Pharmacokinetics and dynamics Flashcards
What does ADME mean?
absorption, distribution, metabolism, excretion
What do we use to measure drug conc and why?
Plasma - all drugs are in equilibrium in the plasma
What are Cmax and Tmax
Cmax = the peak level of action of a drug
Tmax = the time at which drug action is at its peak
Give an example of zero order drug kinetics
IV infusion - drug is instantly in plasma
Give examples of routes of administration that show first order kinetics
IM/SC/oral
What is Bioavailability (F)?
Measure of extent of absorption from administration site to measurement site (plasma)
What factors affect bioavailability?
absorption
first-pass metabolism
What is the distribution phase of drug kinetics?
Distribution around the body occurs after drug reaches circulation
To leave plasma it must pass the plasma membrane
How do drugs leave the plasma
Only uncharged drugs can pass through membrane passively
Certain ionic compounds may go through as ion pair
Some pass through via active transport/carrier mediated transport
What are the features of compounds that can rapidly cross plasma membranes?
Low degree of ionisation
High lipid/water partition in non-ionised form
Relatively low molecular weight (small molecules)
biological affinity with transporters/facilitated diffusion
What is volume of distribution (Vd)
The volume into which a drug appears to be distributed with a concentration equal to that in plasma
A proportionality constant relating the blood/plasma concentration to the amount of drug in the body
Reversible process - drugs can leave and re-enter plasma
What affects the volume of distribution?
the drugs reversible affinity for tissue proteins vs plasma protein
What unit is Vd given in?
L/kg
What are the values of total body water and ECF?
Body water ~ 0.6L/kg
Body ECF ~ 0.1-0.3L/kg
Where does a drug with a Vd of 0.1-0.3L/kg accumulate?
most likely water soluble so mainly in ECF
Where does a drug with a high Vd accumulate?
other sites, not ECF e.g., fentanyl in fat
Give examples of barriers to drug distribution
Blood-brain barrier
Placenta - slows down, not complete barrier
Describe the blood-brain barrier as a barrier to distribution
Multiple tight junction, transporter and efflux pump
Control entrance and expulsion of molecules
Prevents uptake of most drugs
However, if diseased barrier can become leaky
Similar with the testes
Describe the placenta as a barrier to distribution
Trans-placental transfer of drug1: if a drug can be absorbed orally it likely to cross the placenta
Ion trapping of drugs in fetus (particularly basic drugs)
What is the drug elimination rate?
The amount of parent drug eliminated from the body per unit time
Irreversible removal of parent drug (not metabolites)
Unit = mass or moles/t
What are the main routes of drug elimination?
Kidneys
Hepatobiliary system
Lungs
What are the secondary routes of drug eliminiation
milk
sweat
How are drugs metabolised?
Liver converts lipophilic drugs into hydrophilic form (inactive) => excreted
What are CYP enzymes?
non-specific enzymes found in the liver that catabolise drugs
cause: oxidation, reduction, hydrolysis
What is the significance of UGTs (uridine diphosphate glucuronyl transferases)?
Cats are deficient in it -> Limited ability to perform glucuronidation, paracetamol toxicity
What factors affect the passive filtration of drugs in the glomerulus of the kidney?
GFR
Plasma binding proteins
What factors affect the secretion of drugs from the proximal tubule of the kidney?
Affinity for transporters
Lipophilicity
Polarity
What factors affect the re-absorption of drugs in the distal tubule of the kidney?
lipophilicity and polarity
Urine pH
What is drug clearance (CL)?
A measure of the efficiency of the body to clear a drug
The volume of blood/plasma cleared of parent drug per unit time
Unit = L/h/kg
What is the half life of a drug?
The time it takes for the plasma conc of a drug to halve
Always the same if the drug experiences first order kinetics
What is polypharmacy?
When multiple drugs are taken simultaneously
What are drug-drug interactions?
Altered pharmacologic response to one drug caused by the presence of a second drug
What types of drug0drug interactions are there?
Pharmaceutical: interaction prior to administration
Pharmacokinetic: tissue/plasma levels of one drug altered by another one
Pharmacodynamic: action of one drug is altered by another one
What are the possible outcomes of drug-drug interactions?
Summation
Potentiation
Synergism
What is potentiation in drug-drug interactions?
When a drug on its own does not have an effect but may affect/be affected in combination with another drug
What is summation in drug-drug interactions?
combined effect of two drugs produces a result that equals the sum of the individual effects of each agent
What is synergism in drug-drug interactions?
Drug combinations produce a therapeutic or toxic effect greater than sum of each drug’s action
Give an example of summation in drug-drug interactions
e.g. midazolam lowers the dose of propofol needed for anaesthesia
Give an example of potentiation in drug-drug interaction
e.g. probenecid reduces penicillin excretion in urine and increases effectiveness of penicillin
Give examples of synergism in drug-drug interactions
e.g. sulphonamide-trimethoprim (enhanced effects)
Toxicity: aminoglycosides and furosemide
What are the pharmaceutical mechanisms on drug-drug interactions?
Physical
Chemical
Describe physical drug-drug interactions
Incompatibility / interaction:
- Binding to plastic
- Insolubility in certain solutions
Describe the chemical interaction of drugs
Stability of drugs is often pH dependent
Oxidation/reduction reactions
Complex formation eg chelation of drugs
Inactivated by certain vehicles
What are the pharmacokinetic mechanisms of drug-drug interactions?
absorption
distribution
metabolism
excretion
Give examples of absorption as a mechanism of drug-drug interactions
Change in gastric pH and bacterial flora
Chelation of drug in stomach
Altered gastric emptying: can increase or decrease absorption
Interference with intestinal efflux protein (P-glycoprotein)
Give examples of distribution as a mechanism of drug-drug interactions
Competition plasma protein binding but this is not as clinically significant as originally thought
Some drugs reduce blood flow to organs, leading to a) reduced absorption from intra-muscular or sub-cutaneous administration or b) reduced clearance
Give examples of metabolism as a mechanism of drug-drug interactions
Inhibition or induction of liver enzymes (CYP P450) leading to decreased or increase drug clearance.
Give examples of excretion as mechanism for drug-drug interactions
Urinary pH will alter clearance of renally excreted drugs i.e. more alkaline will increase excretion of weak acids
Give examples of drug that inhibit CYP P450 metabolism
Chloramphenicol
fluoroquinolones,
cimetidine
azole anti-fungals
calcium channel blocker,
omeprazole
propofol
Give examples of drug that induce CYP P450 metabolism
Barbiturates (eg phenobartibal, primidone)
cyclosporin
carbamazepine
What are the pharmacodynamic mechanisms of drug-drug interactions?
additive
synergistic
negation
Describe additive interaction of drugs
can be beneficial or detrimental
Enables reduced doses to be administered
Can lead to increased toxicity
Describe negation as a mechanism for drug-drug interactions
Opposing action leading to reduced effect
What are adverse events (ADE)?
Unintended or noxious response to a drug that occurs within a reasonable time frame following administration
What are the common ‘use-patterns’ associated with increased ADE?
Use of human-label drugs
Drugs with low therapeutic indices (more likely to have non-specific effects)
Inappropriate use
Lack of therapeutic goals
Multiple drugs
altered pharmacokinetics (young, old, lactating, pregnant etc.)
what are the types of adverse events?
lack of expected efficacy
unexpected adverse event e.g., exaggerated normal response
Serious adverse event (life-threatening, permanent or prolonged) e.g., hypersensitivity - often idiosyncratic
