Principles of pharmacokinetics Flashcards
Processes involved in pharmacokinetics
Absorption
Distribution
Metabolism
Elimination
Effect of enteric coating on a tablet on its rate of absorption
Slows
pKa of a drug
pH at which half of the drug is in its ionised form
Aspect of drug metabolism where the drug when taken orally is partially metabolised by liver and gut mucosa and so the concentration is reduced before it reaches systemic circulation
First pass metabolism
Mechanisms of absorption of drugs from the GI tract
Active transport
Passive diffusion
Pore filtration
Drug absorption of hydrophilic vs. hydrophobic drugs
Hydrophobic drugs are absorbed better
Site in the GI tract where most absorption takes place
Small intestine
Reverse transporter which actively pumps the dug into the gut lumen from the gut cells and reduces its absorption
P-glycoprotein
Effect of grapefruit juice on P-glycoprotein and drug concentrations
Inhibits P-glycoprotein and increases absorption of certain medications
Time frame for absorption of drugs administered IM
Over 10-30 minutes
Method of administration for most rapid drug absorption
IV
Percentage bioavailability with IV administration of a drug
100%
Two types of diffusion which can be involved in drug permeation
Simple diffusion
Facilitated diffusion
Type of diffusion where permeation takes place passively along a concentration gradient
Simple diffusion
Type of diffusion where permeation takes place along a concentration gradient but helped by the presence of carrier mechanisms
Facilitated diffusion
Type of permeation where a drug is transported against a concentration gradient, requiring energy expenditure
Active transport
Form of a drug in terms of ionisation which can cross the lipid membranes of a cell
Nonionised form
Main plasma protein that binds to acidic drugs
Albumin
Main plasma protein that binds to alkaline drugs
Alpha1-acid glycoprotein
Drugs which have 95-99% protein binding
Diazepam
Chlorpromazine
Amitriptyline
Imipramine
Drugs which have 90-95% protein binding
Phenytoin
Valproate
Clomipramine
Equation for volume of distribution
Volume of distribution = quantity of drug / plasma concentration at the time of administration
Characteristics of a drug the volume of distribution gives information about
If the volume of distribution is high the drug has a high affinity for tissues outside the body water and high lipid solubility
If the drug is highly protein bound its volume of distribution will be low
Junctions found in the blood brain barrier
Tight junctions
Definition of bioavailability
The percentage of a drug which is detected in the systemic circulation after its administration
Percentage of first pass metabolism the rectal route avoids
66%
Physiological changes in elderly people that can affect drug absorption - generally leading to same amount of drug absorption but at a slower rate
Reduced gastric acid secretion
Reduced gastric motility
Reduced small bowel surface area
Reduced first pass metabolism
Physiological changes in elderly people that can affect drug distribution
Increased proportion of body fat Decreased lean body mass Decreased total body water Increased alpha-1-acid glycoprotein levels Decreased albumin levels
Physiological changes in elderly people that can affect drug metabolism
Decreased hepatic blood flow and cytochrome p450 enzyme activity - but only after age 80
Physiological changes in elderly people that can affect drug excretion
Decreased renal function
Solubility of drugs which are the most rapidly absorbed
Lipid soluble
Permeation of a drug
Lipid membrane permeability of the drug
Permeation of a drug
Lipid membrane permeability of the drug
Form of a drug which is able to cross lipid membranes of a cell
Ionised form
Part of a drug - protein bound vs. not bound - which is active
Not protein bound
Reversibility of plasma protein binding of drugs
Reversible
Effect of protein displacement on drugs
Increases the plasma concentration of free drug
Reason why protein displacement is not usually clinically significant
The metabolism of the drug increases in parallel with the free drug concentration
Factors which affect the ability of a drug to cross the blood brain barrier
Molecule size
Lipid solubility
Ionic status
Ionisation of molecules that are easily able to cross the blood brain barrier
Unionised molecules
Name for the areas of the brain which lack a blood brain barrier
Circumventricular organs
Circumventricular organs of the brain
Subfornical organ Area postrema Vascular organ of lamina terminalis Median eminence Pineal gland Part of the pituitary gland
Administration method of a drug which theoretically allows it to cross the blood brain barrier
Nasal
Measure of comparability of plasma levels of two different formulations of a drug given at the same dose and by the same route
Bioequivalence
Mechanism by which a foreign agent is metabolised and eliminated
Xenobiotics
Principle site of drug metabolism
Liver
Four major routes of drug metabolism
Oxidation
Reduction
Hydrolysis
Conjugation
Number of phases of drug metabolism
2
Metabolic routes involved in phase 1 metabolism
Oxidation
Reduction
Hydrolysis
Necessity of going through phase 1 metabolism to reach phase 2
Not necessary in all drugs
Metabolic route involved in phase 2 metabolism
Conjugation
Most common biochemical process in phase 1 metabolism
Oxidation
Attachment of a hydrophilic ionised group to a drug
Conjugation
Most common substance involved in conjugation
Glucuronic acid
Groups added in conjugation
Glucuronic acid Sulphate Amino acids Acetate Methyl
Relative molecular mass under which a metabolised drug can be excreted in the urine
<300
Relative molecular mass above which a metabolised drug must be excreted in the bile
> 300
Outcomes of metabolism
Active drug is metabolised into an inactive metabolite ready to be excreted
Inactive prodrug is metabolised into its active drug
Elimination occurs at a constant rate despite the concentration of the drug
Zero order kinetics
Has no constant half life as half life decreases with decreasing concentrations of the drug
Elimination occurs at a proportional rate to the concentration of the drug - a constant fraction of the drug is eliminated per unit of time
First order kinetics
Most drugs follow ___ order kinetics
First
Substances which follow zero order kinetics
Phenytoin
Ethanol
Slow release preparations of drugs
Depot medication
Patient factors affecting drug excretion
Increased age decreases excretion
Reduction in renal blood flow e.g. due to dehydration decreases excretion
Renal impairment decreases excretion
Volume of plasma cleared of a drug over a specified time period - includes metabolism to an inactive metabolite and excretion
Clearance
Drugs which show renal elimination without significant hepatic metabolism
Lithium Amisulpride Sulpride Gabapentin Acamprosate Amantadine
Time taken for the plasma concentration of a drug to half
Half life
Dose of a drug at which 50% of people experience a specific adverse effect
Median toxic dose
Dose of a drug at which 50% of patients experience a specific therapeutic effect
Median effective dose
Ratio of the median toxic dose to the median therapeutic dose
Therapeutic index
Plasma levels within which the efficacy of a drug is optimum without toxicity
Therapeutic index range
Plasma levels within which a drug appears to have therapeutic efficacy - does not take into account toxicity
Therapeutic window
Pharmacokinetic changes in pregnancy
Delayed gastric emptying Decreased gastrointestinal motility Increased volume of distribution Decreased albumin level Induction of liver metabolism Increased GFR and renal clearance
Trimester in which physiological changes in pregnancy are most pronounced
Third
Change to plasma volume during pregnancy
Increases
Cause of delayed gastric emptying in pregnancy
Increased progesterone levels
Condition under which protein binding interactions of drugs become significant
Renal disease - can cause proteinuria
Part of the GI tract with poor oral absorption for most psychotropics
Stomach
Parts of the body where drug metabolism occurs
Liver
Kidneys
Intestine
Lungs
