LECTURE 5-8: PHARMACOKINETICS Flashcards
life cycle of a drug
Administration -> absorption -> distribution -> action -> metabolism -> elimination
Drug given by oral route is given the abbreviation
PO (per oral)
two main routes of administration
- oral
- parenteral
parenteral administration abbreviations
- IV
- IM
- SC, SQ
Bolus dosing
single dose, all at once
IV constant rate infusions (CRI)
medication continuously administered to a patient and is used to maintain consistent plasma levels of that medication
Absorption
- Getting the drug from the site of administration into the blood
does IV have absorption phase
No
bioavailability
The fraction of drug that gets into the blood
What’s in a tablet or an injection besides the drug?
excipient / bulk / carrier
excipient
inactive substance used to carry an active substance
examples of excipients
– Salts
– Inactive substances such as talcum, lactose
– Solubilising liquids e.g. alcohol, propylene glycol
why add excipient
– to make the drug work better
– sometimes to make the drug easier to work with
what is the rate limiting steps of absorption
solubilisation of the drug into the aqueous environment of the gut
how are majority of drugs absorbed
passive diffusion
factors affecting absorption
- lipophilicity/hydrophilicity
- surface area
- first-pass metabolism
- vascularity / disease process
what is bioavailability compared against, what gives 100% bioavailability
IV
Drug distribution
- Moving the blood from the body to the extravascular space (i.e. the tissues)
pattern of drug distribution
- Where drugs go around the body
volume of distribution
- the propensity that a drug has for leaving the blood and entering the tissues is calculated by the pharmacokinetic term volume of distribution (Vd)
drug distribution depends upon
- regional blood flow
- rapid distribution to organs with high CO - ability to cross lipid membranes
- lipophilicity/ hydrophilicity
- pH partition effect
- extent that drug binds to tissue and fluid constituents (protein binding)
pH partition effect
o Unionised drug readily diffuses across lipid membranes.
o Acidic drugs are more unionised in acidic environments and alkaline drugs are more unionised in alkaline environments “like likes like”
o Plasma is slightly more basic than tissues.
o Therefore weak bases tend to distribute out of plasma and into tissues. In the relatively more acidic environment of the tissues the basic drugs become “trapped”.
most drugs are ___ acids or bases
weak
proteins in blood and tissues have ___ charges
weak
NSAIDs examples
ibuprofen
why do NSAIDs accumulate at site of inflammation despite their low Vd’s (and why they have a low Vd)
- they are highly bound to plasma proteins (e.g. albumin) and so there is little unbound (= free) drug available for distribution, so NSAIDs have low Vd’s
- but during inflammation (when the drug is most needed) it will follow the blood protein into the inflamed area
Do NSAIDs have high or low Vd
low
Vd =
drug amount in body / blood concentration
Metabolism
- The biotransformation of a lipophilic compound into a more hydrophilic compound in order to facilitate elimination
Why needs to be hydrophilic for elimination?
Kidney can do it easier
phase 1 metabolism
- substance is converted to a more polar metabolite
- oxidation, reduction and hydrolysis
- often involves cytochrome p450 enzyme system
Phase II metabolism
- following or independent of phase I
- involves conjugation with an endogenous hydrophilic compound
- this phase makes it more hydrophilic
- gluccurondination is most common
where does phase II occur
liver!!
but sometimes kidney and intestine
hepatic enzymes can be induced by
some older anticonvulsant drugs
hepatic enzymes can be inhibited by
omeprazole
sequelae to metabolism
- excretion of the water-soluble metabolite
- conversion of prodrugs -> active molecule
- enterohepatic cycling
enterohepatic cycling
Drug absorbed from gut straight into hepatic circulation, metabolised and eliminated in the gut, reabsorbed from the gut into hepatic…
Elimination
removal of drug form body
elimination can be accelerated by
diuresis
elimination can be slowed by
kidney disease or heart disease
Metabolism and elimination is quantified by
drug clearance
Major modes of elimination
- Hepatic excretion – passed in faeces via bile
- Renal excretion – passed in urine
- Combination of hepatic AND renal
- Miscellaneous e.g. exhalation, sweat, milk etc
Renal drug removal vie
- Glomerular filtration
- Tubular secretion
renal drug reabsorption by
- Tubular reabsorption
what kind of drugs may be reabsorbed from kidney
highly lipophilic drugs
what is the upper MW limit of filtration through glomerulus
20,000
what affects renal elimination
pH of drug and environment effects drug lipophilicity / hydrophilicty which effect renal elimination
If someone had an entire packet of weak acid drug - how could elimination be hastened
alkalinise their urine - will make drug more ionised meaning less reabsorbed and faster elimination
Drug clearance
- The volume of blood from which a drug is removed per unit time
- Usually expressed in mL/min/kg (alternatively L/hr/kg)
M and E together are quantified by
drug clearance
ratio between the proportion of unioinsed to ionised is determined by
pH of drug relevant to pH of the environment
