A.D.M.E Flashcards
what is pharmacokinetics
the study and characterisation of drug absorption, distribution, metabolism and excretion
what is pharmacodynamics
what the body does to the drug as opposed to what the drug does to the body
what does knowledge of pharmacokinetic properties of a particular drug tell us
what dose to give, how often to give it, how to change the dose in certain medical conditions, how some drug interactions occur
what is absorption
the movement of a drug from the site of administration to the bloodstream
3 mechanisms by which drugs may cross membranes
passive diffusion, facilitated diffusion, active transport
passive diffusion most common
distribution
process of reversible transfer of the drug from the bloodstream to other areas of the body. if the drug does not return to the blood, it has been eliminated.
what is the rate and extent of distribution determined by
- how well perfused the organs/tissues are
- binding of the drug to plasma proteins and tissue components
- permeability of tissue membranes to the drug
- ion trapping
- P-glycoproteins (efflux mechanism)
- pKa
volume of distribution
convenient method of describing how well a drug is removed from the plasma and distributed to the tissues. however, it doesn’t provide any specific info about where the drug is concentrated in a particular organ.
a large Vd implies wide distribution, or extensive tissue binding, or both. conversely, ionised drugs that are trapped un plasma will have small Vd
definition; amount of fluid that would be required to contain the drug in the body at the same concentration as in the blood or plasma.
bioavailability
the proportion if a dose that reaches the systemic circulation in a chemically unaltered form
elimination half life
t1/2
the time required to reduce the plasma concentration to one half of its initial value
can be used to estimate for how long a drug should be stopped if a patient has toxic drug levels
clearance
Cl; volume of plasma in the vascular compartment cleared of drug per unit time by the process of metabolism and excretion
drug can be cleared by renal excretion or by metabolism or both
drug metabolism
drugs are detoxified by a set of xenobiotic-metabolising enzymes;
-cytochrome P450 oxidases, primarily found in the liver
enzymatic action may also convert prodrugs (inactive) to active state
availability of these enzymes is more than sufficient to efficiently metabolise most drugs
exceptions
small number of drugs where concentrations seen in real life use are high enough o saturate the eliminating enzymes e.g. phenytoin, salicylates and ethanol
excretion
elimination of the molecule in its unchanged form, mainly via kidney.
1) glomerular filtration
2) tubular secretion/reabsorption
drug interactions
occur when the effect of the drug is modified by presence of another agent
modifying agents- other drugs, diet, smoking, alcohol
most drug interactions involve changes to the absorption, distribution, metabolism or excretion of drugs
pharmacokinetic vs pharmacodynamic interactions
pharmacokinetic; amount of drug in blood is altered
pharmacodynamic; amount of drug in blood remains the same, but its effect is altered
drug absorption interactions
one drug make the absorption of another drug;
faster or slower, less or more complete
mechanisms;
pH, gastric emptying and intestinal motility, physiochemical interactions
drug distribution interactions
displacement e.g. drug A and B both compete to bind to the same plasma protein
drug metabolism interactions
one drug changes the rate of metabolism of another drug
induction; A increases the rate of metabolism of B, blood concentrations of B fall below normal therapeutic levels. B becomes ineffective
inhibition; A reduces the rate of metabolism of B, blood concentrations increase above that which is safe, B becomes toxic
drug excretion interactions
Drug A increases or reduces the excretion of drug B
blood levels of B fall below or rise above normal therapeutic range
becomes either ineffective or toxic
absorption requirements for passive diffusion
water solubility- almost all drugs are sufficiently water soluble to undergo passive diffusion
lipid solubility- some do lack necessary lipid solubility . in practise, diffusion depends mainly on lipid solubility
efficient molecules of passive diffusion
hydrocarbons, anaesthetics, alcohols, lipids, most drugs
inefficient drugs for passive diffusion
carbohydrates, proteins. ionised molecules
facilitated diffusion
selective gateway allows entry of one group of molecules, but excludes all others
active transport
structurally selective, energy requiring, can operate against concentration gradient
patient characteristics which could effect distribution
oedema, dehydration, obesity, pregnancy - dose needs to be modified accordingly
what compartments can drugs distribute into
plasma, interstitial fluid, intracellular fluid
incomplete oral bioavailability
- failure of disintegration or dissolution
- chemical, enzymatic or bacterial attack
- failure of absorption and p-gp efflux
- first pass metabolism in gut wall or liver
phases of metabolism
phase 1- functionalisation
chemical change-addition of a new functional group
most frequently oxidation, but also reduction
renders the drug more conductive to phase 2
phase 2- conjugation
conjugative or synthetic addition off a polar molecule
drug becomes water soluble and amenable to renal excretion
cytochrome P450
phase 1 oxidative reactions typically involve a cytochrome P450 monooxygenase (CYP)
nomenclature based on nucleic acid and amino acid homology
(nomenclature is genetically based; no functional implication)
CYPs have family, sub family and specific gene e.g. CYP2D6
first pass metabolism in the gut wall
intestinal epithelium is rich in drug metabolising enzymes (CYPs, mainly CYP3A4)
CYP450 activity in intestinal epithelium relative to liver duodenum 50% jejunum 30% ileum 10% colon 25
kidneys and excretion
excretion irreversibly removes drugs or metabolites from the body
the kidneys are the principal organ of excretion, but the liver, GI tract and lungs also may play important roles
excretion by the kidney;1. glomerular filtration - glomerular structure, size constraints, protein binding 2. tubular reabsorption/secretion acidification/alkalisation active transport, competitive/saturable organic acids/bases protein binding
biliary excretion
bile formed in large volumes in the liver->most of the water reabsorbed->concentrated bile stored in the gall bladder->bile excreted into the upper small intestine
drug interactions-changes in pH
stomach-pH is variable
antacids pH^, alcohols and some foods cause acidic secretion pH to decrease
small and large intestine
pH always near neutral
no significant changes seen
gastric emptying and intestinal motility
drug absorption from small intestine is much more efficient than from the stomach, however if drug A alters rate of gastric emptying
- rate of absorption of drug B also altered
physio chemical interactions
two drugs bind together within GI contents and then neither is absorbed. e.g. polyvalent cations, cholestyramine, charcoal
CYP450
gradual onset and offset;
onset–accumulation of inducing agent and increase in enzyme production
offset- elimination of inducing agent and decay of enzymes. result in reduction of plasma concentration of substrate drugs
withdrawal of inducer
patient taking barbiturates and warfarin, barbiturates cause induction-warfarin clearance increased]warfarin dose titrated above normal dose, blood levels now normal
barbiturate suddenly withdrawn and replaced by valproate
warfarin clearance falls- blood levels rise above normal- patient dies
beneficial use of induction
new born infants have poorly developed hepatic metabolic enzymes
conjugate bilirubin inefficiently-some become jaundiced
small doses of barbiturates can be used to induce the liver enzymes and clear the bilirubin
inhibition
not just opposite of induction:
induction- additional CYP450 in the liver
inhibition-no reduction in quantity of CYP450 -existing CYP450 made less effective
probably most significant of all interactions-potentially fatal
fruit juices
grapefruit juice contains antioxidants that inhibit CYP3A4 in the gut wall and liver. leads to increased blood levels of terfenadine and some calcium channel blockers
cranberry juice contains various antioxidants including flavonoids which are known to inhibit CYP450- warfarin levels may rise significantly
drug excretion interactions
mechanism of urinary excretion ; dimple filtration, active secretion (have limited capacity)
mechanism for active secretion; acids, bases,, saturation of mechanisms by one of the competing drugs -other is secreted less efficiently
most important physio-chemical properties
solubility in water, solubility in lipids, electrical charge, size
physiological factors
nature of barriers/membrane
blood supply
site of action
rate of removal
patient factors
age, size/weight, gender. pregnancy, medical condition, ethnicity
benefits of drugs by passing the liver
will not get metabolised by liver (many drugs get therapeutically altered while being metabolised by the liver)
ways you can do this is by giving the drug rectally
factors effecting bioavailability
formulation, physio-chemical properties, physiological factors, patient factors
what is the therapeutic index
ratio of the minimum toxic concentration to the median effective concentration
how to calculate Vd
Vd (L)=dose (gr)/C (gr/L)
or C=dose/Vd
blood brain barrier
specialist cells (glial and endothelial) separate the blood vessels from the cerebrospinal fluid (CSF) exact nature varies depending on location provides additional protection to CNS while regulating transport of essential; molecules ad maintaining a stable environment (homeostasis)
how would weight gain effect Vd
increase in fat (e.g.), depending on drugs solubility, the above may contribute to an increase in Vd, which in tur will require increasing the dose to maintain drug concentration within effective range
excreting organs in the body
kidneys, skin, lungs liver
what may direct a molecule towards excretion by kidney rather than liver
polar molecules get readily filtrated out by the kidney. amphiphilic drugs are more likely to get excreted by the liver into the bile,
how do CYPs differ from one another
substrate, substrate affinity and enzymatic activity
genetic makeup
