Prepared ByDr ShaheenDelivered ByDr Naser
It is the modification of the effect of one drug (the object drug ) by the prioror concomitantadministration ofanother(precipitant drug).
Poly pharmacyMultiple prescribersMultiple pharmaciesGenetic make upSpecific population like. elderly, obese,criticalyill patientSpecific illness E.g. Hepatic disease,Renaldysfunction,Narrow therapeutic index drugsDigoxin, Insulin, Lithium , Antidepressant, Warfarin
Loss of therapeutic effectToxicityUnexpected increase in pharmacological activityBeneficial effectse.gadditive & potentiation (intended)orantagonism (unintended).5) Chemical or physical interactione.gI.V incompatibility in fluid or syringes mixture
Mechanisms of drug interactions
Pharmacokineticsinvolve the effect of a drug on another drug kinetic that includesabsorption ,distribution , metabolismand excretion.
Pharmacodynamicsare related to the pharmacological activity of the interacting drugsE.g., synergism , antagonism, altered cellular transport effecton the receptor site.
1) Altered GIT absorption.
Altered pHAltered bacterial floraformation of drug chelates or complexesdrug induced mucosal damagealtered GIT motility.
Altered pH;The non-ionized form of a drug is more lipidsoluble and more readily absorbed from GIT than theionized form does.
Decreasethe tablet dissolutionofKetoconazole(acidic)
Therefore, these drugs must be separated by at least 2hin the time of administration of both .
b)Altered intestinal bacterial flora ;EX.,40% or more of the administereddigoxindose ismetabolised by the intestinal flora.
Antibioticskill a large number of the normalflora of the intestine
Increasedigoxinconc.and increase its toxicity
c) Complexation or chelation;
Ex2.,Antacid(aluminum or magnesium) hydroxide
Decrease absorption ofciprofloxacin by 85%due to chelation
d) Drug-induced mucosal damage.Antineoplastic agentse.g., cyclophosphamidevincristineprocarbazine
Inhibit absorptionof several drugseg.,digoxin
e) Altered motility
Increase absorption of cyclosporine dueto the increase of stomach empting time
Increase the toxicityof cyclosporine
f) Displaced 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 by displacement by another drugwith higher affinity.
Phenytoin is a highly bound to plasma protein (90%),Tolbutamide (96%), and warfarin (99%)
Drugs that displace these agents areAspirinSulfonamidesphenylbutazone
g) Altered metabolismThe effect of one drug on the metabolism of theother is well documented. The liver is the major site of drugmetabolism but other organs can also do e.g., WBC,skin,lung,and GIT.
CYP450 family is the major metabolizing enzymein phase I (oxidation process).
Therefore, the effect of drugs on the rate of metabolismof others can involve the following examples.
E.g., Enzyme inductionA drug may induce the enzyme that is responsiblefor the metabolism of another drug or even itself e.g.,
Carbamazepine(antiepileptic drug ) increases its ownMetabolism.
Phenytoin increases hepatic metabolism of theophyllineLeading to decrease its level
Reduces its actionandVice versa
N.B enzyme induction involves protein synthesis .Therefore,it needs time up to 3 weeks to reach a maximal effect
Eg., Enzyme inhibition;It is the decrease of the rate of metabolism of a drug byanother one .This will lead to the increase of the concentration of the target drug and leading to the increase of its toxicity .
Inhibition of the enzyme may be due to the competitionon its binding sites , so the onset of action is shortmay be within 24h.
When an enzymeinducer( e.g.carbamazepine) is administered with aninhibitor(verapamil)
The effect of theinhibitor will bepredominant
Ex.,Erythromycin inhibit metabolism ofastemazole and terfenadine
Increase the serum conc.of the antihistaminic leading toincreasing the life threateningcardiotoxicity
Onset of drug interactionIt may be seconds up to weeks for example in caseof enzyme induction, it needs weeks for protein synthesis,while enzyme inhibition occurs rapidly.
Active tubular secretionIt occurs in the proximal tubules.The drug combines with a specific protein to pass throughthe proximal tubules.When a drug has a competitive reactivity to the protein that isresponsible for active transport of another drug .This will reducesuch a drug excretion increasing its con. and hence its toxicity.
Decreases tubular secretion ofmethotrexate.
* Passive tubular reabsorption;
Excretion and reabsorption of drugs occur in the tubulesBy passive diffusion which is regulated by concentrationand lipid solubility.
Ionized drugs are reabsorbed lower than non-ionized ones
Increaseslithiumclearanceand decreases its action
Increases salicylates clearance and decreases its action
It means alteration of the dug action without change in itsserum concentration by pharmacokinetic factors.
EX.,Propranolol + verapamil
Synergistic or additiveeffect
Additive effect : 1 + 1 =2Synergistic effect : 1 +1 > 2Potentiation effect : 1 +0 =2Antagonism : 1-1 = 0
Grapefruit juice and TerfenadineGrapefruit juice and cyclosporinGrapefruit juice and felodipineGrapefruit contains : furanocoumarin compounds that can selectively inhibit CYP3A4
Changes in diet may alter drug action
Theophylline: a high protein, low CHO diet can enhance clearance of this and other drugsMAO inhibitorsWarfarin (anticoagulant)Alcohol with CNS-suppressant drugs may produce excessive drowsinessPhenytoin increases metabolism of vitamin D, vitamin K, and folic acid.Carbamazepine may affect metabolism of vitamin D, and folic acid, leading to possible depletion
Management of an adverse interaction
Dose related events may be managed by changing the dose of the affected drug.Eg.,when miconazole oral gel causes an increase in bleeding time of warfarin then reducing the warfarin dose will bring the bleeding time back into range and reduce the risk of haemorrhageIt is important to retitrate the dose of warfarin when the course of miconazole is complete.
The potential severity of some interaction require immediateCessation of the combination.Eg,.the combination of erythromycin and terfenadine can produse high terfenadine level with the risk of developing Torsades de Pointes.Dose spacing is appropriate for interaction involving the inhibition of absorption in the GI tract .Eg.,avoidig the binding of ciprofloxacin by ferrous salts