Lesson 5 - Drug Interactions (CEU 2024/25) PDF

Lesson 5 Drug interactions 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  Summary 1. Introduction. Pharmacology interactions. 2. Mechanisms for drug interactions. 3.Pharmacokinetic Interactions 4. Pharmacodynamic interactions. 5. Individual and interindivi...

Lesson 5 Drug interactions 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25  Summary 1. Introduction. Pharmacology interactions. 2. Mechanisms for drug interactions. 3.Pharmacokinetic Interactions 4. Pharmacodynamic interactions. 5. Individual and interindividual diversity. Pregnancy. Breastfeeding. Age. Disease 6. Genetic effects on interactions. 2 1. PHARMACOLOGY INTERACTIONS. INTRODUCTION Many patients are treated continuously with one or more drugs for chronic diseases. Pharmacological interactions occur when one drug affects the activity or effectiveness of another drug when they are taken together. These interactions can either increase or decrease the effectiveness of one or both drugs or increase the risk of side effects Drug interactions may be serious – Represent approx. 30% of fatal adverse drug reactions 3  1. PHARMACOLOGY INTERACTIONS. INTRODUCTION There are several types of pharmacological interactions: Ø Drug-Drug Interactions: When two or more drugs interact, they can either enhance or diminish each other's effects. Ø Drug-Food Interactions: The consumption of certain foods can affect the absorption, metabolism, or excretion of medications (grapefruit juice) Ø Drug-Alcohol Interactions: Alcohol can alter the effectiveness and increase the side effects of many medications. Ø Drug-Disease Interactions: A drug might interact with a pre-existing health condition Ø Pharmacokinetic Interactions: These involve changes in the absorption, distribution, metabolism, or excretion of a drug. Ø Pharmacodynamic Interactions: These involve changes in the drug’s effects on the body. For example, combining two drugs that both cause sedation can result in excessive drowsiness 4  Grapefruit juice is considered a drug inhibitor. It is known to inhibit the enzyme CYP3A4, which is involved in the metabolism of many drugs. When grapefruit juice is consumed, it can reduce the activity of this enzyme, leading to higher levels of certain drugs in the bloodstream and potentially increasing the risk of side effects or toxicity. This interaction is particularly notable with medications such as statins, some antibiotics, and drugs used for hypertension. 5 https://youtu.be/FQJ4NO6SDqg?si=x_dby2T2_LaDCxOS 1. PHARMACOLOGY INTERACTIONS. INTRODUCTION A drug interaction can occur whenever a: – New medication is started – Medication is discontinued – Dose is changed – Drug is changed  1. PHARMACOLOGY INTERACTIONS. INTRODUCTION (A) can alter the action of another (B) by one of two general mechanisms: Modifying the pharmacological effect of B without altering its concentration – (pharmacodynamic interaction). Example: Warfarin competes with vitamin K. If vitamin K production in the intestine is inhibited (e.g. by antibiotics), the anticoagulant action of warfarin is increased. Altering the concentration of B (ADME) – (pharmacokinetic interaction). A B 7  1. PHARMACOLOGY INTERACTIONS. INTRODUCTION How to reduce the risk… ü Identify the patient's risk factors. ü Review the pharmacological history of the medication. ü Understand the actions of the drugs being used. ü Consider alternative therapeutic options. ü Avoid complex treatment regimens when possible. ü Educate the patient about their treatment. ü Monitor the therapy regularly. 1. PHARMACOLOGY INTERACTIONS. INTRODUCTION Factors that may contribute to drug interactions… Multiple drug therapies. Multiple prescribers. Multiple pharmacological effects of a drug. Multiple diseases or predisposing conditions. Poor patient compliance. Advancing patient age. Drug-related factors. Summary 1. Introduction. Pharmacology interactions. 2. Mechanisms for drug interactions. 3.Pharmacokinetic Interactions 4. Pharmacodynamic interactions. 5. Individual and interindividual diversity. Pregnancy. Breastfeeding. Age. Disease 6. Genetic effects on interactions. 11 2. MECHANISMS FOR DRUG INTERACTIONS Pharmacokinetic Interactions (ADME) – Altered drug absorption and tissue distribution » Chelation, pH, drug transporters… – Altered drug metabolism » Induction/inhibition – Reduced renal excretion 2. MECHANISMS FOR DRUG INTERACTIONS Pharmacodynamic interactions Occurs when two or more drugs influence each other’s effects at the site of action, altering efficacy or toxicity. These interactions can be: – Additive or synergistic interactions – Antagonistic or opposing interactions Summary 1.Introduction. Pharmacology interactions. 2. Mechanisms for drug interactions. 3.Pharmacokinetic Interactions 4. Pharmacodynamic interactions. 5. Individual and interindividual diversity. Pregnancy. Breastfeeding. Age. Disease 6. Genetic effects on interactions. 14  3. PHARMACOKINETICS INTERACTIONS “occurs when one or more drugs alter the plasma concentration of another drug in the body by modifying its absorption, distribution, metabolism or excretion “ 1. Absorption interactions Drug A Drug B INFLUENCE on Drug A ABSORPTION INTERACTION 1.COMPLEXATION & ADSORPTION ANTACIDS,FOOD & FORMATION OF POORELY CEPHROFLOXACINE, MINERALS SUPPLEMENTS SOLUBLE AND UNABSOBABLE PENCILLAMINE CONTAINING AL,Mg,Fe,Zn & COMPLEX WITH SUCH HEAVY Ca IONS METAL IONS. 2.ALTERATION OF GI PH ANTACIDS ENHANCED DISSOLUTION AND SULPHONAMIDES, ABSORPTION RATE. ASPIRIN FERROUS SULPHATE SODIUM DECREASED DISOLLUTION AND BICARBONATE,CALCIUM HENCE ABSORPTION. CARBONATE 3.ALTERATION OF GUT MOTILITY ASPIRIN DIAZEPAM, RAPID GASTRIC LEVODOPA, METOCLOPRAMIDE EMPTYING,INCREASED RATE OF MEXILETINE ABSORPION. LEVODOPA, LITHIUM DELAYED GASTRIC CARBONATE, ANTI CHOLINERGICS EMPTYING;DECREASED RATE OF MEXILETINE ABSORPTION.  Drug A Drug B INFLUENCE on Drug A 4.ALTERATION OF GI MICROFLORA DESTRUCTION OF BACTERIAL FLORA INACTIVATES DIGOXIN IN DIGOXIN ANTI BIOTICS LOWER INTESTINE. 5.MALABSORPTION SINDROME VITAMIN NEOMYCIN INHIBITION OF ABSORPTION A,B12,DIGOXIN  3. PHARMACOKINETICS INTERACTIONS The must important mechanism of distribution interaction is alteration in PP-drug binding. 2. Distribution interactions Competitive displacement interactions Displaced drug Displacer Phenylbutazone, chloral increased risk of Anti coagulants hydrate hemorrhage. Increased hypoglycemic Tolbutamide Sulphonamides effect.  3. PHARMACOKINETICS INTERACTIONS 3. Metabolism interactions Mechanisms of metabolism interactions include: 1. Enzyme induction: Increased rate of metabolism, increase the elimination 2. Enzyme inhibition: Decreased rate of metabolism. It is the most significant interaction in comparison to other interactions and can be fatal (overdose risk) 3. Metabolism interactions 1.ENZYME INDUCTION CORTICOSTEROIDS, ORAL DECREASED PLASMA LEVELS; CONTRACEPTIVES, BARBITURATES COUMARINS, PHENYTOIN DECREASED EFFICACY OF DRUG A ORAL CONTRACEPTIVES, RIFAMICIN DECREASED PLASMA LEVELS ORAL HYPOGLYCAEMICS 2.ENZYME INHIBITION ENHANCED ABSORPTION OF TYRAMINE RICH FOOD MAO INHIBITORS UNMETABOLISED TYRAMINE. COUMARINS METRANIDAZOLE INCREASED ANTI COAGULANT ACTIVITY. ALCOHOL PHENYL BUTAZONE INCREASED IN PLASMA ACETALDEHYDE LEVELS  3. PHARMACOKINETICS INTERACTIONS 4. Excrection interactions The most common mechanisms of excretion interactions are: Ø Alteration in renal blood flow Ø Alteration of urine PH Ø Competition for active secretions Ø Forced diuresis  4. Excrection interactions 1.CHANGES IN ACTIVE TUBULAR SECRETION PENCILLIN,CEPHALOSPO PROBENICID ELEVATED PLASMA LEVELS RINS,NALIDIXIC ACID OF ACIDIC DRUGS 2.CHANGES IN URINE PH INCREASED PASSIVE AMPHETAMINE ANTACIDS,THIAZIDESAC REABSORPTION OF BASIC E TAZOLAMIDE DRUGS.INCRESED RISK Of TOXICITY 3.CHANGES IN RENAL BLOOD FLOW DECREASED RENAL LITHIUM BICARBONATE NSAIDS CLEARANCEOF LITHIUM.RISK OF TOXICITY Summary 1.Introduction. Pharmacology interactions. 2. Mechanisms for drug interactions. 3.Pharmacokinetic Interactions 4. Pharmacodynamic interactions. 5. Individual and interindividual diversity. Pregnancy. Breastfeeding. Age. Disease 6. Genetic effects on interactions. 23  4. PHARMACODYNAMICS INTERACTIONS These interactions may be DIRECT OR INDIRECT.  4. PHARMACODYNAMICS INTERACTIONS DIRECT: When drugs with similar or opposite pharmacological effects are used simultaneously. Antagonism: The interacting drugs have opposing actions Example: Acetylcholine and noradrenaline have opposing effects on heart rate. Addition or summation: Interacting drugs have similar actions and the resulting effect is the total of the responses of the individual drugs. Example: CNS depressants like sedatives and hypnotics,…etc Synergism or potentiation: It is an enhancement of action of one drug by another Example: Alcohol enhances the analgesics activity of aspirin.  4. PHARMACODYNAMICS INTERACTIONS. INDIRECT: In which both drugs have unrelated effects. Example: Salicylates decrease platelet aggregation capacity, impairing homeostasis in warfarin-induced haemorrhage.  Avoiding Drug Interactions For patients https://youtu.be/S8QHQlzxbHQ?si=IE4j-I82OucLe3yT For more information… Summary 1.Introduction. Pharmacology interactions. 2. Mechanisms for drug interactions. 3.Pharmacokinetic Interactions 4. Pharmacodynamic interactions. 5. Individual and interindividual diversity. Pregnancy. Breastfeeding. Age. Disease 6. Genetic effects on interactions. 27 5. INDIVIDUAL DIVERSITY genetic origin, environmental factor, (eating habits...) and ETHNICITY Example: African-Americans with heart failure have improved life expectancy with a combination of hydralazine and a nitrate, while the same treatment may not have the same effect in white Americans. Chinese individuals metabolize ethanol differently from Europeans, resulting in higher acetaldehyde levels, which can cause flushing and palpitations. 28  5. INDIVIDUAL DIVERSITY AGE AND DRUG INTERACTIONS Drugs commonly produce greater and more prolonged effects at the extremes of life. – Body composition changes with age, the distribution volume of liposoluble drugs increases, because the body’s adipose tissue percentage increases during ageing.. – Elderly people consume more drugs drug interactions has also increased 5. INDIVIDUAL DIVERSITY AGE AND DRUG INTERACTIONS 30 5. INDIVIDUAL DIVERSITY AGE AND DRUG INTERACTIONS Several important enzymes, including hepatic micro-somal oxidase, glucuronyltransferase, acetyltransferase and plasma esterases, have low activity in neonates. The activity of hepatic microsomal enzymes decline slowly with age. 31 5. INDIVIDUAL DIVERSITY AGE AND DRUG INTERACTIONS Age-Related Variation in Sensitivity to Drugs. Examples: Benzodiazepines, produce more confusion and less sedation in elderly than in young people Hypotensive drugs cause postural hypotension more commonly in elderly. 32 5. INDIVIDUAL DIVERSITY PREGNANCY Ø Maternal plasma albumin concentration is reduced, influencing drug protein binding. Ø Cardiac output is increased, leading to increased renal blood flow, and increased renal elimination of drugs. Ø Lipophilic molecules rapidly cross the placental barrier, whereas transfer of hydrophobic drugs is slow. Ø The placental barrier excludes some drugs. Ø Drugs that are transferred to the fetus are eliminated more slowly than from the mother. 33 5. INDIVIDUAL DIVERSITY DISEASE A disease can cause pharmacokinetic or pharmacodynamic variation as a result of increased drug concentration following a ‘standard’ dose – Hypothyroidism is associated with increased sensitivity to several drugs (e.g. pethidine). 34  5. INDIVIDUAL DIVERSITY DISEASE Ex: Diseases that influence receptors: myasthenia gravis, an autoimmune disease characterised by antibodies to nicotinic acetylcholine receptors and increased sensitivity to neuromuscular blocking agents (e.g. vecuronium) and other drugs that may influence neuromuscular transmission. 35 Summary 1.Introduction. Pharmacology interactions. 2. Mechanisms for drug interactions. 3.Pharmacokinetic Interactions 4. Pharmacodynamic interactions. 5. Individual and interindividual diversity. Pregnancy. Breastfeeding. Age. Disease 6. Genetic effects on interactions. 36  6. PHARMACOGENETICS AND DRUG EFFECTS Resistance to malaria: – Deficiency of X-linked gene for glucose 6-phosphate dehydrogenase (G6PD). Sensitivity to suxamethonium: is due to genetic variation in the rate of drug metabolism. – individuals fail to inactivate suxamethonium rapidly and experience prolonged neuromuscular block 37  6. PHARMACOGENETICS AND DRUG EFFECTS Fast acetylators and slow acetylators White populations include equal numbers of ‘fast acetylators’ and ‘slow acetylators’. This metabolisms is controlled by a single recessive gene associated with low hepatic acetyltransferase activity (NAT2). Fast Acetylators: Individuals who metabolize drugs quickly due to higher activity of the NAT2 enzyme. This can lead to faster clearance of drugs from the body, potentially reducing the drug's effectiveness and requiring higher or more frequent dosing. Slow Acetylators: Individuals who metabolize drugs more slowly due to lower activity of the NAT2 enzyme. This can result in prolonged drug exposure, increasing the risk of side effects and toxicity, and often requires adjustments in dosing to avoid adverse effects. 38  6. PHARMACOGENETICS AND DRUG EFFECTS Fast acetylators and slow acetylators These variations can impact drug therapy and dosing, and are particularly relevant for medications like isoniazid – Isoniazid causes two distinct forms of toxicity. peripheral neuropathy: in slow acetylators Hepatotoxicity: fast acetylators 39 Questions?????