Pharmacokinetics Flashcards
Pharmacokinetics
Time course of drugs in body
Drug targets
- receptors
- ion channels
- enzymes - inhibit, false substitution, pro-drug
- transporters - inhibit, false substitution
When you take a drug, steps are:
- liberation
- absorbed
- enters plasma
- excreted
- bound to plasma
- tissue resevoir if hydrophobic
- non-related receptors may bond
- > wanted = therapeutic site of action
A polin
A pore which allows bigger molecules but is normally gated
Pinocytosis
Vesicle fuses with others -> might not need to cross memvrane
Main way a drug crosses lipid membrane
Conc. different -> has to be liphophilic enough to go through but not so much to stay in membrane
Partition coefficient =
[drug] chlorophorm / [drug] water
What does partition coefficient tell us
Solubility -> charged/ uncharged (acid/base)
At 50% ionisation [HA] / [A] =
1
Urine can change ____
pH
Dosage needs to be controlled in pregnant women because
drugs can accumulate in foetus -> ion-trapping from kidney to placenta
Why is enteral G.I. a good method of drug intake?
Doesn’t need to be sterile, convenient
Enteral G.I. intake includes:
- oral
- under tongue (pareteral) - can be thought of as transdermal
- rectum
Every time the drug circulates it goes through which organ?
Liver
Why is buccal/ sublingual/ rectal preferred?
Directly to general circulation so avoids first pass
- > useful with younger children
- useful for some irritants
- when patient unable to take drug -> vomiting/ unconscious
- supposetery
Outline oral intake
Lipid soluble + ion -> weak acids may be bsorbed
- surface area -> stomach is small so mainly in intestines where peristalsis helps dissolve tablet
What can affect oral intake of drugs?
Gut contents - decrease drug. conc. + impaired access to mucosa
Diarrhoea - babies
e.g. tetracycline + milk - chemical interaction
Bioavailability =
How much drug reaches systemic circulation
F = area under the curve/ dose
What are the steps from dose to systemic circ.
stomach - gut - first pass
Bioequivalence
Same 500g gives same amount of drug into plasma from 1 drug brand to the next
What is a 100% bioavailable way of introducing a drug?
Intravascular -> venous/arterial
Drug distribution
Reversible transfer of a drug from 1 location to another in the body depending on physiochemical nature of drug
4 types of distribution pattern:
- Drug remains in vascular system
- Low molecular weight - soluble compounds are uniformly distributed throughout the body of water
- Specific concentration in 1 or more tissues
- Non-uniform distribution based on lipid/water solubility
Apparent volume fo distribution
VD = The volume of fluid the drug would occupy if it were evenly distributed through the volume at concentration in plasma
= Dose/ Cp 0
VD = 3-5
Distribution in vascular system
VD = 30-50
Total body of water
Drug binding
The less a drug is bound the more effective it is
Binding is:
non-specific and reversible
Albumin
Plasma protein that binds to acidic drugs
Glycoproteins bind to
basic drugs
Consequences of protein binding:
- Activity decreases
- Absorption - free conc. low so constant conc. gradient -> sink effect
- Distribution - restricted to binding protein areas
- Storage - dissociates when free drug conc. low
- Elimination - depends on rate limiting step of elimination -> half-life can be longer if less filtered through renal glomerulus or shorter if more brought to liver
- Interactions - low specificity -> competition for binding sites -> more free drug so higher conc. can be toxic e.g. warfarin by acidic drugs
Tissue perfusion limits
transport
Biotransformation phases
- Oxidations, reductions, hydrolyses
2. Conjugations - liver - major site of drug metabolism
Mechanism of elimination in nephron:
- Glomerular filtraion
- molecules > 60kg/mol
- passively filtrates blood (20%) - Tubulor secretion (80%)
- enzymes transporting drugs from plasma to urine
- > competition reduces renal clearance
- > clearance rate increases by 650 mill - Tubular reabsorption
- acidic/basic increases reabsorption of weak acid/base
Hepatic excretion
Bile is produced at a rate of 0.5-1 l/day and is a major route of excretion for a few drugs (e.g.
cromoglycate) and rather more metabolites (e.g. morphine glucuronide). Drug excreted in the bile
may be reabsorbed in the intestine and so enter an enterohepatic circulation. A significant
proportion of drug in the body may be within this enteric pool.
First order elimination
Rate of elimination is proportional to the plasma concentration of the drug, Cp. Cp will decline exponentially when drug administration is stopped. Under these conditions it is possible to define a plasma halflife - the time taken for the plasma concentration to fall by 50%. The plasma half-life is thus an important measure of the speed of drug elimination.
Zero order elimination
Rate of elimination is independent of the plasma concentration, a situation
which arises when the process of elimination (e.g. active secretion) has become saturated.
(Michaelis-Menten kinetics apply in this situation.)
ClT =
Kel x VD = [t0.5 =0.693/ClT x VD ]
Metabolism in liver:
- More reactive groups
2. large compounds accumulate + conjugate
