Pharmacokinetics Flashcards
Define pharmacodynamics
Study of the drug effect and mechanisms of action
Define pharmacogenetics
The effect of genetic variability in the pharmacokinetics and pharmacodynamics of a drug on an individual
What are the main processes in drug therapy?
Pharmaceutical process - is the drug getting into the patient
Pharmacokinetic - is the drug reaching its site of action
Pharmacodynamic - is the drug producing the required pharmacological effect
Therapeutic process - is the pharmacological effect being translated into a therapeutic effect
What are the components of the pharmacokinetic process?
Absorption
Distribution
Metabolism
Elimination
What is bioavailability (F)?
The fraction of a dose that finds it way into a body compartment - usually the circulation
What is the bioavailability for an IV bonus?
100%
How is bioavailability calculated?
The area under the curve in a graph of plasma concentration against time
What factors can affect bioavailability?
Absorption
- drug formulation
- age
- food - lipid soluble > water soluble
- vomiting, malabsorption etc
First pass metabolism
Where can first pass metabolism occur?
Gut lumen - gastric acid, proteolytic enzymes, grapefruit juice
Gut wall - p-glycoprotein efflux pumps drugs out of the intestinal enterocytes back into the lumen
Liver
What is first pass metabolism?
Any metabolism occurring before the drug enters the systemic circulation
What are the two key factors affecting distribution?
Protein binding
Volume of distribution
Which proteins can drugs bind to?
Albumin (acidic drugs)
Globulins (hormones)
Lipoproteins (basic drugs)
Acid glycoproteins (basic drugs)
What factors can affect protein binding?
Hypoalbuminaemia
Pregnancy
Renal failure
Displacement by other drugs
How can volume of distribution be calculated?
Dose divided by [drug] at t0
What is the relationship between half life and volume of distribution?
Half life is proportional to Vd
What can tissue distribution be affected by?
Specific receptor sites in tissues Regional blood flow Lipid solubility Active transport Disease states Drug interaction
What is the aim of drug metabolism?
Normally so that drugs can be water-soluble and so eliminated rapidly from the body
What happens in phase 1 metabolism?
Oxidation and reduction
Uses CYP450 enzymes
What can affect CYP450 enzyme activity?
Enzyme-inducing and inhibiting drugs Age Liver disease Hepatic blood flow Cigarettes Alcohol
Where can CYP450 enzymes be found?
Liver
Gut
Lung
What are the main enzyme inducer drugs?
Phenytoin
Carbamazepine
Barbiturates
Rifampicin
Alcohol
Sulphonylureas
What are the main enzyme inhibiting drugs?
Omeprazole
Disulfiram Erythromycin Vaporic acid Isoniazid Cimetidine Ethanol (acute) Sulphonamides
What are the different routes of elimination of drugs?
Kidney Lungs Breast milk Sweat Tears Genital secretions Bile Saliva
What three processes determine renal excretion of drugs?
Glomerular filtration
Passive tubular reabsorption
Active tubular secretion
Define clearance
Ability of the body to excrete a drug
Relationship between clearance and GFR?
Normally equal
If GFR decreases, so does clearance
What is the relationship between half life and clearance?
Half life is inversely proportional to clearance
As clearance increases, half life decreases
What are first order kinetics?
Rate of elimination is proportional to drug level.
A constant fraction of drug is eliminated per unit of time.
Half-life can be defined.
Linear
What are zero order kinetics?
Where rate of elimination is constant and independent of drug concentration. Gives a straight line when linear
What does clearance/volume of distribution equal?
k - the elimination constant
How can half life be calculated?
(0.693 x Vd) / clearance
How do HRH factors affect clearance?
Heart - CVS system factors affect blood flow to the main organs of elimination
Renal - factors affecting renal elimination
Hepatic - factors affecting hepatic elimination
Why are zero order kinetics unpredictable?
Fixed rate of elimination per unit time
Therefore, small dose changes can produce large increments of dose or lead to toxicity
Cannot calculate a half life
When is drug monitoring required?
Zero order kinetics
Long half life
Narrow therapeutic window
Risk of DDIs
Known toxic effects eg bone marrow suppression
Monitoring therapeutic effect eg BP, glucose
After how many half-lives is a steady state achieved?
4 to 5
Irrespective of dose or frequency of administration
Define pharmacokinetics
Study of the movement of a drug through the body
What the body does to the drug
Give pharmacokinetic features of digoxin
Large Vd
Excreted by kidneys
Long half life
What does a loading dose allow?
Achieve a rapid therapeutic dose level - can skip forward a few days if there is a long half life
Antidote for digoxin?
Digifab
Symptoms of a digitoxic patient?
Bradycardia
Xanthopsia (see yellow)
Vomiting
Which pathway is most paracetamol metabolised by normally?
Glucaronide and sulphate pathways
Which is the bad pathway for paracetamol and why?
P450 oxidation
Produces NAPQI which is conjugated with glutathione to produce inactive metabolites
How is a paracetamol overdose treated?
Glutathione replacement - N-acetylcysteine
Equation to work out loading dose?
Loading dose = Vd x target drug concentration
Way does the slope of an elimination curve represent?
The elimination rate constant (k)
k = ratio of clearance to Vd
At what types of sites can drugs work?
Cell surface receptors Nuclear receptors Enzyme inhibitors Ion channel blockers Transport inhibitors Inhibitors of signal transduction proteins
Define affinity
The tendency of a drug to bind to a specific receptor type
Define efficacy
The ability of a drug to produce a response as a result of the receptor or receptors being occupied - describes the maximum effect of a drug
Define potency
Dose required to produce the desired biological response.
Describes the different doses of two drugs requires to exact the same effect
How is the therapeutic index calculated?
EC50 of adverse effect / EC50 of desired effect
i.e.
Toxic dose (TD50) / effective dose (ED50)
What is the therapeutic index (in words)
The range of doses that can effectively treat a condition while still remaining safe
What is the difference between time of onset of drugs that inhibit and drugs that induce CYP enzymes (like how long does it take for the effects of the DDIs to be seen?)
Inhibition of enzymes happens quickly (hours to days)
Induction of enzymes happens over days to weeks
How to calculate the loading dose?
Vd x CpSS (steady state plasma concentration)
Give some examples of DDIs
Agonism/antagonism at the same receptor
Agonism/antagonism at different receptors
Non-selective drugs
Enhanced effect by other means eg digoxin toxicity enhanced by hypokalaemia caused by a loop diuretic
Example of agonism/antagonism at the same receptor? (DDI)
Opiate analgesics and naloxone
Beta blockers and beta 2 agonists
Example of agonism/antagonism at different receptors?
Amlodipine and bendroflumethiazide
Warfarin and aspirin
Give an example of a drug which is not selective which can lead to ADRs
Antidepressants - interact with many receptor subtypes
- adrenergic
- noradrenergic
- serotoninergic
- cholinergic
Which drugs commonly have DDIs?
Anticonvulsants Antibiotics Anticoagulants Antidepressants/antipsychotics Antiarrhythmics
Which foods can cause interactions and how?
Grapefruit juice - inhibit several CYP450 enzymes which reduces clearance of drugs
Cranberry juice - inhibits CYP2C9
Which drugs should you not have grapefruit juice with?
Simvastatin
Amiodarone
Which drugs should you not have cranberry juice with?
Warfarin - enhances its anticoagulant effect
How can renal disease lead to adverse effects?
Reduced clearance
Disturbances of electrolytes may predispose to toxicity, especially potassium
How can hepatic disease affect drug activity?
Reduced clearance of hepatically metabolised drugs
Reduced CYP450 enzymes
Longer half-lives
What is the classic drug to be careful of in hepatic disease?
Opiates in cirrhosis - small doses can accumulate leading to coma
How can cardiac disease affect drug activity?
Excessive response to hypotensive agents
Reduce organ perfusion
-hepatic
-renal
What factors increase the risk of ADRs?
Careless prescribing
Polypharmacy
Patients at extremes of age due altered PK profile and co-morbidities
Multiple medical problems
Drugs with narrow therapeutic index
Drugs used near their minimum effective concentration - increased risk of treatment failure
What are the different severities of ADRs?
Major - permanent/life threatening
Moderate - requires additional treatment
Mild - trivial/unnoticeable
What are some patient causes of variability in drug response?
Body weight Age Gender Genetics Condition of health Placebo effect
What are some causes related to administration that can affect drug response?
Dose Formulation Route of administration Repeated administration of drugs -allergies -resistance -tolerance
What are some causes of variability in drug response due to drug interactions/kinetics
Chemical/physical GI absorption Protein binding/distribution Metabolism (stimulation/inhibition) Excretion Receptor (potentiation/antagonism) Changes in pH/electrolytes
Define specificity
Drug is limited to one receptor - the complementary drug and receptors
Will not activate other receptors even at high concentrations
Define selectivity
The clinical effect the drug has and can be measured with specific therapeutic indices
Increase the conc can cause it to bind to other receptors
But has a greater affinity for one receptor
What are some pharmacokinetic-related DDIs which affect absorption?
- changes in gut motility eg opiates and atropine increase Cmax and Tmax
- calcium salts bind to tetracyclines to reduce their absorption
- cholestyramine binds to warfarin and digoxin to reduce their absorption
What are some pharmacokinetic-related DDIs which affect distribution?
Object drugs administered at a dose where there are more binding sites than molecules. Precipitant drugs administered so there are more molecules than binding sites so they displace object drugs
Administering a precipitation drug can cause object drug levels to rise to toxic levels
What are some pharmacokinetic-related DDIs which affect metabolism?
Can affect the metabolism of themselves or other drugs by induction or inhibition of enzymes
What are some pharmacokinetic-related DDIs which affect excretion?
Can decrease the protein binding of another drug which accelerates its excretion.
Can inhibit tubular secretion resulting in increased plasma levels eg NSAIDs can reduce tubular secretion
What are on target ADRs?
ADRs which are due to the exaggerated therapeutic effect of the drug eg due to increased dosing
-drugs for hypertension can cause dizziness
Often include effects on the same receptor type but found in different tissues
What are off target ADRs?
Involves interaction of other receptor subtypes secondarily to the one intended for the therapeutic effect
Can occur with metabolites that can act as a toxin
Also includes inappropriate immune responses
