molecule may or may not result in activation of the receptor. By activation, we mean that the receptor is affected by the bound molecule in such a way as to elicit a tissue response agonists, which 'activate' the receptors If a drug binds to the receptor without causing activation and thereby prevents the agonist from binding, it is termed a receptor antagonist. • The tendency of a drug to bind to the receptors is governed by its affinity, whereas the tendency for it, once bound, to activate the receptor is denoted by its efficacy. PST 05104 Pharmacology & Therapeutics 35 NTA Level 5 Semester 1 Facilitator Guide Selectivity of Drug Responses Drug molecules exhibit preferential affinity for receptors as follows: The cell will respond only to the spectrum of drugs that exhibit affinity for the receptors expressed by the cell. The greater the extent to which a drug molecule exhibits high affinity for only one receptor, the more selective will be the drug‘s actions, with lower potential for side effects. The higher the affinity and efficacy of a given drug, the smaller the amount of drug necessary to activate a critical mass of drug receptors to effect a tissue response, and the lower the potential for nonselective actions. As the concentration of a drug increases, the drug will combine with receptors for which it has lower affinity and may generate off-target effects. Thus selectivity of a drug to a specific receptor is obtained at low to moderate doses. STEP 3: Types of Receptor 45Minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are the types of receptors? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below There are four receptor types or superfamilies namely: Type 1-Ligand-gated ion channels (ionotropic receptors) Type 2- G-protein-coupled receptors (GPCRs) [metabotropic receptors or seven-transmembrane-spanning (heptahelical) receptors Type 3-Kinase (Enzyme) linked and related receptors PST 05104 Pharmacology & Therapeutics 36 NTA Level 5 Semester 1 Facilitator Guide Type 4-Nuclear receptorsIntranuclear/intracellular receptors (e.g. gonadal and glucocorticosteroids hormones) Type 1-Ligand-gated ion channels/Trans membrane ion channel (ionotropic receptors) Conduct ions across membrane in response to ligand binding, voltage gradient or second messenger; e.g., H+/K+-ATP‘ase Transmembrane ion channels allow the passage of ions from one side of a membrane to

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

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

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Drugs Acting on Endocrine System Pharmacology and Therapeutics • Source Session/Topic 8 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 8: Pharmacodynamics of Drugs Acting on Endocrine System Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe mechanism of action of Drugs Acting on Endocrine System Describe drug interactions associated with Drugs Acting on Endocrine System Describe side effects of Drugs Acting on Endocrine System Describe contraindications of Drugs Acting on Endocrine System Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD Projector Handout 8.1: Pharmacodynamics of drugs for thyroid disorders and reproductive function SESSION OVERVIEW Step Time Activity/ Content Step Time Activity/ Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning Tasks Introduction, Learning Tasks 2 2 45 minutes 45 minutes Presentation/ Mechanism of Action of Drugs Acting on Mechanism of Action of Drugs Acting on 2 2 45 minutes 45 minutes Buzzing Endocrine System Endocrine System Buzzing Endocrine System Endocrine System 3 3 20 minutes 20 minutes Presentation/ Drug Interactions Associated With Drugs Drug Interactions Associated With Drugs 3 3 20 minutes 20 minutes brainstorming Acting on Endocrine System Acting on Endocrine System brainstorming Acting on Endocrine System Acting on Endocrine System 4 4 20 minutes 20 minutes Presentation Side Effects of Drugs Acting on Endocrine Side Effects of Drugs Acting on Endocrine 4 4 20 minutes 20 minutes Presentation System System System System 5 5 20 minutes 20 minutes Presentation/ Contraindications of Drugs Acting on Contraindications of Drugs Acting on 5 5 20 minutes 20 minutes Brainstorming Endocrine System Endocrine System Brainstorming Endocrine System Endocrine System 6 6 05 minutes 05 minutes Presentation Key Points Key Points 7 7 05 minutes 05 minutes Presentation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics 57 NTA Level 5 Semester 1 Facilitator Guide SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Mechanism of Action of Drugs Acting on Endocrine System (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes What asre the mechanisms of action of Drugs Acting on Endocrine system? ALLOW few pairs to respond and let other pairs add on points not mentioned WRITE their response on the flip chart/board CLARIFY and SUMMARIZE by using the content below Drugs for Diabetes Mellitus Insulins Insulin acts by binding to transmembrane glycoprotein receptors. Receptor occupancy results in: Activation of insulin-dependent glucose transport processes (in adipose tissue and muscle) via a transporter known as ‗Glut-4‘; Inhibition of adenylyl cyclase-dependent metabolism (lipolysis, proteolysis, glycogenolysis); Intracellular accumulation of potassium and phosphate, which is linked to glucose transport in some tissues. Secondary effects include increased cellular amino acid uptake, increased DNA and RNA synthesis and increased oxidative phosphorylation. Biguanides (Metformin) Mechanism remains uncertain. Effects of metformin include: Reduced glucose absorption from the gut Facilitation of glucose entry into muscle by a non-insulin responsive mechanism Inhibition of gluconeogenesis in the liver Suppression of oxidative glucose metabolism and enhanced anaerobic glycolysis. PST 05104 Pharmacology & Therapeutics 58 NTA Level 5 Semester 1 Facilitator Guide Sulphonylureas (tolbutamide, glibenclamide, gliclazide) and Related Drugs The hypoglycaemic effect of these drugs depends on the presence of functioning B cells. Sulphonylureas, like glucose, depolarize B cells and release insulin. They do this by binding to sulphonylurea receptors (SUR) and blocking ATP-dependent potassium channels (KATP); the resulting depolarization activates voltage-sensitive Ca2+ channels, in turn causing entry of Ca2+ ions and insulin secretion. Thiazolidinediones (rosiglitazone and pioglitazone) Glitazones bind to the peroxisome-proliferating activator receptor γ (PPARγ), a nuclear receptor found mainly in adipocytes and also in hepatocytes and myocytes. It works slowly, increasing the sensitivity to insulin possibly via effects of circulating fatty acids on glucose metabolism. Acarbose Acarbose is a reversible competitive inhibitor of intestinal α-glucoside hydrolases and delays the absorption of starch and sucrose, but does not affect the absorption of ingested glucose. The postprandial glycaemic rise after a meal containing complex carbohydrates is reduced and its peak is delayed. Mechanism of action of drugs for treatment of thyroid disorders and reproductive function REFER Students to Handout 8.1: Pharmacodynamics of drugs for thyroid disorders and reproductive function STEP 3: Drug Interactions Associated with Drugs Acting on Endocrine System (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are drug interactions associated with drugs acting on endocrine system occur? ALLOW few students to respond WRITE their responses on the flip chart/ board CLARIFY and SUMMARISE by using the content below Biguanides (Metformin etc) o Other oral hypoglycaemic drugs are additive with metformin. o Ethanol predisposes to metformin-related lactic acidosis. PST 05104 Pharmacology & Therapeutics 59 NTA Level 5 Semester 1 Facilitator Guide Sulphonylureas (tolbutamide, glibenclamide, gliclazide) and Related Drugs o Monoamine oxidase inhibitors potentiate the activity of sulphonylureas by an unknown mechanism. o Several drugs (e.g. glucocorticosteroids, growth hormone) antagonize the hypoglycaemic effects of sulphonylureas by virtue of their actions on insulin release or sensitivity. Thiazolidinediones (rosiglitazone and pioglitazone) o Glitazones are additive with other oral hypoglycaemic drugs. o They potentiate insulin, but this combination is contraindicated in some countries because of concerns that it might increase the risk of heart failure. o Pioglitazone is an inducer of CYP3A and may cause treatment failure with concomitantly administered drugs which are CYP3A substrates (e.g. reproductive steroids). STEP 4: Side Effects of Drugs Acting on Endocrine System (20 minutes) The following are the dise effects of drugs for treatment of Diabetes Mellitus; Insulin: Hypoglycemia, Headache, Allergic reactions, Flu like symptoms, Weight gain, Hypokalemia, Lipoatrophy, Itching, Rash , Injection site reaction Chlorpropamide:

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Drugs Acting on Respiratory System Pharmacology and Therapeutics • Source Session/Topic 9 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 9: Pharmacodynamics of Drugs Acting on Respiratory System Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe mechanism of action of Drugs acting on Respiratory System Describe drug interactions associated with Drugs acting on Respiratory System Describe side effects of Drugs acting on Respiratory System Describe contraindications of Drugs acting on Respiratory System Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD projector Handout 9.1: Pharmacodynamics of drugs for cough, cold and allegy PST 05104 Pharmacology & Therapeutics 68 NTA Level 5 Semester 1 Facilitator Guide SESSION OVERVIEW Step Time Activity/ Content Step Time Activity/ Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning Tasks Introduction, Learning Tasks 2 2 40 minutes 40 minutes Presentation/ Mechanism of Action of Drugs acting on Mechanism of Action of Drugs acting on 2 2 40 minutes 40 minutes Buzzing Respiratory System Respiratory System Buzzing Respiratory System Respiratory System 3 3 25 minutes 25 minutes Presentation/ Drug Interactions Associated With Drugs Drug Interactions Associated With Drugs 3 3 25 minutes 25 minutes brainstorming acting on Respiratory System acting on Respiratory System brainstorming acting on Respiratory System acting on Respiratory System 4 4 20 minutes 20 minutes Presentation Side Effects of Drugs acting on Respiratory Side Effects of Drugs acting on Respiratory 4 4 20 minutes 20 minutes Presentation System System System System 5 5 20 minutes 20 minutes Presentation/ Contraindications of Drugs acting on Contraindications of Drugs acting on 5 5 20 minutes 20 minutes Brainstorming Respiratory System Respiratory System Brainstorming Respiratory System Respiratory System 6 6 05 minutes 05 minutes Presentation Key Points Key Points 7 7 05 minutes 05 minutes Presentation Evaluation Evaluation PST 05104 Pharmacology & Therapeutics 69 NTA Level 5 Semester 1 Facilitator Guide SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Mechanism of Action of Drugs acting on Respiratory System (40 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes What are the mechanisms of action of Drugs acting on respiratory system? ALLOW few pairs to respond and let other pairs add on points not mentioned WRITE their response on the flip chart/board CLARIFY and SUMMARIZE by using the content below The following are the mechanisms of drugs used to treat Asthma and chronic obstructive pulmonary disease (COPD); Beta 2 (β2)-Agonists o β-2- Agonists (e.g. salbutamol and the long-acting β2-agonist salmeterol) are used to treat the symptoms of bronchospasm in asthma (both in an acute attack and as maintenance therapy) and o Intravenous salbutamol is also used in obstetric practice to inhibit premature labour). o Agonists occupying β2-adrenoceptors increase cyclic adenosine monophosphate (cAMP) by stimulating adenylyl cyclase via stimulatory G-proteins. o Cyclic AMP phosphorylates a cascade of enzymes. o This causes a wide variety of effects including: Relaxation of smooth muscle including bronchial, uterine and vascular; inhibition of release of inflammatory mediators; increased mucociliary clearance; increase in heart rate, force of myocardial Muscarinic Receptor Antagonists o There is increased parasympathetic activity in patients with reversible airways obstruction, resulting in bronchoconstriction through the effects of acetylcholine on the muscarinic (M2, M3) receptors in the bronchi. PST 05104 Pharmacology & Therapeutics 70 NTA Level 5 Semester 1 Facilitator Guide The final common pathway is via a membrane-bound G-protein which when stimulated leads to a fall in cAMP and increased intracellular calcium, with consequent bronchoconstriction. Antimuscarinic drugs block muscarinic receptors in the airways leading to bronchodilation. Methylxanthines It is not clear exactly how theophylline produces bronchodilation. Its pharmacological actions include the following: Relaxation of airway smooth muscle and inhibition of mediator release (e.g. from mast cells). Theophylline raises intracellular cAMP by inhibiting phosphodiesterase. However, phosphodiesterase inhibition is modest at therapeutic concentrations of theophylline Antagonism of adenosine (a potent bronchoconstrictor) at A2-receptors; Anti-inflammatory activity on T-lymphocytes by reducing release of platelet-activating factor (PAF). Glucocorticosteroids Glucocorticosteroids are used in the treatment of asthma and in severe exacerbations of COPD because of their potent anti-inflammatory effect. This involves interaction with an intracellular glucocorticosteroids receptor that in turn interacts with nuclear DNA, altering the transcription of many genes and thus the synthesis of pro-inflammatory cytokines, β2-adrenoceptors, tachykinin-degrading enzymes and lipocortin (an inhibitor of phospholipase A2, reducing free arachidonic acid and thus leukotriene synthesis). They are used both in maintenance therapy (prophylaxis) and in the treatment of the acute severe attack. Mast Cell Stabilizers (Cromoglicate and Nedocromil) The degranulation of mast cells and eosinophils is an important step in the response to an allergen. Degranulation leads to release of a variety of proinflammatory factors, including histamine, leukotrienes, and various cytokines. These factors then act on tissues to elicit the classic signs of an allergic reaction. Mast cell stabilizers work by preventing this degranulation from occurring. The mechanism by which they accomplish this is still not confirmed. Mast cell stabilizers have a variety of other actions that may contribute to their efficacy. They suppress the actions of chemotactic factors on eosinophils, neutrophils, and monocytes, and they may reduce movement of leukocytes in asthmatic airways. PST 05104 Pharmacology & Therapeutics 71 NTA Level 5 Semester 1 Facilitator Guide Leukotriene Modulators o Leukotriene B4 is a powerful chemo-attractant (eosinophils and neutrophils) and increases vascular permeability producing mucosal oedema. o Leukotrienes C4, D4 and E4 (cysteinyl leukotrienes) are potent spasmogens and pro-inflammatory substances (‗SRS-A‘). o Leukotriene modulators fall into two classes, namely leukotriene receptor antagonists and 5-lipoxygenase inhibitors. o Leukotriene C4 and D4 antagonists:

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Antiemetics and Drugs for Peptic Ulcer Disease Pharmacology and Therapeutics • Source Session/Topic 10 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 10: Pharmacodynamics of Antiemetics and Drugs for Peptic Ulcer Disease. Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe mechanism of action of Antiemetics and Drugs for Peptic Ulcer Describe drug interactions associated with Antiemetics and Drugs for Peptic Ulcer Disease Describe side effects of Antiemetics and Drugs for Peptic Ulcer Disease Describe contraindications of Antiemetics and Drugs for Peptic Ulcer Disease Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD projector SESSION OVERVIEW Step Time Activity/ Content Step Time Activity/ Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning Tasks Introduction, Learning Tasks Introduction, Learning Tasks 2 2 40 minutes 40 minutes Presentation/ Mechanism of Action of Antiemetics and Mechanism of Action of Antiemetics and Mechanism of Action of Antiemetics and 2 2 40 minutes 40 minutes Buzzing Drugs for Peptic Ulcer Disease Drugs for Peptic Ulcer Disease Drugs for Peptic Ulcer Disease Buzzing Drugs for Peptic Ulcer Disease Drugs for Peptic Ulcer Disease Drugs for Peptic Ulcer Disease Presentation/ Drug Interactions Associated With Drug Interactions Associated With Drug Interactions Associated With 3 3 20 minutes 20 minutes Presentation/ Antiemetics and Drugs for Peptic Ulcer Antiemetics and Drugs for Peptic Ulcer Antiemetics and Drugs for Peptic Ulcer 3 3 20 minutes 20 minutes brainstorming Antiemetics and Drugs for Peptic Ulcer Antiemetics and Drugs for Peptic Ulcer Antiemetics and Drugs for Peptic Ulcer brainstorming Disease Disease Disease Disease Disease Disease 4 4 20 minutes 20 minutes Presentation Side Effects of Antiemetics and Drugs for Side Effects of Antiemetics and Drugs for Side Effects of Antiemetics and Drugs for 4 4 20 minutes 20 minutes Presentation Peptic Ulcer Disease Peptic Ulcer Disease Peptic Ulcer Disease Peptic Ulcer Disease Peptic Ulcer Disease Peptic Ulcer Disease 5 5 20 minutes 20 minutes Presentation/ Contraindications of Antiemetics and Drugs Contraindications of Antiemetics and Drugs Contraindications of Antiemetics and Drugs PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics 79 79 79 NTA Level 5 Semester 1 Facilitator Guide NTA Level 5 Semester 1 Facilitator Guide Brainstorming for Peptic Ulcer Disease 6 05 minutes Presentation Key Points 7 05 minutes Presentation Evaluation 8 05 minutes Presentation Take Home Assignment SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Mechanism of Action of Antiemetics and Drugs for Peptic Ulcer Disease (40 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes What are the mechanisms of action of antiemetic and drugs for peptic ulcers? ALLOW few pairs to respond and let other pairs add on points not mentioned WRITE their response on the flip chart/board CLARIFY and SUMMARIZE by using the content below The following are the mechanism of action for drugs for treating Peptic Ulceration; Antiacids o Antacids have a number of actions which include neutralizing gastric acid and thus relieving associated pain and nausea, reducing delivery of acid into the duodenum following a meal, and inactivation of the proteolytic enzyme pepsin by raising the gastric pH above 4–5. o In addition, it is thought that antacid may increase lower oesophageal sphincter tone and reduce oesophageal pressure. H2-Receptor antagonists o H2-receptors stimulate gastric acid secretion and are also present in human heart, blood vessels and uterus (and probably brain). PST 05104 Pharmacology & Therapeutics 80 NTA Level 5 Semester 1 Facilitator Guide Competitive H2-receptor antagonists when used in clinical use block/inhibit gastric acid secretion. Prostaglandin Analogues Misoprostol is a synthetic analogue of prostaglandin E1 which inhibits gastric acid secretion, causes vasodilatation in the submucosa and stimulates the production of protective mucus. Proton Pump Inhibitors The proton-pump inhibitors inhibit gastric acid by blocking the H+/K+-adenosine triphosphatase enzyme system (the proton pump) of the gastric parietal cell. Examples are omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole. Bismuth chelate (a mucosal protective agent) Colloidal tripotassium dicitratobismuthate precipitates at acid pH to form a layer over the mucosal surface and ulcer base, where it combines with the proteins of the ulcer exudate. This coat is protective against acid and pepsin digestion. It also stimulates mucus production and may chelate with pepsin, thus speeding ulcer healing. It has a direct toxic effect on H. pylori and may be used as part of triple therapy. Sucralfate (a mucosal protective agent) Sucralfate is used in the management of benign gastric and duodenal ulceration and chronic gastritis. Its action is entirely local, with minimal if any systemic absorption. It is a basic aluminium salt of sucrose octasulphate which, in the presence of acid, becomes a sticky adherent paste that retains antacid efficacy. This material coats the floor of ulcer craters, exerting its acid-neutralizing properties locally, unlike conventional antacid gels which form a diffusely distributed antacid dispersion. In addition it binds to pepsin and bile salts and prevents their contact with the ulcer base. Mechanism of action of Antiemetics REFER Students to Handout 10.1: Pharmacodynamics of drugs for thyroid disorders and reproductive function STEP 3: Drug Interactions Associated with Drugs for Peptic Ulcer Disease (20 minutes) Activity: Brainstorming (5 minutes) Ask students to brainstorm on the following question: What are drug interactions associated with antiemetics and drugs for peptic ulcer disease? PST 05104 Pharmacology & Therapeutics 81 NTA Level 5 Semester 1 Facilitator Guide ALLOW few students

NTA Level 5 • Semester 1 • PST05104 Pharmacodynamics of Analgesics, Antipyretics and Anti-inflammatory Drugs Pharmacology and Therapeutics • Source Session/Topic 11 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. Session 11: Pharmacodynamics of Analgesics, Antipyretics and Anti-inflammatory Drugs Total Session Time: 120 minutes Prerequisites None Learning Tasks By the end of this session students are expected to be able to: Describe mechanism of action of analgesics, antipyretics and anti-inflammatory drugs Describe drug interactions associated with analgesics, antipyretics and anti-inflammatory drugs Describe side effects of analgesics, antipyretics and anti-inflammatory drugs Describe contraindications of analgesics, antipyretics and anti-inflammatory drugs Resources Needed: Flip charts, marker pens, and masking tape Black/white board and chalk/whiteboard markers Computer and LCD projector SESSION OVERVIEW Step Time Activity/ Content Step Time Activity/ Content Step Time Method Content Method Method 1 1 05 minutes 05 minutes Presentation Introduction, Learning Tasks Introduction, Learning Tasks Introduction, Learning Tasks PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics PST 05104 Pharmacology & Therapeutics 89 89 NTA Level 5 Semester 1 Facilitator Guide NTA Level 5 Semester 1 Facilitator Guide 2 45 minutes Presentation/ Mechanism of Action of Analgesics, 2 45 minutes Buzzing Antipyretics and Anti-Inflammatory Drugs Buzzing Antipyretics and Anti-Inflammatory Drugs Presentation/ Drug Interactions Associated With 3 20 minutes Presentation/ Analgesics, Antipyretics and Anti- 3 20 minutes brainstorming Analgesics, Antipyretics and Anti- brainstorming Inflammatory Drugs Inflammatory Drugs 4 20 minutes Presentation Side Effects of Analgesics, Antipyretics and 4 20 minutes Presentation Anti-Inflammatory Drugs Anti-Inflammatory Drugs 5 20 minutes Presentation/ Contraindications of Analgesics, Antipyretics 5 20 minutes Brainstorming and Anti-Inflammatory Drugs Brainstorming and Anti-Inflammatory Drugs 6 05 minutes Presentation Key Points 7 05 minutes Presentation Evaluation PST 05104 Pharmacology & Therapeutics 90 NTA Level 5 Semester 1 Facilitator Guide SESSION CONTENTS STEP 1: Presentation of Session Title and Learning Tasks (5 minutes) READ or ASK students to read the learning tasks and clarify ASK students if they have any questions before continuing. STEP 2: Mechanism of Action of Analgesics, Antipyretics and Anti-Inflammatory Drugs (45 minutes) Activity: Buzzing (5 minutes) ASK students to pair up and buzz on the following question for 2 minutes What are the mechanisms of actions of analgesics, antipyretics and anti-Inflammatory drugs? ALLOW few pairs to respond and let other pairs add on points not mentioned WRITE their response on the flip chart/board CLARIFY and SUMMARIZE by using the content below Anti-inflammatory, Antipyretic, Analgesics have different mechanisms of action: Non-Steroidal Anti-Inflammatory Drugs o Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin biosynthesis by inhibiting cyclo-oxygenase (COX). o This is the basis of most of their therapeutic, as well as their undesired actions. COX is a key enzyme in the synthesis of prostaglandins and thromboxanes, important mediators of the erythema, oedema, pain and fever of inflammation. o There are two main isoforms of the enzyme, namely a constitutive form (COX-1) that is present in platelets, stomach, kidneys and other tissues, and an inducible form, (COX-2), that is expressed in inflamed tissues as a result of stimulation by cytokines and is also present to a lesser extent in healthy organs, including the kidneys. Drugs like Aspirin inhibits cyclooxygenase activity, it diminishes the formation of prostaglandins and thus modulates those aspects of inflammation in which prostaglandins act as mediators. Acetaminophen, although a useful analgesic and antipyretic, has weak anti-inflammatory activity and is therefore not useful in the treatment of inflammation such as that seen with rheumatoid arthritis. PST 05104 Pharmacology & Therapeutics 91 NTA Level 5 Semester 1 Facilitator Guide Analgesic action Prostaglandin E2 (PGE2) is thought to sensitize the nerve endings to the action of bradykinin, histamine, and other chemical mediators released locally by the inflammatory process. Thus, by decreasing PGE2 synthesis, aspirin and other NSAIDs repress the sensation of pain. NSAIDs are superior to opioids in the management of pain in which inflammation is involved; combinations of opioids and NSAlDs are effective in, treating pain in malignancy. Antipyretic action Fever occurs when the set-point of the anterior hypothalamic thermoregulatory centre is elevated. This can be caused by PGE2 synthesis, stimulated when an endogenous fever-producing agent (pyrogen) such as a cytokine is released from white cells that are activated by infection, hypersensitivity, malignancy, or inflammation. The salicylates and other NSAIDs lower body temperature in patients with fever by impeding PGE2 synthesis and release. They reset the "thermostat" toward normal and rapidly lower the body temperature of febrile patients by increasing heat dissipation as a result of peripheral vasodilation and sweating. These drugs have no effect on normal body temperature. Glucocorticosteroids Prednisolone and others o These agents lack antipyretic and analgesic activity. o They only have anti-inflammatory activity. o Inhibits expression of pro-inflammatory cytokines IL-2, 3 and 6, TNF, GM-CSF and IFN-γ; o Inhibits production of adhesion molecules – ICAM-1,E-selectin and vascortin – leading to reduced vascular permeability. o Reduces synthesis of arachidonic acid metabolites (prostaglandins, leukotrienes) and reduces histamine release. Other (Slow Acting) Anti-Inflammatory Agents Gold Compounds, Chloroquine and hydroxychloroquine, penicillamine o In contrast to the NSAlDs drugs described earlier, remittive (remission inducing) arthritis drugs are slow-acting. o They do not act by inhibiting cyclooxygenase and have no analgesic or primary anti-inflammatory activity. o These drugs are used primarily for rheumatic disorders, especially in cases where the inflammation does not respond to cyclooxygenase inhibitors. PST 05104 Pharmacology & Therapeutics 92 NTA Level 5 Semester 1 Facilitator Guide They slow the course of the disease and may also induce a remission, preventing further destruction of the joints and involved tissues. Gold compounds: like the other drugs in this group, cannot repair existing damage. Rather, they can only prevent further injury. o The currently available gold preparations are gold sodium thiomalate, aurothioglucose, and auranofin. It is believed that gold salts are taken up by macrophages and suppress phagocytosis and