1 DRUG – DRUG INTERACTIONS Dr.Abdul latif Mahesar King Saud University May 2009

2 DRUG – DRUG INTERACTION when one drug is administered, a response occurs, if a second drug is given and response to 1 st drug is altered,a drug interactions is said to have occurred when one drug is administered, a response occurs, if a second drug is given and response to 1 st drug is altered,a drug interactions is said to have occurred This may beThis may be Desired or beneficialDesired or beneficial e.g. Multi drug treatment of T.B e.g. Multi drug treatment of T.B Naloxone to treat Morphine overdose Undesired or harmful Undesired or harmful aspirin and warfarin aspirin and warfarin

3 Clinically important drug interactionsClinically important drug interactions 1. Drugs that have steep dose response curve and small therapeutic index, small change in concentration at site will lead to substantial changes in effect.1. Drugs that have steep dose response curve and small therapeutic index, small change in concentration at site will lead to substantial changes in effect. e.g. Digoxin, Lithium 2. Drugs that are known enzyme inducers/inhibitors

4 3. Drugs that exibit saturable metabolism e.g. Phenytoin, Theophylline e.g. Phenytoin, Theophylline 4. Drugs used for prolong period and precise plasma concentration are required e.g. oral contraceptive, antiepileptic drugs, lithium e.g. oral contraceptive, antiepileptic drugs, lithium 5.Different drugs used to treat same disease e.g. Theophylline, Salbutamol 6. In patients with impaired kidney and liver functions 7. In elderly who receive several drugs at the same time 7. In elderly who receive several drugs at the same time

5 PHARMACODYNAMIC INTERACTIONS Both drugs act at same target site exerting synergism or antagonism Both drugs act at same target site exerting synergism or antagonism Drugs may act at same or different receptors or process. Drugs may act at same or different receptors or process. eg alcohal + benzpdiazepines (sedation) eg alcohal + benzpdiazepines (sedation) Morphine + Naloxone ( to reverse opioid overdose) Morphine + Naloxone ( to reverse opioid overdose) Rifampicin + INH ( effective anti TB combination.) Rifampicin + INH ( effective anti TB combination.)

6 PHARMACOKINETIC INTERACTIONS Drug act remotely from target site to alter plasma concentration Drug act remotely from target site to alter plasma concentration e.g. enzyme induction /inhibition interaction may be synergistic or antagonistic. interaction may be synergistic or antagonistic. Drug interaction can occur at Drug interaction can occur at 1. out side the body 2. At site of absorption 3. During drug distribution 4. During drug metabolism 5. During drug excretion. 6. On receptor or body system.

7 Interaction out side the body Drugs are added to reservoir or syringes to make drugs soluble they are prepared in salt forms, mixing these drugs may lead to precipitation (incompatibility) Drugs are added to reservoir or syringes to make drugs soluble they are prepared in salt forms, mixing these drugs may lead to precipitation (incompatibility) Dilution in reservoir may also lead to loss of stability. Dilution in reservoir may also lead to loss of stability. Protamine in zinc insulin may bind with soluble insulin and delay its effects. Protamine in zinc insulin may bind with soluble insulin and delay its effects.

8 AT THE SITE OF ABSORPTION Direct chemical interactionDirect chemical interaction e.g. Antacids + Tetracycline's,Iron form insoluble complexes,this can be prevented if drugs are administered at 2hrs apart. Gut motility: drugs which reduce gastric emptying delay absorption of other drugs Gut motility: drugs which reduce gastric emptying delay absorption of other drugs e.g anti cholinergics, antidepressants e.g anti cholinergics, antidepressants.

9 Purgatives reduce time spent in small intestine and reduce absorption.Purgatives reduce time spent in small intestine and reduce absorption. Alteration in gut flora: antimicrobials potentiates ant coagulants by reducing bacterial synthesis of vit.K Alteration in gut flora: antimicrobials potentiates ant coagulants by reducing bacterial synthesis of vit.K Other than gut : Local anesthetics (xylocaine) and adrenaline.Other than gut : Local anesthetics (xylocaine) and adrenaline.

10 DURING DISTRIBUTION Displacement from plasma proteins bindingDisplacement from plasma proteins binding e.g. Sodium valproate displaces Phenytoin Sulphonamides displaces bilirubin ( in neonates) Displacement from tissue binding sites Displacement from tissue binding sites e.g. Quinidine displaces Digoxin

11 Interaction during metabolism Enzme induction:Enzme induction: liver micsrosomal enzymes are induced by a wide variety of drugs and these affect the metabolism of other drugs reducing their concentration and hence effect. liver micsrosomal enzymes are induced by a wide variety of drugs and these affect the metabolism of other drugs reducing their concentration and hence effect. e.g oral contraceptive metabolism is enhanced if Phenytoin is co-administered,leading to unplanned pregnancy e.g oral contraceptive metabolism is enhanced if Phenytoin is co-administered,leading to unplanned pregnancy eg loss of anticougulant effect of Warfarin leading to danger of thrombosis if barbiturates are administered. eg loss of anticougulant effect of Warfarin leading to danger of thrombosis if barbiturates are administered. chronic use of alcohal shows tolerance to general anesthetics. chronic use of alcohal shows tolerance to general anesthetics.

12 Enzyme inhibition Certain drugs inhibit the liver microsomal enzymes,hence increase the activity of drugs which are to be metabolized by these enzymes. Certain drugs inhibit the liver microsomal enzymes,hence increase the activity of drugs which are to be metabolized by these enzymes. Eg. Cimetidine potenciates the effects of propranolol,theophylline, warfarin and othersEg. Cimetidine potenciates the effects of propranolol,theophylline, warfarin and others

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14 Enzyme inducers. PhenobarbitalPhenobarbital Rifampin Rifampin Grisofulvin Grisofulvin Phenytoin Phenytoin Ethanol Ethanol Carbamazepine Carbamazepine

15 Enzyme inhibitors PhenylbutazonePhenylbutazone Metronidazole Metronidazole Cimetidine Cimetidine Omperazole Omperazole

16 Interaction during excretion this occurs in kidneythis occurs in kidney by latering binding and hence filtration by latering binding and hence filtration by inhibitin tubular secretion by inhibitin tubular secretion eg probenecid and pencillins eg probenecid and pencillins by latering urine flow and or urine PH. by latering urine flow and or urine PH.

17 Haemodynamic flow variation in heaptic blood flow may influence the rate of inactivation of drugs as in reduced cardiac out put.variation in heaptic blood flow may influence the rate of inactivation of drugs as in reduced cardiac out put. drugs which reduce cardiac out put like Propranolol may reduce the metabolism of other drugs. drugs which reduce cardiac out put like Propranolol may reduce the metabolism of other drugs.

18 -Pharmacodynamics: synergism/ antagonism - interaction may lead to toxicity (concurrent administration of 2 nephrotoxic drugs can produce kidney damage) -In vitro due to their chemistry. As thiopental + suxamethonium, must not be mixed in same syringe because of formation of insoluble complex. (called incompatibility)

19 Drug interaction can make medications more effective or may decrease the effectiveness or they can cause unexpected & potentially dangerous (harmful) Side effects OR can be useful as multi drug Treatment as in (TB, AIDS).

20 If one drug changes RATE at which other drugs move from stomach to small intestine, their rate of absorption into blood will be affected.If one drug changes RATE at which other drugs move from stomach to small intestine, their rate of absorption into blood will be affected. If one drug changes level of ACIDITY in stomach, absorption of other drugs may change.If one drug changes level of ACIDITY in stomach, absorption of other drugs may change. If one drug binds to another, neither may be absorbed at all.If one drug binds to another, neither may be absorbed at all.

21 Atropine & opiate; inhibit the gastric emptying; and hence slows the absorption of the drugs from GIT Antacids, Ca ++ & Iron form an insoluble complex Tetracyclin & retard its absorption; thereby reducing effectiveness of the drug in fighting infection. Colestyramine, a bile acid-binding resin, binds to warfarin/ digoxin/ diuretics, prevent their abs.??? Adrenaline + LA; slow its abs & prolongs its local effect.

22 B- Drug may alter drug distribution: Mechanisms: -Competition for plasma protein binding -Displacement from tissue binding sites -Alterations in local tissue barriers (P-glyco proteins inhibition in BBB).

23 -Displacement from tissue binding sites would tend to transiently increase blood concentration of !displaced drug. This effect is transient because of compensatory increase in drug disposition. When one displacing drug additionally reduces elimination of the 1 st drug, so that free concentration is increased not only acutely but also chronically at new steady state, severe toxicity may occur.When one displacing drug additionally reduces elimination of the 1 st drug, so that free concentration is increased not only acutely but also chronically at new steady state, severe toxicity may occur.

24 Salicylates displace methotrexate from albumin and also reduce its secretion into nephron by competition with anion secretory carrier. Quinidine, verapamil, & amiodarone displace digoxin from tissue binding sites & reduce its renal excretion leading to digoxin toxicity

25 Drugs metabolism:Drugs metabolism: Drugs can either inhibit/ induce drug-metabolizing enzymes. Enzyme inducers (stimulation of cytochrome P450 in liver): requires some days -Barbiturates -Ethanol -Carbamazepine?? -Phenytoin -Rifampicin?? -Efavirenz?? -They also increase glucuronidation (phase II) metabolism

26 Enzyme inhibitors: (inhibit cytochrome P450); more quickly than enzyme induction -Amiodarone -Androgen?? -Chloramphenicol -Cimetidine; decrease warfarin metabolism -Ciprofloxacin, clarithromycin, erythromycin -Cyclosporine, ??isoniazide,?? ketoconazole, -Delavirdine?? -Disulfiram. ؟؟

27 Renal excretion:Renal excretion: - Renal excretion of weak acid/base may be influenced by drugs that affect urinary pH ionization ex. Antacids (Mg/ Al- OH) alkalinize urine thus increase renal Clearance of salicylates.

28 Inhibition of active tubular secretion of some drugs & inhibition of renal transporter (P-glycoproteins ) can inhibit renal excretion & increase serum drug concentration. Ex. Probenecid inhibit renal tubular secretion of penicillin & increase its blood level Other drugs may be directly toxic to kidneys, reducing their function & resulting in higher levels of drugs.Other drugs may be directly toxic to kidneys, reducing their function & resulting in higher levels of drugs.

29 Pharmacodynamic interactions: ! 2 drugs may / may not act on the same R to produce DI.Pharmacodynamic interactions: ! 2 drugs may / may not act on the same R to produce DI. -β-adrenoceptor antagonists diminish ! effectiveness of β - agonist (salbutamol) -Many diuretics causes hypokalemia, w predispose digoxin tox?? -MAOIs increase ! amounts of adrenaline & aggravate ! effect of ephedrine/ tyramine -Bleeding increase in GIT if warfarin + aspirin -NSAID inh biosynthesis of PGs that cause renal vasoD/ natriuretics;; HTN.

30 OTC medications can also interact e Rx medication. Some examples of this type of interaction include: Antihistamines, often used for allergies & colds, can increase ! sedative effects of barbiturates, tranquilizers, & some Rx pain relievers.Antihistamines, often used for allergies & colds, can increase ! sedative effects of barbiturates, tranquilizers, & some Rx pain relievers. Decongestants in cold & cough medications can interact e antihypertensive drugs to aggravate high BP.Decongestants in cold & cough medications can interact e antihypertensive drugs to aggravate high BP.

31 Mixing antidiabetic medication (e.g., oral hypoglycemics) & β blockers (e.g., Inderal) can decrease ! response of ! antidiabetic drug?? & increase frequency & severity of hypoglycemia episodes.Mixing antidiabetic medication (e.g., oral hypoglycemics) & β blockers (e.g., Inderal) can decrease ! response of ! antidiabetic drug?? & increase frequency & severity of hypoglycemia episodes. Bec: (increase in heart rate & in BP are masked e prop).

32 Other types of drug interactions Other types of drug interactions Drug effects can be additive (effect + effect = double effect); Potentiation means that drug A boosts ! effects of drug B, often by increasing ! levels of drug B in ! blood.Drug effects can be additive (effect + effect = double effect); Potentiation means that drug A boosts ! effects of drug B, often by increasing ! levels of drug B in ! blood. Synergism (effect + effect = > than double effect); = 5. can be beneficialSynergism (effect + effect = > than double effect); = 5. can be beneficial Antagonistic (effect vs effect = < than double effect).Antagonistic (effect vs effect = < than double effect).