F7. Drug interactions and adverse drug reactions Flashcards
an interaction is said to occur when…
An interaction is said to occur when the effects of one drug are changed by the presence of another drug, food, drink, or an environmental chemical agent.
factors contributing to drug interactions?
-Multiple drug therapy.
-Multiple prescribers.
-Multiple pharmacological effects of drug.
-Multiple diseases/predisposing illness.
-Increased by conditions such as renal impairment.
-Poor patient compliance.
-Advancing age of patient.
-Drug related factors.
mechanisms of drug-drug interactions?
-Pharmacokinetic Drug-Drug Interactions: Use of two or more drugs affect the absorption, distribution, metabolism and/or elimination (ADME) of at least one drug.
-Pharmacodynamic Drug-Drug Interactions: involve either an additive, synergistic, or antagonistic interaction that may favor or harm the patient.
Describe pharmacokinetics mechanisms
Reciprocal influence of absorption, distribution, metabolism, and elimination affecting the effective concentrations at their sites of action.
Describe changes in absorption- pharmacokinetics mechanism
-2 drugs may interact to alter rate of uptake. E.g., tetracycline + Fe2+ salts or Ca2+ (milk).
-Oral route most frequently used for drug administration, therefore interactions influencing
absorption most likely to occur within GI tract.
Describe changes in absorption- pharmacokinetics mechanism. Interaction could cause?
-Faster or slower drug absorption.
-More, or less complete absorption.
Describe changes in absorption- pharmacokinetics mechanism. Influencing factors?
-Changes in gastrointestinal pH.
-Changes induced by chelation.
-Changes in gastrointestinal motility.
-Transporter based interactions.
Describe how changes in GI pH affect absorption?
-Passive absorption of drugs best in uncharged form, governed by pKa
value.
-Rises in pH (antacids, H2 antagonists, PPIs) may influence absorption
of other drugs.
-Ketoconazole - antifungal - insoluble in water and ionized at low pH.
Hence, must be in acidic environment to be absorbed. Acidicsuppression can reduce AUC by 80%.
Describe how changes by chelation and GI motility affect absorption?
-Chelation or formation of insoluble complexes.
-E.g., tetracyclines or ciprofloxacin form insoluble chelates with Ca, Al,
Bi and Fe resulting in reduced antibacterial effect.
-GI motility : changes in motility/gastric emptying may affect
absorption.
-E.g., metoclopramide accelerates absorption of other drugs (use in antimigraine drugs).
Describe how transporter based interactions affect absorption?
-Over 450 human drug transporters.
-ATP-binding cassette (ABC) transporters;
-Solute carrier (SLC) transporters.
Describe how transporter based interactions affect absorption- P-glycoprotein (P-gp) Interactions?
-Encoded by MDR1 (Multi Drug Resistance 1) gene;
-Efflux pump, so, pumps drugs out into lumen;
-Structural diversity of its substrates.
-So that:
Both inhibitors/inducers produce significant interactions.
Describe how transporter based interactions affect absorption- The quinidine–digoxin interaction?
-Digoxin is a P-gp substrate;
-Quinidine is a P-gp inhibitor.
-Quinidine increase the bioavailability of digoxin by inhibiting P-gp efflux in the intestine and the liver during the first-pass effect.
Describe how distribution changes- pharmacokinetics mechanism?
Alteration in Protein-Drug binding: Reduction in the extent of plasma protein binding of one drug caused by the presence of another drug, resulting in an
increased free or unbound fraction of the displaced drug.
ONE NOTE
Describe how metabolism changes- pharmacokinetics mechanism?
-Most metabolic interactions are due to competition for the cytochrome P450 enzyme (CYP), which is expressed
in the liver and catalyzes the phase I oxidation of more than half of all medical drugs.
- Induction: increase in the expression of the enzyme (especially increasing transcription) .
-Drugs, environmental pollutants, industrial chemicals, nutrition .
-Inhibition: several different ways (competitive inhibition, irreversible inhibition)
ONE NOTE
Describe enzyme induction
-Increase activity of metabolising enzymes;
-May take a week or 2 for effect;
-Effect may persist on stopping inducer.
ONE NOTE
Describe enzyme inhibition
-Rapid onset: 1-2 days;
-Often reverse quickly on stopping.
ONE NOTE
Metabolism Interaction: Polymorphism?
one note
Metabolism Interaction: PPIs and Clopidogrel?
-PPIs and particularly omeprazole inhibit cytochrome P450 2C19 (CYP2C19).
-Clopidogrel is a prodrug that is metabolized to its active metabolites in two steps, and CYP2C19 plays an essential part in this.
-Pantoprazole does not affect cytochrome P450, and evidence suggests that it does not interact.
ONE NOTE
Pharmacodynamics Mechanisms?
-Interactions between drugs with additive or opposing effects.
-Direct Pharmacodynamic Interaction
-Indirect Pharmacodynamic Interaction
Direct Pharmacodynamic Interaction?
-Antagonism.
-Addition or summation.
-Synergism or potentiation.
Indirect Pharmacodynamic Interaction?
-Unrelated effects but alters the effect of the
former.
-E.g., salicylates decrease the ability of the
platelets to aggregate thus impairing the
homeostasis if warfarin induced bleeding
occurs.
Mechanisms of drug toxicity?
-On-target Adverse Effect: Drug binds his intended receptor but at an inappropriate concentration or in
the incorrect tissue.
-Off-target Adverse Effect: Drug binds a not intended receptor.
-Toxic Metabolites: The metabolism leads to compounds equally active or toxic.
-Harmful Immune Response: Hypersensitivity reactions.
-Idiosyncratic Response: Rare reaction which reflect individual genetic differences in the response to the
drug.
Adverse Drug Reactions vs Adverse Drug Event?
-Adverse Drug Reaction: “An appreciably harmful or unpleasant reaction, resulting from
an intervention related to the use of a medicinal product, which predicts hazard from
future administration and warrants prevention or specific treatment, or alteration of the
dosage regimen, or withdrawal of the product.”
-In simple terms: “Unwanted or harmful reaction experienced after drug administration” .
-Adverse Drug Event: Medical occurrence temporally associated with the use of a medicinal
product, but not necessarily causally related .
ONE NOTE
Classification of Adverse Drug Reactions (ADRs)?
one note
Describe type A Reactions: Augmented
-Most common (~80%) than type B;
-Largely predictable from drug’s pharmacology;
-Preventable;
-Dose-dependent;
-Reversible on reducing/withdrawing drug;
-Generally associated with low mortality but high morbidity.
type A Reactions: Augmented maybe caused by?
-Exaggeration of therapeutic effect due to an overdose (Pharmacological);
-Disease condition like hepatic or renal failure (Pathological);
-Injury to DNA by therapeutic agent (Genotoxic).
Describe type B reactions: Bizarre
-They are NOT pharmacologically predictable!
-Idiosyncratic;
-Genetic influences.
-Immunological reaction;
-Unpredictable and difficult to detect in clinical trials;
-Often involve a chemically reactive metabolite rather than parent drug;
-Less common, but usually severe - associated with higher mortality.
-E.g., anaphylaxis with β-lactam antibiotics such as penicillins.
-E.g.. Stevens-Johnson syndrome - caused by sulfonamides, trimethoprim, NSAIDs,
penicillins, some anticonvulsants and others.
Type C reactions?
C – Continuing/Chronic Reactions
-Those persisting for a relatively long time.
-E.g., osteonecrosis of the jaw with bisphosphonates such as alendronic acid; benzodiazepine
dependence; analgesic nephropathy.
Type D reactions
D – Delayed Reactions
-Become apparent some time after the use of a medicine making them difficult to detect.
-E.g., leucopenia can occur up to 6 weeks after a dose of lomustine; carcinogenic and
teratogenic effects.
Type E reactions
E – End of Use Reactions
-Associated with withdrawal of a medicine.
-E.g., insomnia, anxiety and perceptual disturbances following withdrawal of benzodiazepines such as midazolam; antidepressants; corticosteroids.
Reporting ADRs?
-Yellow Cards in BNF submit to CSM, who monitor ADRs, especially new medicines and ADRs resulting in
hospital admission.
-Report all black triangle drugs.
