1. Pharmacokinetics Flashcards
What is pharmacokinetics?
The study of movement of a drug into and out of the body, ie What the body does to the drug.
What are the 4 processes in pharmacokinetics?
ADME - Absorption, Distribution, Metabolism, and Elimination.
What is the therapeutic window?
The dose range between the minimum effective dose, and the maximum safely tolerated dose
How is absorption measured?
Bioavailability
What does bioavailability depend on?
Drug formulation, first pass metabolism, pt age, food, lipid vs water solubility of drug, and V&D/malabsorption.
What is first pass metabolism?
Any metabolism that occurs before the drug enters systemic circulation.
Where can first pass metabolism occur?
The liver, the gut lumen, or the gut wall.
What factors in the gut lumen can cause first pass metabolism to occur?
Gastric acid
Proteolytic enzymes
Foods eg grapefruit juice
What are some examples of drugs that undergo gut lumen first pass metabolism?
Insulin
Ciclosporin
Benzylpenicillins
What factors in the gut wall can cause first pass metabolism to occur?
P-glycoproteins efflux pumps (remove contents back into lumen)
What are some examples of drugs that undergo gut wall first pass metabolism?
Ciclosporin
What factors in the liver can cause first pass metabolism to occur?
Inactivation, oxidation, or conjugation. Metabolites can then be sent back to the gut lumen.
Via what can metabolites from the liver be sent back to the gut lumen?
The enterohepatic circulation
What are the 2 key factors in distribution of a drug?
Protein binding
Volume of distribution
What kind of drugs bind to albumin?
Acidic drugs
What kind of drugs bind to globulins?
Hormones
What kind of drugs bind to lipoproteins or glycoproteins?
Basic drugs
How can protein binding be influenced?
Displacement of drugs from proteins by other drugs
What happens when one drug (drug A) is displaced by another from its protein-bound state?
Increased amount of free drug A
When can protein binding drug interactions occur?
When there is:
- high protein binding
- low Vd
- hyperalbuminaemia
- pregnancy
- renal failure
When are protein binding drug interactions important?
When the drug has a narrow therapeutic window
What is the volume of distribution?
Measurement of how widely a drug is distributed throughout body tissues.
What is the significance of a high Vd?
Less drug is available in the blood stream per unit given
Where does drug metabolism chiefly occur in the body? And where else?
The Liver!
But also the gut and the lung
What are the liver phase 1 enzymes?
CYPs
What do CYPs do?
Oxidation, dealkylation, reduction, and hydrolysis.
What does CYPS stand for?
Cytochrome P
What can happen to metabolites after phase 1? (3)
- Further processing by phase 2 enzymes (which then do 2 or 3)
- Go to Kidney to be excreted in urine
- To the gallbladder to be excreted via bile
What are active metabolites?
Products of metabolism of inactive drugs that are now active
Give an example of an inactive drug/active metabolite and its use.
- L-Dopa (metabolised to dopamine) - Parkinson’s
2. Enalaprilat (to enalapril) - Hypertension
What drugs (6) do CYP 450 3A enzymes metabolise?
Ca2+ Channel Blockers Benzodiazepines HIV protease inhibitors Many statins Cyclosporin Antihistamines
What inhibits CYP 3A?
Antifungals
Cimetidine
Macrolides
Grapefruit
What drugs induce CYP 3A?
Carbamazepine Phenytoin Rifampicin Ritonavir St John’s Wort
What does CYP 2D6 metabolise?
Codeine
Beta Blockers
Tricyclics
What inhibits CYP 2D6?
Fluoxetine
Paroxetine
Haloperidol
Quinidine
Who is CYP 2D6 absent in?
7% of Caucasians
Who is CYP 2D6 hyperactive in?
30% of East Africans
Who is CYP 2C9 absent in?
1% of Caucasians and blacks
What does CYP 2C9 metabolise?
Most NSAIDs
Warfarin
Phenytoin
Tolbutamide
What inhibits CYP 2C9?
Fluconazole
What induces CYP 2C9?
Carbamazepine
Ethanol
What can influence CYP450 enzymes?
Enzyme inducing/inhibiting drugs
Where are CYP450 isoenzymes found?
Mostly in the liver
What % of drug metabolism are CYP450s responsible for?
90%
How can CYP450 enzymes explain different metabolism of drugs between different pts?
Genetic differences in individuals -> different levels of activity of different CYP450 isoenzymes
What is the main route of elimination?
Kidney
What does renal excretion of a drug depend on?
Glomerular filtration, passive tubular reabsorption, and active tubular secretion
What is GFR proportional to?
Excretion of unbound drugs (eg gentimicin)
Give an example of a drug that is actively excreted
Penicillin
What is passive reabsorption influenced by?
Urine flow rate, and pH
What is clearance and how is it measured?
Rate of removal by excretion of a drug from the body. Usually roughy equal to GFR.
Define 1st order kinetics
Rate of elimination of drug is proportional to drug level ie a constant % of the drug is eliminated
Define zero order kinetics
Rate of elimination of a drug is constant
When can drugs that are usually 1st order bexhibit zero order kinetics?
At high doses, when enzymes/pathways etc become saturated
What is the issue with drugs that exhibit zero order kinetics?
More likely to result in toxicity
What 4 main reasons are there for drug monitoring?
- If the drug has zero order kinetics
- If the drug has long t1/2
- Narrow therapeutic window
- Greater risk of DDIs
With repeated administration, after how many half lives is a steady state reached?
3-5
How many t1/2s dose it tend to take to eliminate a drug?
3-5
