DRUG DRUG INTERACTIONSINTERACTIONS

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Ciciliya VJ

Drug interaction can be defined as the modifications of the effects of one drug by the prior, concomitant or subsequently administered another drug .

Drug interactions can be either Harmful or Beneficial.

6.5% of adverse drug reactions in USA were attributed to drug interactions (0.2% of these patients may have life-treatening interactions)

The potential drug interactions has been observed to be 17% in surgical patients, 22% in patients in medical wards, 23% in out patients clinics.

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Today the potential for “DI” is high due to the availability of complex therapeutic agents and wide spread poly pharmacy.

Pharmacist play a valuable role in screening of interaction and advising on management when interactions occur.

This may be at the patient bed side, as part of the dispensing process or during the sale of non-prescription medicine.

A role of current emerging importance is the detection of interactions between medicines and other pharmacologically active therapies,such as herbal and alternative remedies.

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Drug interactions represent 3–5% of preventable in-hospital ADRs

Drug interactions are also an important cause of patient visits to physicians and emergency departments.

Contribution of Drug Interactions Contribution of Drug Interactions to the Overall Burden of to the Overall Burden of

Preventable ADRsPreventable ADRs

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Pharmacokinetic interactions-Absorption-Distribution-Metabolism-Excretion

Pharmacodynamic interactions -Pharmacological Synergism -Pharmacological antagonismPhysiological interactionsPharmaceutical interactions

Mechanism of drug interactionMechanism of drug interaction

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One drug alters the rate or extent of absorption, distribution, metabolism or excretion of another drug.

A change in blood concentration causes a change in the drug’s effect.

Pharmacokinetic Drug Pharmacokinetic Drug InteractionsInteractions

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Important interactions that lead to the modification of drug absorption are largely associated with the GIT.

Interactions in the GIT significantly reduce or increase the amount of drug that absorbed into the body.

Some interactions have been used adventageously with parenteral formulations

eg:- adrenaline (vasoconstrictor)- used to slow the absorption of local anaesthetic to prolong anaesthesia.

Drug AbsorptionDrug Absorption

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Change in gastrointestinal pH -Ketoconazole needs acidic conditions in

gutDrug binding in GI tract -E.g. tetracycline and calciumChange in gastrointestinal flora -Antibiotics with OCs         Change in gastrointestinal motility -Metoclopramide and digoxinMalabsorption caused by other drugs -Orlistat (Xenical) and fat soluble vitamins

Altered AbsorptionAltered Absorption

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CHELATION

Heavy metal ions such as iron,calcium ,magnesium and zinc can bind to anionic medicines like ciprofloxacin and tetracycline. This produce a poorly soluble salt form that does not dissolve quickly.

Ion exchange resins can also bind medicines and prevent absorption.

For example:cholestyramine bind to bile salts and lower serum cholesterol,can bind drugs such as thyroxine,digoxin and warfarin and reduces their absorption.

Therapeutic failure has been reported with these medicines.

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CHANGES IN GI MOTILITY

Some drugs alter the rate of passage of drugs through the GIT.

This commonly changes the rate of absorption. eg: 1)metoclopromide increases the gastro intestinal

motility and more importantly for medicines absorbed under the basic conditions of the duodenum and jejunum,opens pyloric sphincter at the stomach outlet.

Eg : Metoclopromide and paracetamol

2)Metoclopromide and digoxin-by metoclopromide less time for digoxin to dissolve less will be absorbed therapeutic failure can occur

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BOWEL FLORA EFFECT

Some medicines can alter the normal microorganism population in the large intestines;these organism plays important role in the kinetics and action of some drugs

Eg:The modification of bowel bacteria by broad spectrum antibiotics can also indirectly affect the activity of coumarin anticoagulants.

These antibiotic can reduce the population of bowel bacteria that synthesise vit K reduce drug absorbed into the body.

Vit K antagonise the action of coumarin anti coagulants Reducing vit k absorption increase the action of

warfarin,will increase bleeding.

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PROTEIN – BINDING DISPLACEMENT

Interactions altering drug distribution commonly associated with drugs that bound to plasma proteins being displaced by another drug .

concentration of free drug in plasma will increase exposing the drug to the normal elimination,also the levels are rapidly reduced.

eg:displacement of methotrexate or warfarin from protein binding by aspirin or other NSAIDs(phenybutazone).

DRUG DISTRIBUTIONDRUG DISTRIBUTION

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Interaction occurs through the induction or inhibition of drug metabolism.

METABOLIC INDUCTIONOne drug increases the metabolism of

another,will decrease the level of substrate in the body and increase the levels of metabolite.

Eg:- phenytoin phenobarbitone and carbamazepine are potent inducers of cytochrome CYP3A4.

-rifampicin-potent inducer of CYP3A4

METABOLISMMETABOLISM

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METABOLIC INHIBITION Inhibition of drug will increase its plasma

levels with the potential for toxicity or enhanced risk of side effects,if the parent drug is the active species.

decreased metabolism of concomitant drug therefore decreased drug excretion and increased drug effect.

eg:diltiazem inhibit CYP3A4 has been used with cyclosporin.

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DRUG TRANSPORTER INTERACTION

Drug transporter which carry drug across cell membrane into cell and or out of cell.

Eg:1.digoxin erythromycin interaction(P-GLYCOPROTEIN,Inhibition by erythromycin occurs)

2.colchicine is transported by Pgp and verapamil can inhibit the transporter.

GENETIC POLYMORPHISM AND DRUG INTERACTION

Genetic polymorphism occurs with CYP2D6,2C19 but not CYP3A4 or 1A2.

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Drug A increases or reduces the excretion (usually renal) of Drug B.

Blood levels of B fall below or rise above normal therapeutic range.

Becomes either ineffective or toxic.

EXCRETIONEXCRETION

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Drugs eliminated by kidneys – alteration in urinary pH, tubular secretion and rate of glomerular flow can alter the amount of drug that is excreted

Lithium + Thiazide diuretics

Excretion InteractionsExcretion Interactions

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PHARMACOLOGICAL SYNERGISM Synergism occurs when two drugs with a similar

pharmacological or side effects are given together produce an additive effect.

Combination of drugs given for therapeutic advantage

eg:opiates and TCAs-pain control

PHARMACODYNAMIC PHARMACODYNAMIC INTERACTION MECHANISMINTERACTION MECHANISM

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Some combination results in side effects eg:ACE inhibitor with aldosterone

antagonist,spironolactone cause hyperkalemia.

Serious and life threatening is non reversible MAO inhibitor(phenelzine) with SSRI(Sertaline) results in increased neurotransmitter serotonin and precipitate serotonin syndrome.

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PHARMACOLOGICAL ANTAGONISM

One drug prevents the pharmacological action of another

eg: 1)thiazide diuretics+NSAIDs reduce diuretic activity.

2)TCA+Antiepileptics lower the seizure threshold.

3)metoclopromide+levodopa block the beneficial effect of dopamine precursor

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Substrate:Drug is metabolised by the enzyme system

Inducer:Drug that will increase the synthesis of CYP450 enzymes

InhibitorDrug that will decrease the metabolism of a substrate

CYP 450 SystemCYP 450 SystemDefinitionsDefinitions

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CYP2D6

CYP450 NomenclatureCYP450 NomenclatureFamily

Sub-Family

Individual Gene

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CYP = cytochrome P450 2 = genetic family D = genetic sub-family 6 = specific gene

Example : CYP2D6Example : CYP2D6

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Responsible for metabolism of: -Most calcium channel blockers -Most benzodiazepines -Most HIV protease inhibitors -Most HMG-CoA-reductase inhibitors -Most non-sedating antihistamines -Cyclosporine

Present in GI tract and liver

Cytochrome P450 3ACytochrome P450 3A

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Absent in 7-9% of Caucasians, 1–2% of non-Caucasians

Over-expressed in up to 30% of East Africans

Catalyzes primary metabolism of: Codeine Many -blockers Many tricyclic antidepressants Inhibited by: Fluoxetine Haloperidol Paroxetine Quinidine

Cytochrome P450 2D6Cytochrome P450 2D6

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Absent in 1% of Caucasians and African-Americans

Primary metabolism of:- Most NSAIDs (including COX-2)- S-warfarin (the active isomer)- Phenytoin

Inhibited by fluconazole

Cytochrome P450 2C9Cytochrome P450 2C9

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Absent in 20–30% of Asians, 3–5% of Caucasians

Primary metabolism of: Diazepam Phenytoin Omeprazole ClopidogrelInhibited by: Omeprazole Isoniazid Ketoconazole

Cytochrome P450 2C19Cytochrome P450 2C19

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Induced by smoking tobaccoCatalyzes primary metabolism of: Theophylline Imipramine Propranolol ClozapineInhibited by: Many fluoroquinolone antibiotics Fluvoxamine Cimetidine

Cytochrome P450 1A2Cytochrome P450 1A2

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1. Take a medication history (AVOID Mistakes mnemonic)

2. Remember high-risk patients - Any patient taking ≥ 2 medications - Patients treated with anticonvulsants, antibiotics, digoxin,warfarin, amiodarone, etc. 3. Check pocket reference or PDA 4. Consult pharmacists or drug info specialists 5. Check up-to-date computer program -Medical Letter Drug Interaction Program* - www.epocrates.com* and others

Drug-Drug Interaction Prevention: Drug-Drug Interaction Prevention:

A Stepwise ApproachA Stepwise Approach

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Allergies?Vitamins and herbs?Old drugs and OTC? (as well as current)Interactions? Dependence? Do you need a contract?Mendel: Family Hx of benefits or problems

with any drugs?

A Good Medication History:A Good Medication History:AVOID MAVOID Mistakesistakes

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Evaluate drug interaction risk on a patient specific basis.

Offer non interacting alternatives to victim or precipitator drugs wherever possible.

If non interacting alternatives are unavailable, use low risk precipitator drugs and/or find a victim drug with parallel metabolic path ways.

If interacting drug must be used concomitantly take steps to mitigate the interaction such as staggering administration times or changing dosage forms. 31

Monitor the patient if it appears that the chance of interaction is high and the out come is likely to be clinically meaningful

Look at any sudden change in patient status as a potential result of a drug interaction and investigate. Remember that starting or stopping a precipitator drug can affect a victim drug and patient status.

Educate all health care professionals about the potential risks of drug interactions.

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Drug A and Drug B bind to different receptors on the same tissue but give opposite or similar effect Aspirin (anti-platelet) +Warfarin/Coumarin (anticoagulant) Increase bleeding

Physiological InteractionsPhysiological Interactions

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Adrenaline constricts the blood vessels but histamine dilates it

Adrenergics decrease GI motility but cholinergics increases the motility

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Phenytoin precipitates in IV dextrose solutions (e.g., D5W)

AmphotericinB precipitates in IV saline

Gentamicin is physically/chemically incompatible when mixed with most beta-lactam antibiotics, resulting in loss of both antibiotics’ effects

Pharmaceutical InteractionsPharmaceutical Interactions

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Use of wrong vehicle for infusion-no drug addition to blood,plasma,amino acid, fat,emulsions,mannitol,heparin, sod.bicarbonate.

Higly acidic solns.like dextrose,fructose are unsuitable for sod. Or pot. Salts of weakly acidic drugs.

Isotonic saline is suitable for most drugs except NA

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Drug-Food interactionsDrug-Food interactions

• Grapefruit juice and Terfenadine• Grapefruit juice and cyclosporin• Grapefruit juice and felodipine• Grapefruit contains : furanocoumarin

compounds that can selectively inhibit CYP3A4

• Tetracycline and milk products• Warfarin and vitamin K-containing

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Potentially dangerous interaction between drug and food.

eg:MAO inhibitors (phenelzine)with tyramine containing foods results metabolic blockade by phenelzine can precipitate potentially fatal hypertensive crisis.

Some results therapeutic failure eg:phenytoin with enteral feeding

mixture.,decrease GI absorption.High diet fibre increase warfarin activity by

impairing absorption of vit KGrape fruit inhibit GI metabolism of

medicines handled by CYP3A4 isoenzyme.Chilli inhibit substance P and is reported to

increase the incidence of coughing in patients on ACE inhibitor. 38

Ginkgo biloba Drug-Herb interactionsDrug-Herb interactions

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St. John’s wort: CYP3A4 inducerSt. John’s wort: CYP3A4 inducer

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St. John’s Wort with:IndinavirCyclosporineDigoxinTacrolimusPossibly many others

Drug-Herbal InteractionsDrug-Herbal Interactions

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List of the most common interacting drug-Antacids-Cimetidine-Digoxin -Warfarin-Theophylline-Ketoconazole

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Liver diseaseRenal disease Cardiac disease Acute myocardial infarction

Drug-Disease InteractionsDrug-Disease Interactions

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Combination of antihypertensives for the treatment of hypertention.

Combination of antibiotics to treat an infection.

Combination of epinephrine with lidocaine to prolong anesthetic effects.

Combination of statins with ezetimibe to treat dislipidemia.

Antidotes like naloxone and flumazenil .Combination of hypoglycemic agents to

treat diabetes.

Beneficial Effects of Drug Beneficial Effects of Drug InteractionsInteractions

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Beneficial pharmacokinetic interactions are much less compared to pharmacodynamic interactions.

Probenecid with penicillin to elevate pencillin level in serum.

Ketoconazole and diltiazem with cyclosporine or tarcolimus to elevate serum levels of these immunosupresants.

P-glycoprotein inhibitors like clarithromycin,ketoconazole etc may improve the response of protease inhibitors in HIV treatment; improve response to anticonvulsants in refractory epilepsy

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The role of pharmacist in preventing and detecting interaction and providing reliable advice on interaction management can greately add to patient’s safety and wellbeing.

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