Drug Interaction and Adverse Drug reaction (ADR) DR A.A BUSARI (MB.BS, M.Sc., MMCP, FWACP) Department of Pharmacology, Therapeutics and Toxicology. College of Medicine, University of Lagos.

Drug interation

DRUG INTERACTIONS It is the modification of the effect of one drug (the object drug ) by the prior or concomitant administration of another drug or agent (precipitant drug).

Outcomes of drug interactions undesired (Harmful Effects) Desired (Beneficial Effects)

Outcome of Interactions: Enhancement in drug action/ improved therapeutic benefits Reduction in desired drug effects Neutralization of drug effects (therapeutic failure) Increased risk of adverse reactions

Forms of DI Drug interaction include - Drug – drug Interactions Drug – herbal Interactions Drug – food Interactions Drug – Chemical Interactions Drug – laboratory test Interactions Pharmacogenetic Interactions.

Risk Factors for Drug Interactions High Risk Patients Elderly, young, very sick, multiple disease Multiple drug therapy, Renal, liver impairment High Risk Drugs Narrow therapeutic index drugs e.g.(digoxin, warfarin, theophylline) Recognized enzyme inhibitors or inducers

Classification of DDI

Site of interaction Outside the body. Inside the body.

Outside the body: Incompatibilities: reaction of IV drugs given together in solutions after mixing that are not longer safe for the patient. This results in an alteration of the structure and stability of the drug combinations (in the solution) leading to: Loss of drug activity. Formation of precipitates. Development of toxic product.

Drug Interactions Inside the body Pharmacokinetic drug interactions Pharmacodynamic drug interactions

PHARMACOKINET IC INTERACTIONS

Pharmacokinetic drug interactions Involve the interactions between drugs leading to alterations in the following: Absorption. Distribution. Metabolism. Excretion.

Interaction at the site of absorption Formation of drug Chelates or complexes. Altered gut Flora Altered GIT Motility. Altered PH. Drug induced Mucosal damage. Malabsorption caused by other drugs. Interaction other than in the Gut.

Absorption Direct chemical interaction in the gut and formation of drug Chelates or complex Calcium (milk), iron, anti acid (Al or Mg hydroxide) + Tetracyclin insoluble complex. levothyroxine , digoxin and some acidic drugs e.g warfarine + Colestyramine decrease their absorption.

PHARMACOKINETIC INTERACTIONS Absorption – Drug interaction can affect the rate and extent of systemic drug absorbtion (bioavailability) from the absorption site resulting in increased or decreased drug bioavailability. Antacids/milk (Ca) + tetracycline Cholestyramine + digoxin, etc Reduced bioavailability of tetracycline and digoxin due to the formation of complexes that are not absorbable)

Absorption Altered intestinal bacterial flora Antibiotics kill a large number of the normal flora of the intestine Antimicrobials may potentiate Oral Anticoagulant by reducing bacterial synthesis of vitamin K. In 10% 0f patients receiving Digoxin…..40% or more of the administered dose is metabolized by the intestinal flora which Increases digoxin conc. and increases its toxicity

Antibiotics and Oral Contraceptives Antibiotics kill bacteria in gut Oestrogen conjugates not hydrolysed Conjugates not re-absorbed Less oestrogen - loss of contraceptive effect (No effect on progestogen component)

CONT’D Altered gut motility OR Slowing of gastric emptying by drugs like antimuscarinic drugs and opiate analgesics anticholinergics + acetaminophen Impact: delay in absorption of acetaminophen OR Accelerated by drugs e.g metclopromide which hasten gastric emptying

CONT’D Altered PH. The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form.

H-2 blockers, anti acid + ketoconazole Decrease gastric acid, dissolution of ketoconazole is decreased, resulting in reduced absorption Therefore, These drugs must be separated by at least 2h in between administration.

CONT’D Drug-induced mucosal damage: Colchicine (which cause local Mucosal damage) can decrease absorption of poorly absorbed drugs e.g. (phenytoin)

CONT’D Malabsorption caused by other drugs: Orlistat (Xenical) Inhibits pancreatic lipases, preventing hydrolysis of ingested fat) Orlistat (Xenical) + fat soluble vitamins (A,D,E,K) malabsorption of Fat-soluble vitamins

Interaction at the site of drug distribution Displacement from plasma protein binding It depends on the affinity of the drug for the plasma protein. The most highly bound drug(s) is capable of displacing others. The concentration of the free drug (the drug displaced) is increased. Sodium valproate displaces phenytoin from its binding site on plasma albumin.

CONT’D Displacement from tissue bindings Quinidine displaces digoxin from its binding site in tissues and cause increase concentration of free digoxin.

PHARMACOKINETIC INTERACTIONS Adsorption Antacids/Charcoal + Paracetamol Antacids/Charcoal + H2 blockers (Reduced bioavailability of the drugs)There is always the possibility of antacid and charcoal adsorbing other drugs Increased GIT transit time Antimuscarinics + Paracetamol Antimuscarinics + Levodopa (Takes longer time for the drugs to reach the small intestine for absorption due to inhibition peristalsis by the antimuscarinic)

Altered drug Metabolism Changes in drug metabolism are the most important causes of unexpected drug interactions. There are several enzyme families involved in drug metabolism, and the cytochrome P450 (CYP) enzyme family is the most important.

CONT’D Inhibition of a cytochrome P450 enzyme increases the concentration of some drugs by decreasing their metabolism. For example, clarithromycin is a strong inhibitor of CYP3A-catalysed simvastatin metabolism, thus increasing the risk of myopathy.

CONT’D Drug inhibition of cytochrome P450 enzymes is also used therapeutically. For example, ritonavir, a strong inhibitor of CYP3A, reduces metabolism of other protease inhibitors thus increasing their effectiveness in treating HIV (so called ‘ritonavir-boosted’ regimens).

CONT’D Induction of a cytochrome P450 enzyme decreases the concentration of some drugs by increasing their metabolism. For example, carbamazepine is a strong inducer of CYP3A that increases the metabolism of the combined oral contraceptive, thus increasing the risk of unwanted pregnancy.

CONT’D Prodrugs Some drugs rely on cytochrome P450 enzymes for conversion to their active form. As this is usually dependent on a single enzyme pathway, prodrugs are particularly vulnerable to changes in metabolism. Inhibition of conversion from prodrug to active drug may lead to inadequate concentrations of the active drug and therapeutic failure. For example, tamoxifen is metabolised by CYP2D6 to its active form endoxifen, and concomitant therapy with the strong CYP2D6 inhibitor paroxetine has been associated with increased mortality in breast cancer.

CONT’D Enzymes Inhibitors CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A Inducers Inhibitors CYP1A2 ciprofloxacin, fluvoxamine, ethinyloestradiol, interferon-alfa phenytoin, rifampicin CYP2C9 fluconazole carbamazepine, rifampicin CYP2C19 fluconazole, fluvoxamine, ticlopidine, fluoxetine, clarithromycin, voriconazole, moclobemide lopinavir/ritonavir, rifampicin, St John’s wort CYP2D6 bupropion, fluoxetine, paroxetine, perhexiline, cinacalcet, doxepin, duloxetine, flecainide, moclobemide, quinine, terbinafine CYP3A erythromycin, clarithromycin voriconazole, itraconazole, ketoconazole, indinavir, ritonavir, saquinavir, diltiazem, verapamil, grapefruit juice , aprepitant, cimetidine, ciprofloxacin, cyclosporin, fluvoxamine, imatinib carbamazepine, modafinil, phenytoin, phenobarbitone, rifabutin, rifampicin, St John’s wort

Alterations in renal clearance Increase in Renal Blood Flow. Inhibition of Active Tubular Secretion. Alterations in Tubular Reabsorption.

hydralazine increases the renal clearance of digoxin Increase in Renal Blood Flow hydralazine + digoxin hydralazine increases the renal clearance of digoxin

probenecid + penicillin Decreases tubular secretion of Active tubular secretion: It occurs in the proximal tubules. The drug combines with a specific transporter protein to pass through the proximal tubules. When two drugs compete for the transporter protein for excretion, one of the drugs will be secreted thus reducing the excretion of the other drug and increasing its plasma concentration. probenecid + penicillin Decreases tubular secretion of Penicillin

Passive tubular Reabsorption Acidification of urine increases reabsorption and decreases excretion of weak acids, and, in contrast, decreases reabsorption of weak bases. Alkalinization of urine has the opposite effect. In some cases of overdose, these principles are used to enhance the excretion of weak bases or acids e.g. sodium bicarbonate + salicylates(weak acid) decrease reabsorption and Increase excretion of salicylates

Pharmacodynamic drug interactions Pharmacodynamics are related to the pharmacological activity of the interacting drugs . Both drugs act on the target site of clinical effect. Synergism Summation or Additive. Potentiation. Antagonism

Syn- together ; ergon- work Drug Synergism Syn- together ; ergon- work

Drug Synergism: This is the facilitation of the effects of one drug by another when given together Types: a. Additive (summation) b. Supra-additive (Potentiation) Synergism: sharma-AB>A+B, Additive and summation diff entity,doesnot talk about potentition/supraadditive Tripathi says synergism as facilitation of the effects of one drug by another when given together, and classifies synergism as additive and supraadditive

Addition/Summation Summation /Addition Effect of drugs A + B = Effect of drug A + Effect of drug B Final effect is same as the algebraic sum of the magnitude of individuals drugs Side effects do not add up Examples of Summation: Different MOA Aspirin : (-) PG synthesis  analgesia + Codeine : Opioid agonist  analgesia + Examples of Addition: Same MOA Ibuprofen: (-) PG synth  analgesia + Paracetamol: (-) PG synth  analgesia+ Pg. 496 sharma opioid Recptors mu and delta, inhbn of ad. cy.—dec camp—dec cell excitablity, activation of K channels-hyperpolarisation,decrease ca conductance

Other Additive Drug Combinations Effect Amlodipine + Atenolol Antihypertensive Glibenclamide + Metformin Hypoglycemic ???additive/???summative NO & Halothane: 373 tripathi Amlo-268 sharma Gli+Met=kdt 274,fig 19.6

Supra-additive/Potentiation SEffect of drug A + B > Effect of drug A + Effect of drug B When two drugs are given together, the final effect is much more than the simple algebraic sum of the magnitude of individuals drugs. Examples: Sulphamethoxazole & Trimethoprim--- sequential blockade of two steps in synthesis of folic acid in micro-organisms.

Pharmacodynamic beneficial combinatoin Other eg. Beta blocker and frusemide

Synergism by altering the pharmacokinetics of the other Synergism by altering Pharmacokinetics of the other: Levodopa + Carbidopa

Other supraadditive drug combinations DRUG PAIR BASIS OF POTENTIATION Ach + Physostigmine Inhibition of break down Adrenaline + Cocaine Inhibition of neuronal uptake Tyramine + MAO inhibitors Increasing releaseable CAT store Ach-105 kdt Adrenaline cocaine-sharma 157,158,159 Mao=sharma 464-tranylcypromine, moclobemide, selegiline iproniazid, Tyramine: 178 sharma mao present liver git metabolise tyramine rapidly-in presence of mao- inhb tyramine met- concof tyr increases and inc releseable cat stores----cheese reaction

Drug Antagonism

DDefinition: Drug Antagonism Combined effect of two drugs is less than the sum of the effects of the individual drugs Effect of drugs A + B < Effect of drug A + Effect of drug B One drug decreases / opposes / reverses / counters the effect of other drug by different mechanisms

Types of Antagonism a. Pharmacological Antagonism : i. Competitive (Reversible) ii. Non-competitive (Irreversible) b. Chemical Antagonism c. Physiological Antagonism d. Physical antagonism

CONT’D B) Chemical Antagonism A) Physical Antagonism Based on physical property of drugs, e.g. charcoal (adsorb alkaloid) in alkaloidal poisoning B) Chemical Antagonism Chemical reaction between two drugs e.g., NaHCO3 HCl

C) Physiological/Functional Antagonism CONT’D C) Physiological/Functional Antagonism Opposite effects of two drugs on same function Two drugs act on two diff. types of receptors & antagonize action of each other, e.g. histamine & adrenaline (adrenaline for treatment of anaphylactic shock); Adrenaline & insulin on blood sugar level

D) Pharmacological Antagonism Opposite effect of two drugs binding to same receptors Receptor antagonism is specific,e.g. atropine  spam of intestine by acetylcholine not by Histamine.or 5-HT (serotonin) Types Competitive Non-competitive Equilibrium Non-equilibrium (Reversible) (Irreversible)

i) Competitive Antagonism (equilibrium or reversible) Competition between agonist & antagonist for specific site or receptor Action of agonist is blocked if conc. of antagonist is  Antagonism can be overcome (surmount) by  conc. of agonist Cont.

CONT’D

II) Non-Equilibrium(irreversible) Antagonist Antagonist binds to receptor with covalent bond Irreversible blocking e.g. adrenaline & phenoxybenzamine

iii) Non-competitive (non-surmountable Antagonist CONT’D iii) Non-competitive (non-surmountable Antagonist Antagonist binds to another site of receptor DRC is flattened + max. response is  e.g., verapamil (noradrenaline)

CONT’D

ADVERSE DRUG REACTIONS

DEFINITION WHO’s definition of an adverse drug reaction, which has been in use for about 30 years, is “a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function

DEFINITION CONT’D Lawrence and Aronson in an article published in lancet 2000 proposed the following as a definition of ADR: “An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.”

CONT’D The terms “adverse reaction” and “adverse effect” are interchangeable, except that an adverse effect is seen from the point of view of the drug, whereas an adverse reaction is seen from the point of view of the patient.

Epidemiology 4% of hospital admissions 1 in 1000 deaths in medical wards 10 to 20 % of in-patients 5% of patients in general practice

CONT’D More frequent in elderly: erratic drug taking multiple pathology altered pharmacokinetics increased sensitivity of CNS and CVS

CLASSIFICATION OF ADVERSE DRUG REACTIONS

Prevention of Adverse drug reactions Never use any drug unless there is good indication. If the patient is pregnant do not use the drug unless the need is imperative. Allergy and idiosyncrasy are important causes of ADRs. Ask if the patient had previous reactions. Ask if the patient is already taking other drugs including self medication

CONT’D Age, hepatic and renal disease may impair clearance of drugs so smaller doses may be needed. Genetic factors may also predispose to certain ADRs Prescribe as few drugs as possible and give clear instructions Where possible use familiar drugs. With new drugs be particularly alert for ADRs and unexpected event. If serious ADRs are liable to occur warn the patient

QUESTIONS Explain the mechanism(s) of drug antagonism Describe the mode of drug interactions between the following concomitantly administered drugs: Calcium supplements and tetracycline Adrenaline and phenoxybenzamine Levodopa and Carbidopa 3. Define Adverse Drug Reactions according to the W.H.O. Briefly discuss with named examples the clinical applications of drug synergism. Briefly discuss factors that could predispose to drug interactions.