Pharmacokinetics Concepts Flashcards
What is pharmacokinetics?
The study of movement of a drug into and out of the body - the study of what the body does to the drug
What is pharmacodynamics?
The study of drug effect and the mechanisms of action - what the drug does to the body
What is pharmacogenetics?
The effect of genetic variability on the pharmacokinetics, or the dynamics of a drug on an individual
What are the main processes involved in drug therapy?
- Pharmaceutical process
- Pharmacokinetic process
- Pharmacodynamic process
- Therapeutic process
What question is asked when considering the pharmaceutical process?
Is the drug getting into the patient
What question is asked when considering the pharmacokinetic process?
Is the drug getting to its site of action
What aspects does the pharmacokinetic process consist of?
- Absorption
- Distribution
- Metabolism
- Elimination
What question is being asked when considering the pharmacodynamic process?
Is the drug producing the required pharmacological effect?
What question is being asked when considering the therapeutic process?
Is the pharmacological effect being translated into a therapeutic effect?
Draw a diagram illustrating the relationship between pharmaceutical process, pharmacokinetic process, pharmacodynamic process, and therapeutic process
Draw a diagram illustrating the stages of ADME in relation to a time-concentration graph
What is meant by oral bioavailability?
The fraction of a dose which finds its way into a body compartment, usually the circulation
What is the bioavailability for an intravenous bolus?
100%
How is the bioavailability worked out for all other routes apart from IV?
You compare the amount reaching the body compartment by that route with intravenous bioavailability
Give the equation for the calculation of oral bioavailability?
= area under the curve (oral) / area under the curve (IV)
What is meant by area under the curve when calculating oral bioavailability?
The area under the curve of plasma concentration x time post dose - this is the total drug exposure
What factors affect bioavailability?
- Drug formulation
- Age
- Food
- Vomiting/malabsorption
- Fire pass metabolism
What is first pass metabolism?
Any metabolism occuring before the drug enters the systemic circulation
In what locations can first pass metabolism occur?
- Gut lumen
- Gut wall
- Liver
What produces the first pass metabolism effect in the gut lumen?
- Gastric acid
- Proteolytic enzymes
- Grapefruit juice
What drugs are affected by the first pass metabolism in the gut lumen?
- Benzylpenicillin
- Insulin
- Ciclosporin
What produces the first pass affect in the gut wall?
P-glycoprotein efflux, which pumps drugs out of the intestinal entrocytes and back into the lumen
What drugs are affected by first pass metabolism in the gut wall?
Ciclosporin
What produces the first pass effect in the liver?
Drugs get oxidised and conjugated
What drugs are affected by the first pass effect in the liver?
- Propanolol
- Morphine
What does the distribution of a drug refer to?
Its ability to ‘dissolve’ in the body
What are the two key factors associated with drug distribution?
- Protein binding
- Volume of distribution
When are many drugs bound to circulating proteins?
Once they are in the systemic circulation
Give 4 proteins that bind drugs in the systemic circulation?
- Albumin
- Globulins
- Lipoproteins
- Acid glycoproteins
What kind of drugs does albumin bind?
Acidic drugs
What kind of drugs do globulins bind?
Hormones
What kind of drugs to lipoproteins bind?
Basic drugs
What kind of drugs do acid glycoproteins bind?
Basic drugs
What binding state must drugs be in to have a pharmacological effect?
Most must be unbound (free)
Why must most drugs be unbound in order to have a pharmacological effect?
Because only the fraction of the drug that is not protein-bound can bind to the cellular receptors, pass across tissue membranes, gain acess to cellular enzymes etc
What does the level of free drug determine?
The action of the drug at its target receptor, and its elimination
What can displacement of drugs from binding sites produce?
Protein binding drug interactions
What affect may changes in protein binding have?
Can cause changes in drug distributino
When are changes in protein binding important?
If one of three criteria are met;
- High protein binding
- Low Vd
- Narrow therapeutic ratio
What factors affect protein binding?
- Hypoalbuminaemia
- Pregnancy
- Renal failure
- Displacement by other drugs
Regarding distribution, what is true of drug that is not bound to plasma proteins?
It is available for distribution to the tissues of the body
Are drugs found in body fluids, or in tissues?
Some are distributed only to body fluids, whereas others are found extensively in body tissues
What is volume of distribution?
A measure of how widely a drug is distributed in body tissues
Give the equation for calculating volume of distribution?
= dose / [drug]10
Where is volume of distribution a useful measure?
Useful in understanding dosing regimes
What is half life proportional to?
Vd and clearance
What is the body fluid distribution in a 70kg man?
- Intracellular space 55% (23L)
- Intravascular space 12% (5L)
- Interstitial space 33% (14L)
What can tissue distribution be affected by?
- Specific receptor sites in tissues
- Regional blood flow
- Lipid solubility
- Active transport
- Disease states
- Drug interactions
What is a drug initially metabolised by?
Phase 1 enzymes
What happens once a drug has been metabolised by phase 1 enzymes?
CYPs perform a variety of functions
What functions are performed by CYPs?
- Oxidation
- Dealkylation
- Reduction
- Hydrolysis
What happens after CYPs have performed their functions on drugs?
It either;
- Gets metabolised by phase II enzymes
- Go to the kidney
- Go to the gallbladder
What happens to drugs metabolised by phase II enzymes?
They then get conjugated with;
- Glucoronide
- Sulphate
- Glutathione
- N-acetyl
What happens to the products of conjugation of drugs that have gone down the phase II metabolism path?
They go to the gallbladder or the kidney
What does whether the products of phase II metabolism go to the kidney or the gallbladder depend on?
The molecular weight
What is true of the end product of conjugation of phase II metabolised drugs?
They are water soluble
What is the advantage of the products of conjugation of phase II metabolised drugs being water soluble?
- It enables rapid elimination from the body
- They are usually pharmacologically inactive
When do drugs go the kidney after phase I metabolism?
If the molecular weight is <300
What happens to the drugs that go to the kidney?
They are excreted in urine
When do drugs go the gallbladder after phase I metabolism?
If the molecular weight is >300
What happens to the drugs that go to the gallbladder?
They are excreted in bile
When can an active metabolite be produced?
- When a pharmacologically inactive compound is metabolised to one with pharmacological activity
- When a pharmacologically active compound is metabolised to other active compounds
What is it called when a drug is metabolised to a pharmacologically active compound in the body?
A ‘pro-drug’
Give two examples of pro-drugs
- Inactive enalaprilat to active enalapril
- L-dopa metabolised to more active metabolite
What is the advantage of L-dopa being metabolised to a more active metabolite?
Improves distribution, and allows it to cross the blood brain barrier
Give two examples of where pharmacologically active compounds are metabolised to other active compounds
- Codeine to morphine
- Lorsartan to EXP3174
What are oxidation and reduction in phase 1 of drug metabolism in part dependant on?
Cytochrome P450 family of enzymse
What can the activity of cytochrome P450 enzymes be influenced by?
Enzyme-inducing and enzyme-inhibiting drugs
Other than enzyme-inducing and -inhibiting drugs, what else affects cytochrome P450 enzymes?
- Age
- Liver disease
- Hepatic blood flow
- Cigarette and alcohol consumption
Other than acting on cytochrome P450 drugs, what else do enzyme inhibiting and inducing drugs do?
Alter the rate of metabolism of other drugs
Where are the cytochrome P450 enzymes present?
Mainly in the liver, but also in the gut and lungs
What are the most important cytochrome P450 types?
- 2D6
- 2C9
- 2C19
- 3A
How does CYP2D6 vary depending on race?
- Absent in 7% of Caucasians
- Hyperactive in 30% in East Africans
What does CYP2D6 metabolise?
- Codeine
- Beta-blockers
- Tricyclics
What is CYP2D6 inhibited by?
- Fluxoetine
- Paroxetine
- Haloperidol
- Quinidine
How does CYP2C9 vary depending on race?
Absent in 1% of Caucasian and Blacks
What does CYP2C9 metabolise?
- Most NSAIDs
- S-warfarin
- Phenytoin
- Tolbutamide
What is CYP2C0 inhibited by?
Fluconazole
What is CYP2CP induced by?
- Carbamazepine
- Ethanol
How does CYP2C19 vary depending on race?
- Absent in 30% of Asians
- Absent in 5% of Caucasians
What does CYP2C19 metabolise?
- Diazepine
- Phenytoin
- Omeprazole
What is CYP2C19 inhibited by?
- Ketoconazole
- Omeprazole
- Isoniazid
- Fluoxetine
- Ritonavir
What is CYP2C19 induced by?
Rifampicin
What is CYP3A involved in the metabolism of?
- Calcium channel blockers
- Benzodiazepines
- HIV protease inhibitors
- Most statins
- Cyclosporin
- Non-sedating anti-histamines
What drugs act as CYP3A inhibitors?
- Anti-fungals
- Cimetidine
- Macrolides
- Grapefruit juice
Give 3 anti-fungals that act as CYP3A inhibitors
- Ketoconazole
- Flucoanzole
- Itraconazole
What drugs act as CYP3A inducers?
- Carbamazepine
- Phenytoin
- Rifampicin
- Ritonavir
- St Johns Wort
What are cytochrome P450 enzymes?
A superfamily of isoforms
What % of human drug metabolism are cytochrome P450 enzymes responsible for?
Around 90%
Give two examples of toxins metabolised by cytochrome P450 enzymes
- Carcinogens
- Pesticides
What is the result of the genetic differences in cytochrome P450 enzymes?
There are genetic differences in metabolism
Clinically, where is metabolism important?
In drug prescribing
What should be considered while prescribing to prevent interactions?
Over the counter medications and food
What factors are important in the metabolism of drugs?
- Race
- Age
- Sex
- Species
- Clinical or physiological condition
Where is the consideration of the effect of race on drug metabolism important?
In the development of pharmacogenetics
How does age affect the metabolism of drugs?
It is reduced in children and the elderly
Give an example of where metabolism is affected by gender?
Women are slower ethanol metabolisers
When is the consideration of the effect of species on drug metabolism important?
When considering drug development
What is the main route of drug elimination?
The kidney
Other than the kidneys, what are the other routes of drug metabolism?
- Lungs
- Breast milk
- Sweat
- Tears
- Genital secretions
- Bile
- Saliva
What processes determine the renal excretion of drugs?
- Glomerular filtration
- Passive tubular reabsorption
- Active tubular secretion
What drugs have their excretion affected by glomerular filtration?
Unbound drugs, e.g. gentamicin
Give an example of a drug where the excretion is affected by passive tubular reabsorption?
Aspirin
What is passive tubular reabsorption affected by?
- Urine flow rate
- pH
Give an example of a drug where the excretion is affected by active tubular secretion
Penicillin
What is clearance?
The ability of the body to excrete the drug
What is clearance mostly affected by?
GFR - if the GFR is reduced, the clearance is reduced
How is half life related to clearance?
They are inversely proportional
What are the categories of elimination kinetics?
- First order kinetics
- Zero order kinetics
Describe the elimination in first order kinetics
Linear
What is meant by elimination being linear?
The rate of elimination is proportional to the drug level - a constant fraction of drug is eliminated in unit time
Can half life be defined with first order kinetics?
Yes
Describe the elimination of drug in zero-order kinetics
Non-linear
What is meant by non-linear elimination?
The rate of elimination is constant
What kind of kinetics do most drugs exhibit at high doses?
Zero order
Why do most drugs exhibit zero order kinetics at high doses?
Because the receptors/enzymes become saturated
What is the problem with zero order drugs?
They are more likely to result in toxicity
Why are zero order drugs more likely to result in toxicity?
- No half life is calculable
- Small dose changes may produce large increments in dose, or lead to toxicity
What are the potential reasons for drugs requiring monitoring?
- Phamacokinetic reasons
- Known toxic effects
What are the pharmacokinetic reasons for drug monitoring?
- Zero order kinetics
- Long half-life
- Narrow therapeutic window
- At greater risk of drug-drug interactions
Give two examples of known toxic effects of drugs that would necessitate drug monitoring
- Bone marrow suppression
- Alteration in U&Es
How long does it take to reach a steady state during repeated drug administration?
3-5 half lives, generally irrespective of dose or frequency of administration
How long does it take to eliminate most of the drug once a steady state is reached?
4-5 half lives
What is the equation for calculating loading doses?
Vd x [Drug]target
What is the equation for calculating half life?
loge0.5 / k
= 0.693 / k
What is k?
The elimination rate constant, which is determined from the slope of the curve
What determines k?
The ratio of clearance to volume of distribution
How do you calculate half life from volume of distribution?
Vd / Cl
What is the result of half life being equal to Vd / Cl?
Half life is proportional to volume of distribution, or inversely proportional to clearance
What might you have to take account of when calculating half life?
Chronic kidney disease
Why may you have to account for chronic kidney disease in the half life calculation?
Clearance from the kidney is proportional to renal function (GFR), and so half life is inversely proportional to clearance
What is the result of most drugs not remaining in the plasma?
Distribution occurs in 2 or more compartments
Is the equilibrium of drugs between different body compartments equal?
No
What is the result of the equilibrium of drugs between different compartments being different?
The rate of elimination can be different
