Principles of Pharmacology Flashcards
what is pharmacology?
the study of drug action and how this influences physiological function
what is therapeutics?
patient focused drug prescribing and treatment of disease
why is selectivity important?
for drugs to be effective therapeutic agents, they must show high degree of selectivity for a particular drug target
to avoid side effects/adverse effects
what are the 4 types of drug target?
receptors
enzymes
ion channels
transport proteins
what are the 4 types of drug-receptor interactions?
electrostatic
hydrophobic
covalent
stereospecific
what classification of drugs bind to and block receptors, produce no response
antagonists
what classification of drugs has an affinity for receptors but sub maximal efficiacy
partial agonists
what classification of drugs has an affinity for a receptor, maximal efficacy
full agonists
what is affinity?
determines strength binding of drug to receptor
what is efficacy?
ability of individual drug molecules to produce effect once bound to a receptor
what is potency?
refers to concentration or dose of drug needed to produce defined effect
what is a high potency drug?
a drug which produces large response at low concentrations
what are electrostatic drug-receptor interactions?
most common mechanism, includes H bonds and Van der Waals forces
what are hydrophobic drug-receptor interactions?
important for lipid soluble drugs
what are covalent drug-receptor interactions?
tend to be irreversible
less common
what are stereospecific drug-receptor interactions?
drugs exist as stereoisomers and interact stereospecifically with receptors
what are the major pharmacokinetic factors? ADME
absorption
distribution
metabolism
excretion
what is the concept of absorption?
passage of a drug from the site of administration into the plasma
what is the concept of bioavaliability?
fraction of initial dose that gains access to systemic circulation
what is the major determinant of absorption and bioavaliability?
the site of administration
what are examples of drug administration?
oral
inhalation
dermal/percutaneous
intra-nasal
intravenous
do drugs tend to be water soluble or lipid soluble?
water soluble
what are the ways drugs move around the body?
bulk flow transfer
diffusional transfer
how does the IV route of administration differ from all other routes?
IV - bulk flow transfer delivers drug directly to intended site of action
all other routes - must diffuse over at least 1 lipid membrane
what are the mechanisms by which chemicals diffuse over plasma membranes? diffusional transfer
simple diffusion
diffusion across aqueous pores (not very common)
carrier mediated transport
electrochemical gradient
what are the main factors affecting distribution?
regional blood flow
plasma protein binding
capillary permeability
tissue localisation
how does regional blood flow affect distribution?
different tissues receive different amounts of cardiac output
more drug is distributed to tissues with most blood flow
this blood flow is also affected by exercise, meals etc
how does plasma protein binding affect distribution?
only free drugs (not bound to plasma protein) can diffuse out of the blood and access tissues
e.g albumin, testosterone binding globulin etc
how does capillary permeability affect distribution?
very lipid soluble drugs can diffuse across endothelial cells
less lipid soluble drugs need transport via carrier proteins
what organ is the hardest to access
Brain - BBB
what organ is easiest to target
liver due to discontinuous capillaries
what is drug metabolism?
conversion of drugs to metabolites that are water soluble and easier to excrete and eliminate
what are the two phases of drug metabolism?
- main aim to introduce reactive group to drug
- main aim to add conjugate to reactive group
where and how are drugs metabolised?
Liver, cytochrome P450 enzymes
what is an issue for orally administered drugs?
absorption through the small intestine into the hepatic portal blood supply may lead to ‘first pass hepatic metabolism’
what is first pass hepatic metabolism
orally administered drugs pass into the hepatic portal system, passing through the liver before systemic circulation
the drug may be heavily metabolised before reaching systemic circulation
how is first pass hepatic metabolism overcome?
larger doses are administered to ensure enough drug reaches systemic circulation
however, the extent of FPHM differs between people so drug effects and side effects are difficult to predict
how are drugs excreted?
mainly via kidney and liver (urine/bile)
but also through lungs and breast milk
what are the major routes for drug excretion in the kidney?
glomerular filtration
active tubular secretion
passive diffusion across tubular epithelium (this is reabsorption so needs to be avoided for excretion)
what is active tubular secretion?
removal of water soluble drugs from tubule to urine
80% of renal plasma passes onto blood supply to proximal tubule
proximal tubule has two active transport carrier systems - one acidic and one basic
what is passive diffusion across the tubular epithelium?
reabsorption from kidney tubule into blood
lipid soluble
extent of reabsorption dependent on urine pH and drug metabolism
what is biliary excretion of drugs?
liver transports drugs from plasma to bile via transporters
bile is then excreted into intestines and eliminated in the faeces
enterohepatic recycling can occur and significantly prolong drug effect (not excreted)
what is bulk flow transfer
intravenous route
what is diffusional transfer
molecule by molecule cross a short diffusion distance
inhaled, intradermal, intramuscular, subcutaneous etc (as they all cross at least one lipid membrane)
what can unionised drugs do?
cross membranes as they are lipid soluble
what do ionised drugs require
carrier proteins as they are not lipid soluble
but are water soluble so easy transfer in blood
less reaches tissue
what does the ionisation of a drug depend on
the pH of the site where it is absorbed relative to the pKa
if pKa = pH then drug equally dissociated
- for acids(low pKa): if pH less than pKa drug is unionised (more acidic pH than the acid = less ionisation)
if pH greater than pKa drug is ionised (if pH is more alkalotic than the acid = highly ionised) - for bases(high pKa): if pH greater than pKa drug is unionised (more alkalotic pH than the base = less ionisation)
if pH less than pKa drug is ionised (pH more acidic than the base = highly ionised)
how does tissue localisation affect drug distribution
lipid soluble drugs will be better distributed to areas with high fat content e.g brain
water soluble drugs will be better distributed to areas with high water content e.g lean muscle
types of capillary permeabilities
continuous - BBB
discontinuous - liver (big gaps)
fenestrated - kidney (medium sized regular gaps)
what is glomerular filtration dependent on
size of drug - smaller is faster
what is active tubular secretion dependent on
available transporters
better for acidic or basic drugs (water soluble)
what is passive reabsorption dependent on
urine pH
extent of drug metabolism
better for lipid soluble drugs
what type of drugs are more likely to be excreted and why
water soluble drugs
reduced passive reabsorption in kidney DCT
therefore excretion of drug is increased
what is enterohepatic circulation
bile created from drugs excreted by liver to hepatic duct
goes to gallbladder
is excreted to intestines
is then reabsorbed by intestines to the liver again and cycle continues
