DRUG INTERACTIONS

1. DRUGINTERACTIONS MSC TID 1 Nyakundi BM April 21st 2010

2. Definition • A drug interaction is defined as a measurable ( modification in magnitude or duration) of the action of one drug by prior or concomitant administration of another substance (including prescription and non prescription drugs,food or alcohol) • Interactions can occur by pharmacokinetic or pharmacodynamic mechanisms

3. Effects of drug interactions • These can be desirable, adverse or inconsequential. • Majority of drug interactions are desirable or inconsequential. • Clinically desirable drug interactions can form part of therapeutic regimens when two or more drugs with different (e.g to lower elevated blood pressure.)

4. Index drug • When describing adverse drug interactions, the term index drug is used for the drug which has its effects cancelled or enhanced by the interacting drug.Occasionally two drugs interact with each other to cause different adverse effects. In such cases , both drugs are index and both are interacting- a double adverse drug reaction is the result.

5. Clinically detectable interactions • Potential adverse interactions vs clinically detectable adverse drug interactions; • Potential adverse interactions occur frequently but clinically detectable adverse drug interactions occur quite infrequently. • Why? Because 1.Many interactions lead to small effects on the index drug and for most index drugs these are clinically unimportant. Example- Interaction between acetaminophen and isoniazid; • Isoniazid given 300mgs/ day for 7 days inhibits the microsomal oxidation of acetaminophen by 70%.However because oxidative metabolism represents only a minor component of the overall elimination of acetaminophen,this resulted in only 15% decrease in the total body clearance of acetaminophen,equivalent to increasing dose of acetaminophen by 18% a clinically undetectable effect. • 2.Many drugs have a wide therapeutic index. Eg penicillin ,interactions leading to 2 or 3 fold change in drug concentration may not lead to adverse effects in most situations

6. Drug interaction mechanisms • Mechanisms of drug interactions-pharmacokinetic and pharmacodynamic. • Pharmacokinetic • 1.Chemical interactions • 2.Interactions affecting oral availability • 3.Protein binding interactions. • 4.Interactions due to altered biotransformation • 5.Interactions due to altered renal excretion.

7. Chemical Interactions • Drugs can react physically or chemically with each other before they are administered to the patient or in case of oral preparations before they are absorbed. • Mixing of drugs before parenteral administration may cause interaction and thereby and significantly decrease the activity of one or both drugs. • Chemical interactions are very unlikely to occur once drugs reach systmic circulation because the concentrations in plasma are low. • Example-oral tetracycline chelates the cations calcium,magnesium,aluminium or iron resulting in a cation-tetracycline complex that cannot be absorbed • Also cholestyramine and colestipol bind some anionic drugs and decrease their absorption.

8. Interactions affecting oral availability • This can be divided into interactions affecting gastric emptying,drug absorption and presystemic elimination. • 1.Gastric emptying-rate of gastric emptying is important when a rapid onset of effect of the drug is desired. Eg in rapid relief from pain or onset of sedation is needed and parenteral drug administration is not possible. • What to be done- take drug on an empty stomach with at least 200cc of water and remain in upright position.

9. Gastric emptying • Slowed gastric emptying occurs in; • Food, recumbency ,autonomic neuropathy,heavy exercise, drugs eg antacids, anticholinergic drugs and narcotics • Enhanced gastric emptying occurs in ; • Drug administration eg metoclopramide,cisapride, domperidone. • This results in earlier and higher peak concentrations of the index drug. • Nb- for drugs that are inactivated in the acid milieu of the stomach eg levodopa and penicillin G ,increased gastric emptying will lead to increased bioavailability.Increased rate of GI transit eg in short bowel syndrome,will decrease absorption of drugs with low dissolution rates or drugs that are very poorly absorbed(griseofulvin or enteric coated tablets)

10. Drug absorption • Most drugs are absorbed in the small intestine by passive diffusion • Some drugs eg oral neomycin,antineoplastic drugs can damage the intestinal absorptive surface and potentially result in decreased absorption of other drugs ( especially those in which drug absorption is incomplete)

11. Presytemic elimination • Drugs have the capacity to be absorbed, metabolised or extracted during transit across the intestinal epithelium into the portal circulation and during the first pass through the liver.This is phenomenon is called presystemic elimination or First pass effect effect.Drugs subject to significant presystemic elimination and consequently low bioavailability include propranolol, metoprolol, chlopromazine,labetalol,amitriptyline,imipramine,felodipine and morphine.These drugs can compete with each hence increasing each others bioavailability eg chlopromazine and propranolol. • Components of the grape fruit juice can increase bioavailability of drugs that are substrates of the cytochrome p450 Isoenzyme ,CYP 3A eg felodipine and cyclosporin.This occurs by inhibition of the intestinal CYP 3A4 by grape juice components

12. Protein binding interactions. • Drugs that are highly bound in plasma are potentially subject to displacement from their carrier proteins by another drug with affinity for the same protein. • When another highly bound drug is added,competitive displacement may occur,resulting in a transient increase in free concentration of the index drug. • This is then followed by rapid redistribution of the index drug,transient increase in the rate of elimination creating anew equilibrium for both drugs • This displacement is only likely to cause a clinically significant effect if the index drug has a small volume of distribution,narrow therapeutic index and rapid onset of action.

13. Interactions due to altered biotransformation • Drug metabolism most often occurs in the liver and involves the conversion of an active non polar drug to more polar metabolites(- generally less active or inactive) that are cleared by the kidneys. • Ocassionally metabolites are pharmacologically active in ways that are similar or disimilar (including toxicity) to the progenitor drug. • Drugs that are extensively metabolized are particularly susceptible to interactions affecting drug metabolism. • Most drugs are metabolized by several different pathways, making prediction of the consequences of metabolic interactions difficult.

14. Interactions involving enzyme inhibition • Many drugs have the potential to inhibit the metabolism of other drugs • A clinically significant interaction may result and is dependent on 1. the magnitude of decrease in clearance and 2.the consequences of the resulting increase in the steady-state serum concentration of the index drug. • Most clinically significant interactions of this type involve the hepatic microsomal oxidative enzymes that can be divided into separate P450 isoenzymes.,eg 1A ,2B, 2C, 2D,2E, and 3A. • Information regarding the predominant isoenzymes involved in the metabolism of a drug and whether a microsomal enzyme inhibitor specifically inhibits a particular isoenzyme is useful in understanding and predicting this type of drug interaction.

15. Enzyme inhibition, cont • The magnitude of inhibition effect in an individual is variable because it depends on the specific enzyme or enzymes inhibited and the quantitative importance of that pathway in overall clearance of the index drug. • example;-isoniazid is a potent inhibitor of the microsomal oxidation of both carbamazepine and acetaminophen. • With acetaminophen,conjugative metabolic pathways (type 2) predominate,resulting in a clinically insignificant 15% decrease in total plasma clearance of acetaminophen. • With carbamazepine,oxidative metabolic pathways (Type 1) predominate and isoniazid inhibits total plasma clearance by 45%.This results in and increase in steady state serum concentration of 85% and a significant risk of toxic effects.

16. Mechanism of enzyme inhibition • This varies from competitive inhibition to irreversible inactivation. • Irreversible inactivation leads to the longest lasting effects. • The time course of the change in serum concentration of an index drug affected by an inhibitory interacting drug is dependent on the new half life of the index drug-needing 4-5 t1/2s to reach a new steady state.

17. Unpredictability of interactions • Many microsomal inhibitors also have the capacity to induce microsomal enzymes. • Therefore depending on the dose, timing or patient settings, inhibition or induction can be seen. • Examples –ethanol and isoniazid.

18. Interactions involving enzyme induction • The microsomal enzyme systems in the liver and other tissues can be induced severalfold by many drugs and chemicals. • Enzyme induction occurs by a number of different mechanisms,but generally leads to increased amounts of the enzyme and consequently, an increase in the highest rate (Vmax) of the biotransformation reaction. • The time course for induction is usually longer than inhibition and may take 2-3 weeks to become maximal in humans. • Inducing agents can be classified as per the specific P450 isoenzymes induced.

19. Effects of enzyme induction • Enzyme induction can enhance the metabolism of the inducing agent-(auto induction) and/or a variety of other drugs and some endogenous compounds eg thyroxine ,cortisol and bilirubin. • Induction can be associated with marked increases in the clearance of the index drug ,resulting in loss of efficacy. • Examples;Rifampicin has been implicated as a cause of 1. graft rejection in patients receiving adequate doses of prednisone and cyclosporin 2.Failure of effect of oral contaceptives. • Example;In patients who are following a methadone maintenance program,introduction of phenytoin has precipitated withdrawal symptoms.

20. Effect of enzyme induction • If the induction interaction is recognized,the dose of the index drug can be increased accordingly. • If the inducing agent is later stopped,the index drug may have to be reduced to prevent toxicity. • In some cases,induction of metabolism can result in increased formation of a toxic metabolite with serious consequences. • Example;Administration of isoniazid may increase the risk of acetaminophen induced hepatotoxicity by increasing theformation of the toxic metabolite of acetaminophen.

21. Agents that alter microsomal enzyme activity • Examples of inhibitors • Ciprofloxacin(1A2),Erythromycin(3A4),Ethanol (acute),Fluconazole (3A4),Grapefruit(3A4),Isoniazid(2E1),Itraconazole(3A4),Ketoconazole(3A4),Oral contraceptives,verapamil. • Examples of Inducers • Barbiturates(phenobarbital)(2B),Charcoal broiled food(1A2),Dexamethasone,Isoniazid(2E1) Ethanol(chronic)(2E1),Rifampicin(3A4),Rifabutin(3A4),Tobacco smoke(1A2)

22. Interactions due to altered renal excretion • Elimination interactions can occur when drugs interfere with Blood flow to the kidney,active tubular secretion and kidney tubular fluid Ph. • Renal blood flow and hence GFR is controlled partially by renal vasodilatory prostaglandins.If the synthesis of these prostaglandins is reduced by eg indomethacin,renal excretion of lithium is reduced with increased lithium serum concentrations. • (Mechanism of action of above is not very clear as Aspirin, a potent prostaglandin synthetase inhibitor, has no effect on lithium concentrations.) • Also the clearance of drugs that are excreted entirely by glomerular filtration are unlikely to be affected by other drugs.

23. Altered renal excretion cont. • In Active Renal tubular secretion,drugs that use the same active transport system in the kidney can compete with one another for excretion. • Example; Probenecid given to increase plasma penicillin levels by delaying excretion. • This interaction can also lead to toxicity eg methotrexate toxicity can be caused by inhibition of its tubular secretion by salicylate.

24. Altered renal excretion cont. • Kidney tubular fluid pH- As with the gut, passive reabsorption of drugs depends on the extent to which the drug stays in the non ionized, lipid soluble form. • Only the non ionized drug is lipid soluble and able to diffuse back.At alkaline Ph, weak acids exist in the ionized state and will be excreted.Renal clearance is increased if the urine is more alkaline.Also at acidic Ph, weak bases will be excreted. • Urine acidification causes increased amphetamine excretion in amphetamine poisoning; • Urine alkalinization causes increased salicylate excretion in salicylate poisoning

25. Pharmacodynamic Interactions • In pharmacodynamic interactions, the effects of one drug are changed by the 2nd drug at its site of action. • Can involve competition for specific sites but can also be indirect and involve interferance with physiological systems. • Examples1.Synergistic/Additive interactions 2.Antagonistic interactions 3.Serotonin syndrome 4.Drug or neurotransmitter uptake interactions

26. Synergistic interactions • Occur when 2 drugs with similar pharmacological effects are given together. • Examples-antidepresants,antiepileptics,antihistamines when given together lead to excessive drowsiness. • Example- Drugs with arrythmogenic potential eg antiarrythmics,neuroleptics,tricyclic antidepressants and those producing electrolyte imbalances eg diuretics can lead to ventricular arrthymias and should be avoided.

27. Antagonistic Interactions • This occurs when a drug with agonist action at a particular receptor site interacts with an antagonist at that site. • Example;-Beta 2 selective drug salbutamol antagonized by non selective Beta drug propranolol. • Example;- Specific antagonists may be used to reverse the effect of another drug at a specific receptor site eg opioid antagonist-Naloxone, Benzodiazepine antagonist-Flumazenil • Also alpha adrenergic agonists eg metaraminol may be used in management of priapism induced by alpha adrenergic antagonists eg phentolamine.

28. Serotonin syndrome • Associated with excess of serotonin that results from therapeutic drugs use,overdose or inadvertent interaction between drugs.It can occur when 2 or more drugs affecting serotonin are given at the same time, or one serotonergic drug is stopped and another started. • Serotonin syndrome includes confusion,disorientation,abnormal movements,exaggerated reflexes,fever,sweating, diarhea,hypotension/hypertension. • Three or more of the above symptoms are neededto make a diagnosis when no other cause is seen.

29. Unrecognized drug interactions • An interaction can occur and likely to go unnoticed like when the interacting drug diminishes the effectiveness of the index drug. • When a patient takes many drugs,the clinician may have a difficult task in establishing continued efficacy and necessity of each agent.One drug can readily cancel the effectiveness of another. • To establish ongoing effectiveness of a drug as part of a multiple drug regimen, one can stop the drug in question and to reassess the patient carefully over time

30. Drug or Neurotransmitter uptake interactions • MAOIs have potential for interactions with other drugs and food. • Food- drug interactions with irreversible MAOIs are the result of inhibition of presystemic elimination of tyramine present in various foods. • The non selective MAOIs eg phenelzine and tranylcypromine inhibit MAO A in the intestinal wall and liver.This leads to increased oral bioavailability of tyramine which is not completely metabolized during absorption and the first pass through the liver. • When tyramine reaches the systemic circulation,it can cause increased release of noradrenaline from sympathetic postganglionic neurones. • POTENTIALLY FATAL HYPERTENSIVE CRISES CAN OCCUR • In this sympathetic overactivity syndrome, there is hypertension ,headache, cardiac arrythmias, hyperpyrexia and excitement.Fatal intracranial hemorrhages and cardiac arrests can also occur. • The risk of interactions continues for several weeks as new MAOI has to be synthesized

31. Interactions involving unknown/multiple mechanisms • Many drug – drug interactions involve more than one mechanism. • Example –quinidine-digoxin interaction;when quinidine is given to patients receiving digoxin,two to three fold increase in steady state levels of digoxin occurs.Various mechanisms involved may be explained by the inhibition of the p-glycoprotein efflux transporter by quinidine.

32. Unrecognized drug interactions • In the late 1990s 16 deaths occurred in japanese cancer patients being treated for herpes zoster infection with the new antiviral drug sorivudine.These patients were taking 5 fluorouracil or other fluoropyrimidine antineoplastic drugs. • Sorivudine is a potent inhibitor of dihydropyrimidine dehydrogenase- the enzyme responsible for inactivation of fluoropyrimidines. • For many new drugs, potential drug interactions are being predicted and tested during development

33. Unrecognized drug interactions • Dysrythmias can occur young healthy individuals taking erythromycin ( or ketoconazole) with terfenadine- a non sedating antihistamine. • The mechanism of this interation is the inhibition of the metabolism of terfenadine (CYP3A4) by erythromycin or ketoconazole causing increased steady state concentrations of terfenadine, a drug that can prolong coduction in the heart and cause the potentially lethal dysrtythmia torsardes des pointes.

34. High Risk Clinical Setting • Physicians may not know or recall ALL the documented or potential interactions.Since the risk is small in most clinical settings,the astute clinician can reduce the risk to the patient by being aware of the clinical settings in which the risk of adverse drug interactions is increased. • These include 1.Index drugs with a narrow therapeutic index.Care must be taken when adding/ removing a drug in patients taking a drug with a low toxic/therapeutic ratio. • Classical example is warfarin.

35. High risk clinical setting • Other examples of drugs with narrow therapeutic index; • Anticancer drugs-5 fluoruracil,Immunosuppressive drugs- cyclosporin,antidysrythmic drugs-quinidine,digitalis glycosides-digoxin,anticonvulsants- phenytoin,oral hypoglycemic drugs-glyburide,aminglycosides- gentamicin and vancomycin,antiretrovirals- zidovudine,antifungals –amphoterricin B,Lithium carbonate and Theophylline.

36. High risk clinical setting • 2.Patients taking many drugs • As the number of drugs taken increases, the risk of drug interaction increases disproportionately. • This increased risk of adverse drug interactions can be from OTC drugs,topical drugs eg timolol eye drops ,herbal teas.

37. High risk clinical setting • 3. Critically ill patients; • These patients have lost their physiological reserve in one or more systems and often require multiple drugs. • Examples include patients with renal, hepatic,respiratory,cardiac or autonomic failure;alzheimers dementia,myasthenia gravis. • In this patients, a drug which usually has a wide therapeutic index when given to a relatively healthy individual may have a low therapeutic index. • Opioids may be given safely to healthy patients with a toothache but not to patients with respiratory failure. • Deterioration in critically ill patients should increase ones vigilance and check on interactions.

38. High risk clinical setting • 4.Patients with HIV • They have a high incidence of skin reactions to sulphur drugs than the general population and also at risk of organ failure from a multitude of infections. • They also receive large numbers of new and toxic combinations of drugs.

39. High risk clinical setting • 5.The passive patient • Passive patients often do not know the reason for taking many of their medications.These are the elderly and psychiatric patients. • The elderly are also prone to adverse drug interactions because of a deterioration of homoestatic mechanisms leading to a lower margin of safety for many drugs. • Active patients can sometimes demand that the benefit /risk ratio of the given drugs to be substantially in their favour.

40. High risk clinical setting • 6.Drug abusers • People who abuse drugs are likely to consume alcohol, Tobacco,illegal recreational, prescription and OTC drugs often in large doses. • They are also frequently erratic in their drug taking behaviours-hence drug interactions are more likely to result in adverse effects

41. Prevention of adverse drug interactions • The principles include • 1.Document all drugs including herbal prearations, OTC,recreational drugs that the patient is taking. • 2.Understand the pharmacokinetics and pharmocodymics of the drugs given ,keeping in mind the important mechanisms of drug interations. • 3.Minimize the number of drugs given to any patient and try to ensure that the benefits outweigh the risks for each. • 4.Be particularly vigilant with patients taking low therapeutic index drugs.

42. Prevention of adverse drug interactions cont. • 5.Be cautious in high risk clinical settings.ICU specialists need to remember interactions all the time. • 6.Whenever a patients course deteriorates, look out for a possible adverse drug interaction.IF the deterioration is due to drug therapy,it probably is reversible. • 7.Use textbooks of drug interactions or modern software programs to search for possible drug induced effects you may not have considered. • 8.Always be vigilant for previously undescribed interations,particularly when prescribing new or unfamiliar drugs.

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