Pharmacokinetics Flashcards
What is first pass metabolism?
Oral drugs are absorbed in the gut (mainly small intestine) and transported to the liver via the portal system.
- they are metabolised in the liver but also at the gut wall
What are the two types of metabolic reactions in the liver
Phase 1 reactions
Phase 2 reactions
What are phase 1 reactions?
Oxidation via CYP450
reduction and hydrolysis
What are phase 2 reactions?
Conjugation of drug or its phase 1 metabolite
- glucuronidation is most important reaction
- drugs that are predominantly metabolised via phase 2 reactions include Lorazepam, Diazepam
What is the purpose of drug metabolisation?
- Makes drugs more polar so they can be excreted in the urine
- Activates pro-drugs
What is enzymes induction and what effect does it have?
Some drugs induce the action of CYP450 enzymes, increasing their activity. This occurs either by binding to the enzyme or increasing the expression of the gene coding for the enzyme.
- increased metabolism of active drug so reduced therapeutic effect
- increased metabolism of prodrug so toxicity develops
Name some common enzyme inducers?
Carbamazepine - 3A4 Phenytoin - 3A4 and C19 Barbiturates ETOH - 2E1 Rifampicin - many including 3A4 St John's Wort - 3A4
What is enzyme inhibition and what effect does it have?
Some drugs reduce the action of CYP450 enzymes causing decreased metabolism
- reduced therapeutic effect of prodrugs
- toxicity of active drugs
Define half life
the time taken for the concentration of a drug to fall by half its original value
What is T1/2 important for calculating?
Dosing interval
T1/2 = Vd x 0.693 / Cl
A long T1/2 can be due to a high Vd or low clearance rate
Define clearance
The volume of plasma cleared of a drug in a unit time
- units are always volume/time e.g. ml/min or L/hr
- Cl = Clm (metabolic/liver) + Clr (renal)
What is clearance important for when it comes to drug dosing?
Calculating the maintenance dose (elimination rate) elimation rate (at steady state) = Cl x Cp Cp (plasma conc)
How do you calculate clearance?
Cl = F x dose / AUC
F = bioavailability
How can you calculate AUC for a drug?
Knowing two T1/2 of the drug you can draw a graph and use the trapezoid method
What is steady state and why is it important?
5 x T1/2
therapeutic drug monitoring must be done at steady state
What are the feature of renal clearance of a drug?
= filtration + secretion - reabsorption
- Drug must be water soluble (polar)
- Only free drug (not protein bound) can be excreted
- competitive transporters
- saturable transporters
What components are important for hepatic clearance?
HC = HBF x ER
HBF = hepatic blood flow
- decreases with age and cirrhosis
ER - extraction ratio
What effect does cirrhosis have on drug pharmacokinetics?
Drug bypasses first pass metabolism due to portal shunting via collaterals
- results in increased bioavailability
Define volume of distribution
the apparent volume into which the drug is distributed
- 15L suggests the drug distributes through the total body water - often lipophilic
Why is Vd important?
Loading dose is required if there is a large Vd in order to get plasma concentration into therapeutic range quickly
Name some important enzyme inhibitors
SSRIs - CYP2D6 (metabolises Tamoxifen to active metabolite)
Omeprazole - CYP2C19 (metabolises Clopidogrel to active metabolite)
Macrolide’s, azaleas, protease inhibitors
- in combination with statins cause increased levels and rhabdo
- increase levels of Tacrolimus/Cyclosporin leading to toxicity
Define bioavailability (F)
the proportion of administered drug reaching the systemic circulation
- IV drugs F = 100%
- drugs with high first pass metabolism have low F, e.g. insulin
How do you caculate bioavailability (F)?
F = 100 x AUC po x Dose IV / AUC IV = Dose po
Define zero order (non-linear) kinetics and give examples.
rate of elimination of the drug is constant and unaffected by the plasma concentration
- ethanol
- phenytoin
- salicylates
Why are zero order kinetics important?
- ## when any enzyme system responsible for metabolising a drug is saturated, the elimination kinetics of that drug will change from 1st to 0 order kinetics
What is 1st order (linear) kinetics?
the rate of drug elimination is proportional to the plasma concentration
- 95% of drugs follow 1st order kinetics at therapeutic levels
What is the action of P-glycoprotein?
transmembrane efflux transporters (active transport system)
Protects body from harmful substances by:
- Removing drugs absorbed in the intestines back into the gut lumen.
- Maintaining the integrity of the blood brain barrier.
- Removing drugs from the kidneys and liver into the urine and bile respectively.
What are the clinical implications of P-glycoprotein and drugs?
- reason for multi drug resistance in cancer cells
- partly responsible for the clearance of medicines via the renal and hepatic systems
- the system is saturable and can be inhibited or induced. This can lead to drug interactions
What are the drug substrates for P-glycoprotein?
Digoxin
Loperamide
Colchicine
Dabigatran
What drugs are inducers of P-glycoprotein?
Phenytoin
Rifampicin
Carbamazepine
St John’s Wort
What drugs inhibit P-glycoprotein?
Amiodarone Ketakonazole/Itrakonazole Erythrmoycin/Clarithromycin Ciclosporin Verapamil Diltiazem Quinidine Protease inhibitors Tacrolimus/Sirolimus Grapefruit juice
Name some important P-glycoprotein mediated drug interactions
P-glycoprotein interactions do not routinely change plasma concentrations nearly as much as CYP450 interactions
- Digoxin metabolism inhibited by Verapamil, Amiodarone, Quinidine, Ciclosporin -> toxicity
note Dabigatran etexilate (pro-drug) is a substrate for P-glycoprotein but not Dabigatran therefore if co-administered with a portent P-glycoprotein inhibitor, will get reduced plasma conc of active drug. This is only relevant to the component of Dabigatran metabolised at the gut wall by P-glycoprotein (not at the liver by liver esterases) so real life interactions are variable.
