Dr. DATTEN BANGUN MSc,SpFKBagian Farmakologi dan Terapeutik,Fakultas KedokteranUniversitas Sumatera UtaraDRUG INTERACTIONS

CONCEPT :Drug interactions involve changes in the duration or intensity of a drugs action caused by the presence of another drug.

Drug interaction : desirable undesirable =adverse drug interaction.

Defining a Drug InteractionA measurable modification (in magnitude or duration) of the action of one drug by prior or concomitant administration of another substance.Drug-drug (Rx, OTC, herbal)Drug-food, drug-alcoholDrug-lab, drug-disease, drug-chemicalWright 1992. Drug Interactions. In: Melmon and Morrellis Clinical Pharmacology 1992

Mechanism of drug interactionPharmacokinetic interactionsAbsorptionDistributionBiotransformation***ExcretionPharmacodynamic interactionsReceptor interactionReceptor sensitivityNeurotransmitter release/Drug transportationElectrolyte balancePhysiological interactionsPharmaceutical interactions

Three Phases of Drug ActionI. PHARMACEUTICAL PHASE

II. PHARMACOKINETIC PHASE

III. PHARMACODYNAMIC PHASE

I. PHARMACEUTICAL PHASE

A solid drug (tablet) has to disintegrate before it can be absorbed The process where a solid (tablet) goes into solution is known as dissolution ALL drugs must be in solution to cross biologic membranes

II. PHARMACOKINETIC PHASE What the body does to the drug- refers to the study of how the body processes drugs .Movement of drugs through the bodyIt includes the 4 basic components of : 1. Absorption 2.Distribution3. Metabolism (Biotransformation) 4. Excretion

III. PHARMACODYNAMIC PHASEWhat a drug does to the body- refers to the study of the mechanism of drug action on living tissue. Drugs may increase, decrease or replace enzymes, hormones or body metabolic functions. Chemotherapeutic drugs alter an abnormal parasite or growth on the body such as bacteria, viruses or neoplastic tissue. examples: antibiotics and antineoplastic drugs.

DRUG DRUG INTERACTION When one drug is administered, a response occurs, if a second drug is given and response to other drug is altered , a drug interactions is said to have occurred

This effect may be I.Desired or beneficial (efficacy without in toxicity) e.g. Multi drug treatment of T.BAmoxicillin + clavulanic acidL-Dopa + CarbidopaNaloxone to treat Morphine overdose*

DRUG DRUG INTERACTION II. Undesired or harmful (toxicity is with in efficacy) Aspirin and Warfarin Propranolol + Salbutamol Paracetamol + Alcohol Gentamycin + loop diuretics

*

DRUG INTERACTIONS

CLASSIFIED AS: ENHANCED EFFICACYA) USEFUL WITHOUT TOXICITY

TOXICITYB) HARMFUL EFFICACY

Drug-Drug interaction may alter drug effect byAdditive effect : 1 + 1 =2Synergistic effect : 1 +1 > 2Potentiation effect : 1 + 0 =2Antagonism : 1-1 = 0

Mechanism of drug interactionPharmacokinetic interactionsAbsorptionDistributionBiotransformationExcretionPharmacodynamic interactionsReceptor interactionReceptor sensitivityNeurotransmitter release/Drug transportationElectrolyte balancePhysiological interactions---- adrenalin in alergic reactionPharmaceutical interactions

Risk Factors for Drug InteractionsHigh Risk PatientsElderly, young, very sick, multiple diseaseMultiple drug therapyRenal, liver impairmentHigh Risk DrugsNarrow therapeutic index drugsRecognised enzyme inhibitors or inducers

Intravenous Nutrition CompatibilityContain many ingredientsAmino acids, dextrose, lipids, electrolytes, vitamins and trace elementsIssues of compatibility can be significant. Precipitates can occur.Many patients receive medications simultaneously. Watch for pH: change in color or clarity

Lipid CompatibilityMany institutions mix lipid in same container with other ingredientsLipid is an oilinwater emulsionElectrolytes destabilize the emulsionFat droplets aggregateClog blood vessels form emboli

Intravenous CompatibilitypH - acid base interactions Concentration - Vancomycin and ceftazidime.Crystal formation Ascorbic AcidPrecipitate formation Ca + PO4

PharmacokineticsMovement of drugs in the bodyFour ProcessesAbsorptionDistributionMetabolismExcretion Drug concentration at sites of action influenced by several factors, such as:Route of administrationDoseCharacteristics of drug molecules (e.g., lipid solubility)

II. Pharmacokinetic interactionsInteractions at the A D M E levelAbsorption(impact on total absorption or time-profile)Chemical/physico-chemical interaction (viz previous slide)Drugs affecting GIT motility: Absorption is decreased by laxatives (purgatives) increased passage through GIT (small intestine) may affect absorption of drug with slow and/or low absorptionSlowed absorption antimuscarinics may decrease the emptying of stomach

Pharmacokinetic interactions1) Altered GIT absorption.Altered pH, Altered bacterial flora, formation of drug chelates or complexes, drug induced mucosal damage and altered GIT motility.Altered pH; The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form does. -------Handerson-Hasselbalch Equation

Ex1., antiacids Decrease the pHDecrease the tablet dissolution of Ketoconazole (acidic)Ex2., H2 antagonistspHTherefore, these drugs must be separated by at least 2hours in the time of administration of both .

b) Altered intestinal bacterial flora ;EX., In 10% 0f patients receive digoxin..40% or more of the administered dose is metabolized by the intestinal floraAntibiotics kill a large number of the normal flora of the intestineIncrease digoxin conc. and increase its toxicity

c) Complexation or chelation;EX1., Tetracycline interacts with iron preparations orMilk (Ca2+ )Unabsorpable complexEx2., Antacid (aluminum or magnesium) hydroxide Decrease absorption of ciprofloxacin by 85% due to chelation

d) Drug-induced mucosal damage.Antineoplastic agents e.g., cyclophosphamide vincristineprocarbazine Inhibit absorption of several drugseg., digoxine) Altered motilityMetoclopramide (antiemitic)Increase absorption of cyclosporine due to the increase of stomach emptying timeIncrease the toxicityof cyclosporine

DistributionDisplacement from tissue proteins: = quinidine may displace digoxine (in addition to decease of its renal excretion) -----digoxine intoxication

Protein BindingDrug DisplacementPlasmaTissueDrug Aprotein boundDrug AfreeDrug AfreeDrug BDrugs A and B both bind to the same plasma protein

Displaced protein bindingIt 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 drug with higher affinity. Phenytoin is a highly bound to plasma protein (90%), Tolbutamide (96%), and warfarin (99%)Drugs that displace these agents are AspirinSulfonamidesphenylbutazone

II. Pharmacokinetic interactionsMetabolisms (biotransformation)Impact on cytochrome P450There are different isoforms of CYP450The most important are CYP450 3A4, 2D6 (the drugs which are substrates can be found in tables)

Altered metabolismThe effect of one drug on the metabolism of the other is well documented. The liver is the major site of drug metabolism but other organs can also do e.g., WBC,skin,lung, and GIT.CYP450 family is the major metabolizing enzyme in phase I (oxidation process). Therefore, the effect of drugs on the rate of metabolism of others can involve the following examples.

CYP 450 SystemDefinitionsSubstrate: Drug is metabolised by the enzyme system

Inducer: Drug that will increase the synthesis of CYP450 enzymes

Inhibitor Drug that will decrease the metabolism of a substrate

CYP450 NomenclatureCYP2D6FamilySub-FamilyIndividual Gene

Enzyme Induction Leads to production of more enzyme, usually after 3-4 days of exposure to inducer-----drug metabolismMost CYPs are inducible but not CYP2D6Time course of interaction depends on half-life of inducer.

EX1., Enzyme inductionA 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------ tolerancePhenytoin increases hepatic metabolism of theophyllineLeading to decrease its level Reduces its actionand Vice versaN.B enzyme induction involves protein synthesis .Therefore, it needs time up to 3 weeks to reach a maximal effect

Induction: So whats the big deal?Increased P450 activity can increase metabolism of substrates and lead to decreased levels and effects of substratesClinical concern Subtherapeutic levels can lead to decreased/lack of efficacy, e.g. with ARVs decreased levels can lead to viral resistance!Ex:Phenobarbitone increase the metabolism of estrogen-(active substance in oral contraceptive)-----its blood level decreases---- spotting or even pregnant

Enzyme InductionRifampicin has short half-life and induction apparent with 24 hours

Phenobarbitone has longer half life so time to complete induction takes longerCarbamazepineCigarette smoke

EX2., 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 .Inhibition of the enzyme may be due to the competitionon its binding sites , so the onset of action is short may be within 24h. N.B; When an enzyme inducer (e.g.carbamazepine) is administered with an inhibitor (verapamil) The effect of the inhibitor will be predominant

Enzyme InhibitionOften rapid, reversible and relatively short acting. E.g. erythromycin and cyclosporin NB erythromycin is a substrate and an inhibitor of CYP 3A4

May be prolonged due to long half- life of drug. E.g. amiodarone and S-Warfarin NB amiodarone is an inhibitor of CYP2C9 but not a substrate for this CYP

Inhibition: So whats the big deal?Inhibition decreases P450 activity, which can decrease metabolism/clearance of substrates and lead to increased levels and effects of substratesClinical concern-- Increased effects can mean increased risk of toxicities!

II. Pharmacokinetic interactionsExcretion : mainly renalInhibition of tubular secretion Uricosuric drug probenecid decrease tubular secretion of some drugs, e.g. Penicilins, -Decreases tubular secretion of methotrexate.Thiazide diuretics cause relative Na+ depletion and thereby they indirectly increase Li+ reabsorbtion Decreased renal clearence of Li+ = CNS toxicity

Excretion mainly renalInhibition of tubular reabsorbtion: Decreased reabsorption of sulfonamides during concomitant administration of acidic drugs (e.g. Vitamin C) and aspirin in particular

Excretion Interaction

Change in renal blood flow Methotrexate and NSAIDs

NSAIDS can decrease renal blood flow by inhibition of renal prostaglandins. Reduced clearance of MTX and active (toxic) metabolite

* Passive tubular reabsorption;Excretion and reabsorption of drugs occur in the tubules By passive diffusion which is regulated by concentration and lipid solubility.N.B., Ionized drugs are reabsorbed lower than non-ionized ones Ex1., Sod.bicarb. Increases lithium clearance and decreases its actionIncreases excretion of jengkolic acidEx2., Antacids Increases salicylates clearance and decreases its action

III. PHARMACODYNAMIC PHASEWhat a drug does to the body- refers to the study of the mechanism of drug action on living tissue. Drugs may increase, decrease or replace enzymes, hormones or body metabolic functions. Chemotherapeutic drugs alter an abnormal parasite or growth on the body such as bacteria, viruses or neoplastic tissue. examples: antibiotics and antineoplastic drugs.

THEORY OF DRUG-RECEPTOR INTERACTIONS

The majority of drugs are believed to exert their effects by combining with a specialized area on the cell or within the cell called receptors. Drug + Receptor Drug receptor (binding) = ResponseA drug receptor may be on the cell surface or within the cell Receptors come in many shapes that are specific for particular drugs.The greater the degree of specificity and selectivity for receptors, the fewer undesirable side effects and the greater drug efficacy.

Pharmacodynamic interactionsReceptor interactionCompetitiveNon-competitiveSensitivity of receptorNumber of receptorAffinity of receptorAlter neurotransmitter release /drug transportationAlter water/electrolyte balance

Pharmacodynamic interactionsReceptor interactionCompetitiveNon-competitiveSensitivity of receptorNumber of receptorAffinity of receptorAlter neurotransmitter release /drug transportationAlter water/electrolyte balance

Pharmacodynamic Interaction

Drug A alters the effect of Drug B without a change in concentration of Drug B

Pharmacodynamic interactions;It means alteration of the dug action without change in its serum concentration by pharmacokinetic factors.EX., Propranolol + verapamil Synergistic or additive effect

Pharmacodynamic InteractionsBenzodiazepines(and antihistamines, anticonvulsants, barbiturates)AlcoholCNS depressantCNS depressantAdditive CNS depressionRespiratory depression, hypotension, coma

Pharmacodynamic interactionsOften take a 2 - agonist (salbutimol) to induce broncodilationOften take blockers (propanolol) to reduce heart, rate force of contraction

AsthmaticsHypertensionDiminished effect of 2 - agonist

Pharmacodynamic interactionsAntidepressantsSympathomimeticsMonoamine Oxidase Inhibitors (MAOIs) Inhibit breakdown ofNoradrenaline DopamineDecongestants (pseudoephidrine)Asthma (salbutimol)Foods rich in tyramine Beer, Hot Dogs, Wine, BeansMAOIs enhance effects of these drugs (pseudoephidrine and salbutimol)And enhance the action of tyramine

Pharmacodynamic InteractionsNSAIDsAntihypertensivesFor inflammation/ headache.Most block Prostaglandin synthesis.

PGE2 and PGI2 cause renal arteriolar dilation1 Antagonist 1 AntagonistAngiotensin Converting Enzyme (ACE) InhibitorsDiuretics

Loss of ability to dilate renal arterioles (via PGE2 and PG2) can lead to hypertensive crisis in people taking antihypertensives

PHARMACODYNAMIC INTERACTIONS:

BY ALTERING DRUG RECEPTOR SITES OR BY SECONDARY PHARMACOLOGICAL MECHANISMS

MAY BE SYNERGISTIC.

SYNERGISTIC PHARMACODYNAMIC DRUG INTERACTIONS

DRUG

INTERACTS WITH

RESULTS IN

TUBOCURARINE

AMINOGLYCOSIDES

QUINIDINE

PROCAINE

PROLONGED

PARALYSIS

ORAL

HYPOGLYCAEMICS

SALICYLATES

PROPRANOLOL

EXCESSIVE

HYPOGLYCAEMIA

DIGITALIS

PROPRANOLOL

GUANETHIDINE

VERAPAMIL

BRADYCARDIA

ANTIHYPERTENSIVES

DIURETICS

ENHANCED

HYPOTENSION

DRUG INTERACTIONS MAY BE ANTAGONISTIC

PRIMARY DRUG

INTERACTS WITH

RESULTING IN

SALBUTAMOL

-PROPRANOLOL

ANTIAGONISM OF

BRONCHODILATION

ANTIHYPER-

TENSIVES

-NSAIDS

ANTAGONISM OF

HYPOTENSIVE

EFFECT (Na+ -

RETENTION)

- SELECTIVE COX 2

INHIBITORS

NO SIGNIFICANT EFFECTS ON Na

SULPHONAMIDES

-L. ANAETHETICS

-(PABA)

ANTAGONISM OF

ANTIMICROBIAL

EFFECTS

WARFARIN

OESTROGENS

WARFARIN EFFECT

ANTAGONIZED BY

INCREASED

CLOTTING FACTOR

SYNTHESIS

OPIOIDS

NALOXONE

ANTAGONISM

Pharmacodynamic Drug Interactions in Palliative CareAnticholinergic effectsConstipationLowered seizure threshold Serotonin syndromeCNS depressionQTc prolongation

Food-Drug Interactions

Definition of TermsDrug-nutrient interaction: the result of the action between a drug and a nutrient that would not happen with the nutrient or the drug alone

Food-drug interaction: a broad term that includes drug-nutrient interactions and the effect of a medication on nutritional status

Food-Drug InteractionFor example, a drug that causes chronic nausea or mouth pain may result in poor intake and weight loss

Therapeutic ImportanceTherapeutically important interactions are those that:Alter the intended response to the medicationCause drug toxicityAlter normal nutritional status

Patients at Risk for Food-Nutrient InteractionsPatient with chronic diseaseElderlyFetusInfantPregnant womanMalnourished patientAllergies or intolerances

Food and Drug-Related Risk FactorsSpecial dietsNutritional supplementsTube feedingHerbal or phytonutrient productsAlcohol intakePolypharmacyDrugs of abuseNon-nutrients in foodsExcipients in drugs or food

Food/Nutrient Effects on DrugsAbsorptionPresence of food and nutrients in intestinal tract may affect absorption of drugAntiosteoporosis drugs Fosamax or Actonel: absorption negligible if given with food; 60% with coffee or orange juice

Food/Nutrient Effects on DrugsAbsorptionAbsorption of iron from supplements 50% when taken with foodBest absorbed when taken with 8 oz of water on empty stomachFood may GI upsetIf take with food, avoid bran, eggs, fiber supplements, tea, coffee, dairy products, calcium supplements

Grapefruit Inhibits Metabolism of Many DrugsInactivates metabolizing intestinal enzyme resulting in enhanced activity and possible toxicityEffect persists for 72 hours so it is not helpful to separate the drug and the grapefruitMany hospitals and health care centers have taken grapefruit products off the menu entirely

Drugs known to interact with grapefruit juiceAnti-hypertensives (filodipine, nifedipine, nimodipine, nicardipine, isradipine)Immunosuppressants (cyclosporine, tacrolimus)Antihistamines (astemizole)Protease inhibitors (saquinavir)Lipid-Lowering Drugs (atorvastatin, lovastatin, simvastatin)Anti-anxiety, anti-depressants (buspirone, diazepam, midazolam, triazolam, zaleplon, carbamazepine, clomipramine, trazodone

Food/Nutrient Effects on Drug Action: CaffeineIncreases adverse effects of stimulants such as amphetamines, methylphenidate, theophylline, causing nervousness, tremor, insomniaCounters the antianxiety effect of tranquilizers

Food/Nutrient Effects on Drug Action: AlcoholIn combination with some drugs will produce additive toxicityWith CNS-suppressant drugs may produce excessive drowsiness, incoordinationActs as gastric irritant; in combination with other irritants such as NSAIDs may increase chance of GI bleed

Food/Nutrient Effects on Drug Action: AlcoholShould not be combined with other hepatotoxic drugs such as acetominophen, amiodarone, methotrexateCan inhibit gluconeogenesis when consumed in a fasting state; can prolong hypoglycemic episode caused by insulin or other diabetes meds

Food Drug Effect

Foods Omeprazole in Action (Full stomach) lansoprazole Itraconazloe in Bioavailability

Cran berry Warfarin in Bleeding Juice

Vitamin C Basic drugs e.g Pseudoephedrine Excretion Tetracyclines Absorption

SummaryEverything interactsFood shares same ADME as do drugsQuestion all conclusive studiesWhen in doubt, do more research

*****A drug has go from its entry point to the tissues where it has to react Where it enters the body ..IM, PO etc to where it has to reactFor the drug to work, it must penetrate the cell Biotransport refers to the movement of drugs across biologic membranes Cell structure and molecular size of drugs effect the movement across the cell membrane.

*All drugs must be in solution to cross biologic membranesThis is the only way for a drug to reach its site of action

**Pharmacodynamic drugs are capable of changing the normal physiologic function of the body. examples: slowing the heart rate, increasing urinary output. Drugs can only alter an existing function, they cannot create new responses.Drugs exert multiple effects on the body.Drugs act on a biochemical level to alter the normal physiologic function of the organism****Pharmacodynamic drugs are capable of changing the normal physiologic function of the body. examples: slowing the heart rate, increasing urinary output. Drugs can only alter an existing function, they cannot create new responses.Drugs exert multiple effects on the body.Drugs act on a biochemical level to alter the normal physiologic function of the organism*Receptors may be a portion of cell membrane, a transport protein, a structural protein, an enzyme that is inhibited by drugs, or the nucleic acid of a cell. Receptors come in many shapes that are specific for particular drugs Receptors dont exist in the body merely to bind drugs rather, their normal function is to bind endogenous molecules such as hormones, neurotransmitters etc.************