Drug-drug and drug-disease interactions Flashcards
Types of drugs to consider
- Prescribed drugs
- Herbal remedies
- OTC medications
- Dietart factors
- Lifestyle factors
What is drug interaction?
Modification of one drug’s actions by another
Individual variations to drugs
- Loss of efficacy
- Unexpected side-effects or toxicity
- Types of variability are pharmacokinetic (different conc. of drug reaching site of action) and pharmacodynamic (different degree of response)
Effect on medication of being child
- Drug metabolism slower - organs are immature
- Renal excretion less efficient
- Drug sensitivity changes
- Body fat to mass changes
Effect on medication of being elderly
- Failing organ function decreases drug metabolism
- Renal excretion less efficient
- Drug sensitivity changes as receptor numbers deplete
- Poly-pharmacy and co-morbidities
- Body fat and mass changes
Effect on medication of being pregnant
- Decrease in plasma protein binding
- Increased plasma volume and extracellular fluid
- Increased cardiac output - increased renal blood flow and GFR = increased renal drug elimination
Pharmaco-genetics
how different individual genotypes relate to different drug responses
Pharmaco-genomics
pharmaco-genetics applied to whole human genome
Mixed function oxidases
- Found in liver, often referred to as cytochrome P450 family
- Good at breaking down meducations
- Changes toxicity and effectiveness of drug
Ethnicity and drug response
- Genetic differences account for some variations
- Diet also important
- ACEi not used in afro-caribbean background because of angio-oedema
CYP 1A2
Increases/decreases anti-psychotic drugs metabolism
Increases adverse reaction of traduce dyskinesia
CYP 2C9
Increases/decreases warfarin, phenytoin and losartan metabolism
Increases adverse reaction of bleeding, toxicity, ataxia and confusion
CYP 2C19
Increases/decreases diazepam, omeprazole metabolism
Increases adverse effects of prolonged sedation and acid suppression
CYP 2D6
Increases/decreases B-blockers metabolism
Increases adverse reaction to excessive bradycardia
Har,ful drug interactions
- 15% of adverse drug reactions
- Elderly, hepatic/renal impairment, polypharmacy (on multiple drugs) and pts on drug with narrow therapeutic range (phenytoin) are at increased risk
Pharmacodynamics
- Agonism at receptor - 2 drugs of same/similar class (e.g. opioids competing for receptor)
- Antagonism at receptor - opiate analgesics and naloxone, B-blockers and beta2 agonists
- Non-selective nature of drug - antidepressants intercta with many receptor subtypes
- Enhanced effect by other means - increased digoxin toxicity by hypokalaemia caused by loop diuretic e.g. furosemide
Pharmacokinetics
- ADME - 4 stages of pharmacokinetics (absorption, distribution, metabolism, excretion)
- Parenterally = passes first pass metabolism
- Excreted in urine and bile
Absorption
- Changes in gut motility - opiates and atropine slow gut down - Cmax and Tmax
- Metoclopramide speeds gut up - Cmax and Tmax
- Interfere with absorption and enterhepatic circulation - calcium salts bind tetracyclines in gut, cholestyramine binds warfarin and digoxin, activated charcoal binds drugs in gut after overdose
Distribution
- Many drugs alter distribution by displacing another drug from plasma or tissue binding sites
- Causes transient increases in unbound drug
- Subsequently corrected by increased elimination
- Total drug concentration reduced but free value recovers at steady state
Metabolism
- 2 phase metabolism for many drugs
- Liver is main site of metabolism
- Drug → derivative → conjugate
- Phase 1: CYP450 family, low substrate specificity metabolises a wide range of drugs
- Phase 2: e.g. glucuronidation increases solubility and allows easier renal elimination , converted to active metabolite
Enzyme inducing drugs
- Warfarin and carbamezapine
- Increased activity of cytochrome family
- Warfarin metabolised quicker = failure of treatment
- Drugs that induce CYP450 increase metabolism of other drugs and increase own metabolism
- Carbamezapine induces CYP3A4 - warfarin is metabolised and carbamezepine causes faster warfarin clearance, reduced anticoagulant activity, therapy failure
CYP 450 induction
- Slow onset (1-2 weeks) because new enzyme production induced
- Induction persists some time after stopping inducing drug and whilst enzyme levels normalise
- Removing inducer will disturb equilibrium
- Warfarin may have been adjusted so INR is stable despite interaction
- Removal leads to reduced CYP3A4 activity - warfarin metabolism slows over 1-2 weeks, warfarin levels climb, risk of over-anticoagulation and bleeding
Herbal remedy for depression
St John’s Wort
Why is St John’s Wort dangerous
increases metabolism of oral contraceptive, digoxin, phenytoin, warfarin
CYP 450 inducers
Anticonvulsants Antibiotics Steroids Alcohol St John's Wort HIV therapies
Macrolide antibiotics and warfarin
- All antibiotics kill gut bacteria - vit K falls, increased anticoagulant effect, increased INR
- Macrolide antibiotics (clarithromycin) - inhibit CYP450, warfarin metabolism reduced, increased INR
CYP 450 inhibition
- Relatively quick onset
- Related to half life and clearance of drug and plasma concentration at time of interaction
- Usual effect is reduced metabolism of drugs - increased effect and toxicity
CYP 450 inhibitors
Anti-arrythmics Antibiotics Anti-ulcers Antidepressants HIV drugs Statins Sodium valproate
QTc interval prolongation
- Increased risk of lethal cardiac arrhythmia
- Drugs may prolong this interval and cause torsade des pointes
- Leads to PEA
- Genetic and acquired forms
- Ion channels and sympathetic abnormalities
- QTc lengthened by anti-arrythmics
- Another drugs prolong QT
- Any drug impairs metabolism of QTc prolonging drug may cause long QT
Drugs increasing risk of long QTs
- Anti-arrythmics - quinidine, aotalol
- Antibiotics - macrolides (erythromycin, clarithromycin)
- Anti-fungal agents
- Anti-histamines
- Psychotropic drugs
- Motility agents
Hepatic disease
Decreased clearance of hepatically metabolised drugs
Decreased CYP450 activity
Increase half life and toxicity - classic is opiates in cirrhotic patients
Renal disease
Reduced clearance of renal excreted drugs - digoxin
Increased electrolyte and fluid distributions = increased toxicity
Nephrotoxic drugs worsen renal function
Cardiac disease
Decreased metabolism of drugs dependent on hepatic blood flow
Increased response to cardiovascular drugs
Other diseases
Exacerbation of asthma by beta-blockers and NSAIDs
Decreased seizure threshold with some antibiotics like ciprofloxacin
Grapefruit juice
- Inhibits CYP450 isoenzymes
- Decreased clearance of many drugs - simvastatin, amiodarone and terfenadine (long QT)
- May lead to increased exposure of drugs
Cranberry juice
- Treats urinary sepsis
- Inhibits bacterial adherence to urothelium
- Inhibits CYP2C9 isoform - decreased clearance of warfarin, increased anticoagulant effect, increased risk of haemorrhage, pt should be advised not to drink if on warfarin
