2.1 Pharmacokinetics Flashcards
What is pharmacokinetics?
What the body does to a drug
What key factors should you consider with a drug?
Drug- drug interactions Bioavailability Half life Drug elimination Intra-subject variability Patient specific pharmacokinetic parameters allows tailored dosing regimens to be initiated
What should you consider with pharmacokinetics?
Renal function Stress Pyrexia Alcohol Smoking Age Sex Diet Infection Liver function GI function
Etc.
What is bioavailability?
A measure of drug absorption into body compartment where in can be used - typically circulation
(F)
Drugs administers via IV is said to be 100%
Other routes referenced as a fraction of IV
What is bioavailability affected by?
Absorption
E.g due to formula, age, food, vomiting/malabsorption (Crohn’s)
First pass metabolism (shunted via hepatic portal vein into liver for metabolism)
E.g metabolism before reaching systemic circulation
What determines how well a drug dissolves and is distributed through interstitium from circulation?
Blood flow and capillary structure
Highly vascularised Vs poorly vascularised tissue
Lipophilicity and hydrophilicity
(Lipophilic drugs will readily cross through call membranes whereas hydrophobic drugs require junctions in the endothelium)
Protein binding
(Albumin - acidic drugs, globulins, glycoproteins
What type of drugs will be able to afford a response and/or be eliminated?
Only free drugs typically
Displacement of a drug from a binding site can result in protein binding drug interaction
Clinically important if
- highly protein bound
- narrow therapeutic index
- low Vd
How can increased free drug illicit a response?
Second drug displaces first drug from binding proteins
More free first drug to elicit a response through receptor
Potentially causing harm = entering toxic dose conc
E.g in pregnancy. Renal failure, hypoalbuminemia among others
What is Vd?
Volume distribution. A measure of how widely a drug is distributed in the body.
Vd = DOSE / (DRUG)plasma
The amount of fluid required to contain the total amount (dose) of drug in the body at the same conc as in the plasma (DRUG)plasma.
What does a large/small Vd indicate?
Large = drug is distributed throughout tissue
Small = drug is confined to plasma and extracellular fluid.
What processes do phase 1 enzymes in the liver carry out on drugs?
Oxidation
Dealkylation
Reduction
Hydrolysis
Convert drugs into lipophilic metabolites
What processes do phase 2 enzymes carry out on drugs in the liver?
Glucuronide
Sulphate
Glutathione
N acetyl
Before its excreted
What effects the route and mechanism of metabolism?
Size, lipophilicity, hydrophilicity, structural complexity
What are the modes of activation in drugs?
Active to inactive
Inactive to active
Active to active
What can influence phase 1 metabolism?
Age, hepatic disease, blood flow, alcohol and cigarette smoking
What routes allow drug elimination from the body?
Primarily via the kidney Also - pulmonary - biliary - faecal sweat - genital secretions - saliva - breast milk
What is drug elimination affected by?
1) GFR and protein binding (e.g gentamicin)
2) competition for transporters (e.g penicillin)
3) lipid solubility, pH, flow rate (aspirin)
What is clearance of a drug?
The rate of clearance from all routes - both metabolism and excretion taken together by definition (mL/min)
Mostly GFR
What is half life? T1/2 and what is its relation to clearance?
The time in which concentration of a drug in the plasma decreases by half
If GFR is reduced them clearance is reduced and t1/2 increases
Reasoned that t1/2 is inversely proportional to clearance
Half life will increase when clearance is compromised, renal or hepatic stenosis, haemorrhage, reduced metabolism, reduced plasma drug extraction and drug-drug interactions
-metabolism and excretion are rate limited by physiological processes
What s the rate of elimination proportional to in
- 1st order kinetics
- 0 order kinetics
1st = rate of elimination is proportional to drug conc 0 = rate of elimination is constant (receptor/enzyme saturation)
What order of kinetics do most drugs exhibit
First order kinetics (t1/2 is constant)
Ethanol, aspirin and phenytoin exhibit zero order = unpredictable half life
What is the clinical importance of drug monitoring?
Pharmacokinetics Zero order kinetics Long half life Narrow therapeutic window Drug-drug interactions Reported or expected toxic effects Therapeutic effect - response
What is the aim of half life considerations?
To maintain a minimum effective conc of drug
T1/2 alone does not give us info about duration of therapeutic effect
When plasma concentration has been reached, how should dosing be altered?
Dosing should match clearance to maintain the desired therapeutic effect
Only amount of drug that has been eliminated needs to be replaced in subsequent doses - incorporating bioavailability
