Drug interaction Flashcards
= when one drug modifies the action of another (may increase or decrease the second drug’s action). Sometimes -> unwanted effects, sometimes beneficial
- Physiochemical: relating to properties of drug or its pharmaceutical preparation
- Pharmacokinetic: alterations in the way the boddy handles the drug. May affect absorption, metabolism or excretion
- Pharmacodynamic: activity of one drug is affected. May be direct (same receptor system) or indirect (different mechanisms, same end-effect)
Chance of significant interaction increases with
* Number of drugs used
* Disease/comorbidity: effects of any interaction often exaggerated
Pharmaceutical interactions
Mechanism, examples
Occur because of a chemical or physical incompatability between the preparations being used
Examples
* Sodium bicarbonate + calcium will precipitate as calcium carbonate when co-administered in the same giving set
* Insulin may be denatured if prepared in solutions of dextrose -> lose its pharmacological effect
* Drug may react with giving set or syringe, and therefore require special equipment: Paraldehyde requires a glass syringe, GTN is absorbed by polyvinyl chloride -> special polyethylene administration sets preferred
Interaction between sodium bicarbonate and calcium
Example of a pharmaceutical interaction
Will precipitate out of solution as calcium carbonate when co-administered in the same giving set
Pharmacokinetic interactions affecting absorption
Mechanisms (2), examples (3)
Due to
* One drug binding another in the lumen of GI tract (e.g. activated charcoal)
* Altering function of GI tract (e.g. metoclopramide/analgesics in migraine, PGP inducers/ inhibitors)
Examples
* Charcoal (activated by steam to cause fissuring, greatly increasing the surface area) can adsorb drugs in the stomach, preventing absorption through GI tract
* Metoclopramide reduces GI stasis in migraines and speeds absorption of co-administered analgesica (favourable)
* PGP inducers e.g. rifampicin, phenytoin may reduce oral bioavaiability, PGP inhibitors e.g. amiodarone and verapamil may increase oral bioavailability
PGP is an efflux transporter, located in luminal membrane of entire intestinal membrane, reduces oral bioavaiability of many drugs by pumping them back into lumen of gut.
Pharmacokinetic interactions affecting metabolism
Mechanisms (4) with examples
Drugs that affect cardiac output **
* Decrease in cardiac output (e.g. beta-blockers)** -> reduce flow of blood carrying absorbed drug to site of action -> slower onset (e.g. suxamethonium)
* If relatively greater reduction in hepatic blood flow -> slower drug elimination
Chelating agents
* Combines drug with toxic element to prevent tissue damage, e.g. sodium calcium edetate chelates lead
**Competition for binding sites to plasma proteins **
* Of importance only for highly protein-bound drugs where enzyme systems are close to saturation at therapeutic levels e.g. if phenytoin (90% protein bound) is displaed from binding sites by co-administered drug when therapeutic levels at upper limit of normal -> e.g. 10% reduction in binding will almost double pnhenytoin level. Hepatocyte metabolism is readily saturated -> zero order kinetics, plasma level remains high rathe than re-equilibrating
**Alteration of metabolic capacity of a drug **
* E.g. Amiodarone inhibits metabolism of S-warfarin by CYP2C9 -> increased plasma levels of active form of warfarin
Interaction between suxamethonium and beta-blockers
Predominant factor influencing time to fasciculation onset following sux administration is cardiac output.
Prior administration of beta-blockers -> reduced cardiac output -> slower onset of suxamethonium
Interaction between amiodarone and warfarin
+ which NSAID has similar interaction
Amiodarone inhibits metabolism of S-warfarin by CPY2C0 –> can significantly increase plasma levels of active form of warfarin -> iatrogenic coagulopathy
Similar interaction occurs with NSAID phenylbutazone
Interactions used in treatment of lead and cyanide poisoning
Chelation: example of pharmacokinetic interaction affecting drug distribution
Sodium calcium edetate chelates lead -> used in treatment of lead poisoning
Dicobalt edetate chelates cyanide ions -> used in treatment of cyanide poisoning (may occur following prolonged infusions of sodium nitroprusside)
Interactions involving CYP450 family
Induction of CYP450 enzymes increases metabolism:
* Decreased duration of action for drugs inactivated by metabolism, e.g. anticonvulsants and dexamethasone reduce duration of action of vecuronium by inducing CYP3A4
Inhibition of CYP450 enzymes decreases metabolism
* Prolonged duration of action for drugs inactivated by metabolism
* Reduced activity of drugs which require ACTIVATION by CYP450 enzymes e.g. omeprazole inhibits CYP2C19 and prevents conversion of clopidogrel to active metabolite
Examples of CYP450 inducers and inhibitors
Anticonvulsants, dexamethasone, rifampicin, ethanol, cimetidine etc
Examples of CYP450 inducers
* Anticonvulsants and dexamethasone induce CYP3A4
* Rifampicin induces a number of isoenzymes including 2B6, 2C9, 2D6, 3A4
* Broccoli induces 1A2, Ethanol induces 2E1
Examples of CYP450 inhibitors
* Cimetidine is a more potent** inhibitor** of 1A2, 2D6 and 3A4 than ranitidine
* Grapefruit juice inhibits CYP3A4
Interaction between omeprazole and clopidogrel
Omeprazole inhibits CYP450 enzyme CYP2C19
Clopidogrel is a prodrug, must be converted to active form by CYP2C19
Therefore omeprazole reduces antiplatelet activity of clopidogrel by inducing CYP2C19.
Interaction between anticonvulsants/dexamethasone and vecuronium
Vecuronium is metabolised by CYP430 enzyme CYP3A4
Therefore drugs which induce CYP3A4 e.g. anticonvulsants, dexamethasone, will reduce duration of vecuronium
Interaction between sodium bicarbonate and aspirin
Clinical utility
Sodium bicarbonate makes urine more alkaline, which enhances excretion of weak acids e.g. aspirin, barbiturates
Example of pharmacokinetic interaction affecting excretion.
-> Mx of aspirin overdose may include fluids (to produce diuresis) + sodium bicarbonate (to alkalinise urine and promote renal excretion of aspirin)
Pharmacodynamic interactions
Activity of a drug is affected
Pharmacodynamic interactions may be direct (same receptor system) or indirect (different mechanisms, same end-effect)
Examples of direct interactions:
* Competitive antagonism e.g. flumenazil to reverse effects of benzodiazepines, naloxone to reverse effects of opiods
* Activity of phenylephrine is reduced by alpha-1 adrenergic blockers used in treatment of BPH e.g. doxazosin, tamsulosin, indoramin, prazosin, terazosin, alfuzosin.
Examples of indirect interactions:
* MAOI and pethidine: increase in noradrenaline caused by MAOI is potentiated when re-uptake is inhibited by pethidine
* Neostigmine inhibits acetylcholinesterase -> increases acetylcholine concentration in the synaptic cleft -> Ach conpletes for nicotinic receptors with non-depoolarising muscle relaxants, reversing their effects
* Diuretics may inadvertently cause digoxin toxicity by increasing serum potassium
* Adrenaline and milrinone are positive ionotropes which interact indirectly: adrenaline works via GPCR, milrionone acte intracellularly by inhibiting phosphodiesterase, both increase intracellular cAMP levels.
Interaction between phenylephrine and drugs used to treat BPH
Example of direct pharmacodynamic interaction
Phenylephrine acts on alpha-1-adrenergic receptors.
Alpha-1 adrenergic blockers are used in treatment of BPH e.g. doxazosin (and alfuzosin, prazosin, terazosin), indoramin, tamsulosin may render alpha-adrenergic agonists e.g. phenylephrine ineffective.
What is an isobologram
Curves for additive, synergistic and antagonistic interactions
Describes the combined effect of two different drugs
Plot the fractional concentration (fraction of dose required individually) of drug A against drug B when given together to give desired therapeutic effect.
Straight line y=x indicates purely additive effect: i.e. half the concentrations of each drug combine to produce original target effect.
If curve is not linear: interaction is occuring
* Antagonistic: convex curve (e.g. at concentration a/2 of drug A, concentration >b/2 of drug B is required)
* Synergistic: concave curve (e.g. at concentration a/2 of drug A, concentration <b/2 of drug B is required).
