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Transcript
Pharmacokinetic drug interactions Phil Rowe Reader in Pharmaceutical Computing Liverpool School of Pharmacy Pharmacokinetic Drug Interactions Drug interactions Lecture 2 Interactions based upon: • Distribution • Metabolism Pharmacokinetic Drug Interactions Distribution One drug changes the way in which another drug is distributed around the body. Pharmacokinetic Drug Interactions Alleged mechanism Drug B Plasma Tissue Drug A protein bound Drug A free Drug A free Drugs A and B both bind to the same plasma protein Pharmacokinetic Drug Interactions What would really happen? More drug will be driven into all tissues including eliminating organs such as liver and kidney Clearance increases and so total drug levels in blood fall. Can be shown mathematically that this effect will exactly cancel out the effect of displacement into tissues. Concentration of free drug in tissues is not altered. Pharmacokinetic Drug Interactions Why did anybody ever believe in displacement interactions? Commonly quoted example was Warfarin + Phenylbutazone This combination did kill patients ... But mechanism is not displacement. (Truth will be revealed later) Pharmacokinetic Drug Interactions Clinical significance of displacement interactions None Zero Zilch Not a sausage Absolutely sweet Football Association Pharmacokinetic Drug Interactions Metabolism One drug changes the rate of metabolism of another drug A increases the rate of metabolism of B = Induction A reduces the rate of metabolism of B = Inhibition Pharmacokinetic Drug Interactions Metabolism (Induction) Drug A speeds up the metabolism of Drug B. Blood concentrations of B fall below normal therapeutic levels. B becomes ineffective Pharmacokinetic Drug Interactions General increase in hepatic function • Liver grows larger and blood flow increases • Drug metabolising enzymes (inc Cyt P450) increased • Increased clearance of a wide range of drugs, environmental chemicals and endogenous substances Pharmacokinetic Drug Interactions Examples of drugs causing liver enzyme induction •Rifampicin •Griseofulvin •Carbamazepine •Barbiturates •Phenytoin (Three anti-epileptics! Valproate is NOT inducer) Pharmacokinetic Drug Interactions Examples of induction interactions Inducer Drug with reduced effect Barbiturates Warfarin Griseofulvin Warfarin Phenytoin Oral contraceptives Rifampicin Theophylline Pharmacokinetic Drug Interactions Withdrawal of inducer Patient taking barbiturates and warfarin Barbiturates cause induction - warfarin clearance increased Warfarin dose titrated above normal dose (Blood levels normal) Barbiturates suddenly withdrawn and replaced by valproate Warfarin clearance falls - blood levels rise above normal Patient dies Pharmacokinetic Drug Interactions Beneficial use of induction New born infants have poorly developed hepatic metabolic enzymes. Conjugate bilirubin inefficiently - some become jaundiced Small doses of barbiturates can be used to induce the liver enzymes and clear the bilirubin Pharmacokinetic Drug Interactions Monitoring induction How do find out whether a drug or environmental chemical is an inducer? • Measure hepatic Cyt P450 • Pharmacokinetics of a model substance • Endogenous metabolites Pharmacokinetic Drug Interactions Measure Cyt P450 Expose animals/humans to substance Controls exposed to placebo Obtain liver tissue and measure P450 • Most definitive test of induction. • Extremely difficult in humans. • No guarantee that humans and an animal model will respond in same way. Pharmacokinetic Drug Interactions Kinetics of model substance Antipyrine commonly used because: • Not strongly protein bound • Almost exclusively eliminated by hepatic metabolism • Has no sig. inducing/inhibiting properties of its own Pharmacokinetic Drug Interactions Antipyrine Compare t½ or clearance (Cl better) with/without exposure to the suspect substance. e.g. Comparison of workers exposed to insecticides with controls: Mean antipyrine t½ Controls 13.1 h Exposed 7.7 h Pharmacokinetic Drug Interactions Endogenous metabolites e.g. 6b-hydroxycortisol Hormone cortisol - small % normally metabolised to 6b-hydroxycortisol (6HC) by hepatic Cyt P450. Inducer - more P450 - greater % of cortisol converted to 6HC. Measure 6HC in urine to monitor induction. Pharmacokinetic Drug Interactions Significance of induction interactions Real significance. Loss of effectiveness of warfarin or theophylline could be fatal Loss of effectiveness of oral contraceptives even worse Pharmacokinetic Drug Interactions Metabolism (Inhibition) Drug A slows down the metabolism of Drug B. Blood concentrations of B increase above normal therapeutic levels. Increased chance of toxicity from B. Pharmacokinetic Drug Interactions INHIBITION Drug A Cyt P450 NADPH O2 Pharmacokinetic Drug Interactions INHIBITION Not simple opposite of induction. Induction - Additional P450 in the liver Inhibition - No reduction in quantity of P450. Existing P450 made less effective. Pharmacokinetic Drug Interactions A problem ??? Same substance may appear in lists of both inducers and inhibitors!!! Explanation - May both increase the quantity of P450 and inhibit it as well. Actual effect seen depends upon the balance of the two effects. Pharmacokinetic Drug Interactions Example e.g. Alcohol usually seen as an inducer, but acute intoxication may not give enough time for new enzyme to be synthesised. We only see inhibitory effect (instant). Pharmacokinetic Drug Interactions Antifungals – e.g. Itraconazole Cimetidine EXAMPLES OF INHIBITORS Disulphiram Fluvoxamine & Fluoxetine Macrolide antibiotics – e.g. Erythromycin Phenylbutazone – (Powerful but limited use) 4-Quinolones – e.g. Ciprofloxacin Pharmacokinetic Drug Interactions (Not exclusive) THE TRUTH!! This is the real explanation for the interaction between phenylbutazone and warfarin. Phenylbutazone inhibits the hepatic metabolism of warfarin. Especially the S isomer (the most active). Nothing to do with binding displacement. Pharmacokinetic Drug Interactions Significance of interactions based upon inhibition Probably the most significant interactions of all. Several potentially FATAL. If you want to kill a patient, this is probably best way. Pharmacokinetic Drug Interactions Herbal remedies The fact that it's "natural" doesn't automatically mean it's safe. Inhibitors Inducers Milk thistle (Silibinin) St John's wort Garlic Peppermint oil (Menthol) Pharmacokinetic Drug Interactions Herbal remedies Example. St John's wort may significantly reduce the effectiveness of the following by induction of hepatic Cyt P450 and intestinal P-Glycoproteins • Anticonvulsants • Cyclosporin • Digoxin • Protease inhibitors • Oral contraceptives • Theophylline • Warfarin Pharmacokinetic Drug Interactions Fruit juices • Grapefruit juice contains antioxidants (probably flavonoids) that inhibit CYP3A4 in the gut wall and liver. Leads to increased blood levels of terfenadine and some calcium channel blockers (Appendix 1 of BNF gives details). • Cranberry juice contains various antioxidants including flavonoids, which are known to inhibit cytochrome P450. Warfarin levels may rise significantly. (See Pharm.J. 27th Sept 2003) Pharmacokinetic Drug Interactions Terms with which you should be familiar • Induction • Inhibition Pharmacokinetic Drug Interactions What you should be able to do • Explain why interactions do not arise due to displacement from protein binding •Describe the mechanisms of induction and inhibition • Cite examples of drugs that may induce or inhibit metabolism • Describe the consequences of induction or inhibition • Recognise the danger of sudden withdrawal of an inducer • Describe methods for monitoring induction Pharmacokinetic Drug Interactions