Drug-Drug Interactions

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Drug-Drug Interactions:

Drug-Drug Interactions Dr. Najlaa Saadi Ismael Department of Pharmacology college of Medicine - Mosul University of Mosul

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Drug – Drug interaction: It is the modification of the effect of one drug ( the object drug ) By The prior or concomitant administration of another ( precipitant drug ).

Outcomes of drug interactions:

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

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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

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Site of interaction: Outside the body. Inside the body.

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Outside the body: Incompatibilities: reaction of IV drugs resulting in solutions after mixing that are not longer safe for the patient alter stability(change the PH) or structure leading to: Loss of drug activity. Formation of precipitates. Development of toxic product.

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Penicillin and aminoglycoside should never be placed in the same infusion fluid because of formation of inactive complex. Protamine zinc insulin + soluble insulin lead to reduces the immediate effect of the dose. With calcium – ceftriaxone precipitates in the lung and kidneys premature neonates. Pheyntoin with infusion fluids particularly dextrose so care should be taken to follow the manufacture's instruction including the use of an in – line filter.

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Drug Interactions Inside the body Pharmacokinetics drug interactions Pharmacodynamics drug interactions

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Pharmacokinetics drug interactions Involve the effect of a drug on another from the point of view that includes: Absorption. Distribution. Metabolism. Excretion.

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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.

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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 , digoxine and some acidic drugs e.g warfarine + Colestyramine decrease their absorption.

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Altered intestinal bacterial flora Antibiotics kill a large number of the normal flora of the intestine Antimicrobials may potentiates 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 Increase digoxin conc. and increase its toxicity

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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)

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

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

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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 the time of administration.

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

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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 vitamin s

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Interaction other than the gut Addition of vasoconstrictors e.g adrenalin to local anesthetics delay absorption and prolong local anesthesia

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Effect of drug distribution Displacement from plasma protein binding It depends on the affinity of the drug to plasma protein. The most likely bound drugs is capable to displace others. The free drug is increased. Sodium valproates displaces phyentoin from its binding site on plassma albumin in addition to inhibit its metabolism.

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Displacement from tissue bindings Binding Quinidine with digoxin and cause increase concentration of free digoxin in addition to impair renal excretion.

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Altered drug Metabolism The effect of one drug on the metabolism of the other is well documented. The liver is the major site of drug metabolism CYP450 family is the major metabolizing enzyme in phase I (oxidation process).

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Effect on drug metabolism Enzyme induction : the drug called( inducer ) A drug may induce the enzyme that is responsible for the metabolism of another drug or even itself e.g : Carbamazepine (antiepileptic drug ) increases its own Metabolism Phenytoin increases hepatic metabolism of Oral Contraceptives Leading to decreased level Reduced action and Unplanned Pregnancy Phenobarbital + warfarin increase metabolism of warfarin (danger of thrombosis)

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Most important enzyme inducers: Carbamazipine . Phenytoin . Phenobarbital. Rifampicine .

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Enzyme inhibition: It is the decrease of the rate of metabolism of a drug by another one. This will lead to the Increase of the concentration of the target drug and leading to the increase of its toxicity . Cimetidine + Theophylline cimetidine reduces the clearance of theophylline causing an increase in adverse effects

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Quinolones (Ciprofloxacin) + Theophylline Inhibit oxidative metabolism of theophylline

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Inducer ( carbamazepine ) + Inhibitor ( verapamil ) The effect of the Inhibitor will be predominant

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Most important enzyme Inhibitors Cimetidine . Erythromycine . Quinolones . Sodium valproate .

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

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

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Active tubular secretion: It occurs in the proximal tubules. The drug combines with a specific protein to pass through the proximal tubules. When a drug has a competitive reactivity to the protein that is responsible for active transport of another drug This will reduce such a drug excretion increasing its conce . probenecid + penicillin Decreases tubular secretion of Pecicillin

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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

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Pharmacodynamics Interaction 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

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Results of drug interactions: Synergism: occures when the effects of 2 drugs having the same action or increase the actionof another drugs 1. Summation(Additive): Ex. β- adrenoceptor blocker + thiazide additive anti hypertensioneffect 1 + 1 = 2 2. Potentiation : When one drug Increase the action of another 1 + 1 = more than 2 Ex. Trimethprim + sulfamethaxazole

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Antagonism When the action of one drug opposes the action of another. 1 + 1 = 0 (or 0.5) Ex. Histamine and Adrenaline on Bronchi(physiological antagonism) Flumazenil and diazepam they compete reversibly for the same drug receptor( competitive antagonism )

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Interactions directly on Receptor or body system Actions on receptors Beneficial interaction Naloxone for morphin over dose( opiod receptor) Unwanted interaction Atenolol +cold remedies containing ephedrine or Phenylephrine loss of antihypertensive effect

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Action on body system NSAIDs especially indomethacin + α adrenoicepter blocker lead to loss some antihypertensive efficacy By inhibition of production of vasodilator prostpglandins by the kidney leading to sodium retention

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Onset of drug interaction It may be seconds up to weeks. For example in case of enzyme induction, it needs weeks for protein synthesis. while enzyme inhibition occurs rapidly.

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Thank you For Attention

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