Pharmacokinetics Flashcards
Types of Drug Administration
Oral Inhalation I.v. I.m. Dermal
Can be divided into enteral and paraenteral.
What are the 2 ways that drugs can move?
Bulk flow transfer (moving with the flow of fluid, for water soluble drugs)
Diffusion also transfer (small distances, lipid soluble drugs)
What are the 4 major mechanism of transport? Which one is not common and which one is least relevant?
- diffusion
- diffusion across aqueous pores (least relevant because it has to be very small <0.5nm)
- carrier mediated transport
- pinocytosis (least common)
What are most drugs?
Weak acids or weak bases
Therefore drugs exist in ionised (polar) and non-ionised (non-polar) forms – the ratio depends on the pH
Aspirin and morphine - molecule types
Aspirin is a weak acid
Morphine is a weak base
Pharmacokinetics
The journey of the drug through the body
A - Absorption
D - Distribution
M - Metabolism
E - Excretion
ADME
A - Absorption
D - Distribution
M - Metabolism
E - Excretion
-> Important because it determines the dose of the drug available to the tissues
It what forms do most drugs exist?
ionised (polar) and unionised (non-polar)
-> the ratio depends on the pH
What is pKa? How can it be calculate it?
The pKa is the dissociation constant for weak acids and weak bases.
Calculate it with the Henderson Hasselbach equation:
pKa = pH + log (BH+ / B) -> for weak bases pKa = pH + log (AH / A-). -> for weak acids
How do weak acids/bases act in acidic/alkaline environments?
Weak acids will be more unionized in acidic environments
Weak bases will be more unionized in alkaline environments.
Does the pKa of a drug change?
pKa of drug DOES NOT change
pH of different body compartments DO change
Logarythm
y = log b (x)
b^y = x
How can you calculate the proportion of the ionised and unionised drug?
If you know the pH of the body compartment:
10 ^ (pKa - pH) = [AH] / [A-]
10 ^ (pKa - pH) = [BH+] / [B]
Which factors influence drug distribution?
- Regional blood flow
- Extracellular binding (Plasma-protein binding)
- Capillary permeability (tissue alterations – renal, hepatic, brain/CNS, placental)
- Localisation in tissues
How does density of capillaries differ with metabolic activity of tissues?
Highly metabolically active tissues
-> denser capillary networks
Influences of PPB on distribution
- if a drug is ppb it is not leaving the blood
- warfarin is heavily ppb (90%)
- Aspirin 50-60% ppb
- careful when co-administering 2 ppb drugs as they can be displaced
Which drugs tend to be ppb?
acidic drugs (e.g. aspirin)
warfarin is strongly ppb.
Influences of capillary permeability on drug distribution
- lipid soluble drugs have good access to all tissues (even the brain) and will be easily distributed.
- Water soluble drugs have poor access to tissues and are dependant on saturable carrier proteins for access to tissues -> less well distributed
fenestrated, discontinuous, discontinuous, BBB with TJs
What kinds of drugs are not majorly affected by capillary permeability?
Capillary permeability is not really important for lipid soluble drugs, however, water soluble drugs need specific transport mechanisms.
Influences of localisation of drug on distribution
Fat: large body tissue, small blood supply (2% CO)
Very fat soluble drugs (e.g. general anaesthesia) distribute in adipose tissue, hence drowsiness over a longer time period due to release of drug into adipose tissue -> slowly leaks back in
What is the oil/water partition coefficient?
How well a drug dissolves in water / oil.
e.g. 98% stored in body water (tissues) , 2% in body fat
What are the 2 major routes of drug excretion?
Liver (some drugs are concentrated in the bile)
Kidney (ultimately responsible for the excretion of most drugs)
Enterohepatic cyclinge
drug/metabolite excreted into gut (via bile) then reabsorbed, taken to liver
and excreted again… leads to drug persistence.
Water soluble conjugate added to drug, bacteria in gut remove the conjugate and the drug is free again in its lipid soluble form which diffuses back into the hep portal vein and the liver. Once in the liver it can also enter the circulation.
What drugs are usually excreted by the liver?
usually large molecular weight conjugates
Kidney: What percentage of plasma is filtered, how much passes by?
20% filtered
80% passes by
What are the steps in drug elimination through the kidneys?
1) Glomerular filtration (dependant on size)
2) active secretion (dependant on available transporters)
3) passive reabsorption (dependant on urine pH and the extent of drug metabolism) -> if it is lipid soluble enough it will diffuse right back
Massive amount of active secretion!!!!
Drug excretion through the liver
Biliary excretion (large molecular weight molecules can concentrate) Active transport systems – into bile (bile acids and glucuronides)
What are some less important routes of drug excretion?
lungs, skin, gastrointestinal secretions,
saliva, sweat, milk, genital secretions
“Bioavailability”
Proportion of the administered drug that is available within the body to exert its pharmacological effect
-> linked to absorption
“Apparent volume of distribution”
The volume in which a drug appears to be distributed
- an indicator of the pattern of distribution
-> linked to distribution
“Biological half-life”
Time taken for the concentration of drug (in blood/plasma) to fall to half its original value
-> linked to metabolism/excretion
“Clearance”
Blood (plasma) clearance is the volume of blood (plasma) cleared of a drug (i.e. from which the drug is completely removed) in a unit time
(Related to volume of distribution and the rate at which the drug is eliminated. If clearance involves several processes, then total clearance is the sum of these processes.)
-> linked to excretion
How are drugs actively secreted in the kidneys?
The kidneys have a large number of transporters that recognise basic acidic drugs and move them across the membrane and into the urine.
-> massive amount of active secretion in the kidneys
