1 - General Principles of Pharmacology Flashcards
what is pharmaoclogy
study of drugs
phamacodynamics
study of biochemical and physiological effects of drugs on the body
- what the drug does to the body
what is drug: target interaction
drugs exert their effect by binding to specific target protein molecules
targets; receptors/enzymes/ion channels.
what is an agonist drug
drug can stimulate its target to produce a desired response
what is an antagonist drug
drug blocks the target to prevent binding of the natural agonist
sources of drug can be
- natural, e.g alkaloids (Atropine)
- semi- synthetic (prepared by chemical modification of natural drugs) e.g cyclopentalate
- synthetic - prepared by chemical synthesis in labs
drugs should have high specificity. what happens if you increase the dose of drug
it can cause the drug to affect targets other than the principle ones, which can lead to side effects
the lower the potency of the drug…
higher dose needed, greater risk of unwanted effects
what is therepeutic index
A measure of the potential of a drug to cause harm
Expressed as a ratio - between the toxic dose and the therepeutic dose of the drug
narrow TI means
the drug needs to be prescirbed ore carefully as its more harmful
What is pharmacokinetics
study of the absorption, distribution, metabolism/biotransformation and excretion of drug
-what the body does to the drug
Pharmacokinetics examples
- absorbtion
- distribution
- biotransformation
- excretion
most common route of drug entry
oral
alternative drug entry routes
- injection (perenteral) non oral
- local administration (creams/inhaled drugs)
-intrathecal - inject into spine
drug ends up in plasma, then sent to target to exhibit response
when are drugs administered by injection
if drug needs to be absorbed more rapidly or if poorly absorbed from gut/GI irritation
most common route of excretion
kidney (urine)
Absorbtion - elaborate
for a drug to reach target tissue, it needs to be absorbed from site of administration
what do unionised (non-polar) drugs do
readily penetrate cell membranes as they are lipophillic
most drugs are
weak acids or weak bases - can exist in ionised or unionsed forms
what is the balance between ionised/unionised forms determined by?
surrounding pH and the dissociation constant PK
pK of drug
represents the pH at which the drug is 50% ionised
acid is
proton donor
weak acid proton donor equation (henderson-hasselbatch)
50% of the drug is in A- (ionised) form
50% of drug is in HA- (non ionised form)
what does position of equilibrium depend on
pH
where will the reaction shift in an acid environement
left (unionised form)
where will the reaction shift in an alkaline environement for a weak acid
to the right (ionised form)
oral absorption process (acid_
- passes into stomach (acid environment, low pH)
- passes through SI, (alkaline, pH of SI rises)
acid environment, H concentration is high, equib shifts to left, so most of drug is un- ionised form: more readily absorbed
where are weak acids well absorbed
in an acid environemnt ( more readily absorbed in lining of stomach )
what happens when drug passes through intestine
pH starts to rise in intestine, equib shifts to right, and more of drug is in ionised form (A-).
these molecules are more readily absorbed across membrane . drug has weak absorbtion in alkaline environment
where will an acid be concentrated (and less well absorbed)
in a compartment with high pH
in the intestine when equilibrium if shifted to right, what happens
the drug is trapped in ionised form (pH)- the absorption is weaker as the pH is higher
ionised form of weak base
BH+
non ionised form of weak base
B
weak base degree of ionisation formula
weak base in acid environment
high h+ conc, pH shifts to left.
drug present in ionised form (BH+)
describe the weak base in the acid environment
- concentrated
- low pH
- not absorbed in this environment
- drug is trappd in acid enviorment
weak base in alkaline environment
drug at SI, equib. shifts to right so more of the drug is in un-ionised form (B)
describe the weak base in alkaline environment
basic drug, non ionised form
-readily absorbed
- greater ability to cross lipid membranes
an alkaline drug will be concentrated in a compartment with low pH
where is a weak acid such as aspirin more likely to be absorbed
pKa = 3.5
more likley to be absorbed from the stomach (Acid environment)
where is a weak base more likely to be absorbed
Pethidin pKa = 8.6
In the SI, alkaline enviornment
Weak acids more likely to be absorbed where?
stomach. found in un-ionsed form. more readily absorbed
weak base more likely to be absorbed where>
high pk, small intestine. ionised fom
what do low and high pK mean
low pk - strong acid
high pk - strong base
weak acids and bases are well absorbed
strong acids (pk <3) and strong base (pk >10) are poorly absorbed since fullty ionised
75% of an orally administered drug is absorbed within
1-3 hours
factors affecting absorbtion
- gut motility (how rapidly drug moves in gut)
- splanchic blood flow
- drug formulation
- physiochemical factors
drug taken after meal?
slowly absorbed since progress to SI is delayed
how can a drug be formulated to delay absoroption
- special coating around it
- capsules
- tablets with resistant coatings
what is bioavailibilty
(once drug is absorbed) the fraction of the dose that proceeds unaltered from the site of administration and becomes available at the sight of action
what is bioavailibility dependant on
- rate of absorbtion
- first pass metabolism (oral)
first pass metabolism
the breakdown of a drug by biotransformation by enzymes within the gut wall/liver- before reaches the plasma compartment
explains why GTN (angina) effective sublingually but not when swallowed
- if this drug was given orally, would be broken down by 1st pass metabolism.
- to stop this its given sublingually so absorbtion takes place by oral mucosa - can directly enter into vascular system into plasma
following absorption, distribution of drug is not uniform due to
- physiochemical properties of the drug
- differences in blood flow between tissues (tissues with greater vascular supply will get > proportion of drug)
- degree of leakiness of the blood vessels within a particular tissue
- drug may have affinity for a certain tissue e.g melanin or fat
cyclopentalate high affinity for melanin px (drug takes longer to work in dark iris) - plasma protein binding
what is plasma protein binding
drugs travel in plasma - partly in solution (unbound) or to plasma proteins (bound.
* albumin - acidic drugs/non-steroidal/anti-inflammatory
- b globin and a acid bind to basic drugs
protein binding reduces availibilty of the active form of the drug.
what do protein bound drugs show
a restricted tissue distribution + slow elimination
how does elimination of drugs occur
metabolism (biotransformation) + excretion
what does metabolism involve
- the enzymatic conversion of the drug into another chemical entity
polar compounds are excreted
well
non polar compounds are excreted
poorly, as excreted by kidney. tend to get reabsorbed across kidney tubules.
metabolism is important for elimination of non polar compounds
where does drug metabolism occur
mostly takes place in the liver.
purpose is to make the drug more ionised (polar) to hasten secretion by kidneys
drug metabolism - 2 types of chemical transformations called
phase I
phase II reactions
what is the purpose of metabolism
to make the drug more polar (hydrophillic) to hasten its secretion by the kidneys
what is the phase 1 reaction of metabolism
- adding or unmasking a functional group
- e.g -OH, NH2, -SH
- oxidations most common reaction, carried out by cytochrome p450 (CYP)
what is the phase 2 reaction of metabolism (conjugation)
- attatchment of a subsituent group (methy, acetyl)
- these reactions make drug more polar so it can be more readily excreted by kidneys
excretion - how do drugs leave the body
-mostly in urine (unchanged or polar metabolites)
- secreted in bile via liver, loss of drug via faeces
variables affecting drug metabolism
- some drugs increase/inhibit drug metabolising enzymes
- genetic polymorphisms lead to inter-individual variation in drug metabolism
- age
how does age affect drug metabolism
- neonates have immature drug metabolizing mechanism.
- elderly have impaired hepatic metabolism of drugs and also show an impaired glomerular filtration rate reducing renal clearance
