27 - Introduction to Pharmacokinetics Flashcards
Steps of pharmacokinetics 1) 2) 3) 4) a) b)
1) Administration
2) Absorption
3) Distribution
4) Elimination
a) Metabolism
b) Excretion
Factors influencing choice of administration route 1) 2) 3) 4)
1) Patient preference
2) Cost
3) Bioavailability
4) Local system effect
Local vs systemic administration
Local - Drug exerts effect at or near site of introduction. Access to tissues limited by absorption
Systemic - Drug enters bloodstream. Accesses many tissues based on distribution.
When is a drug administered locally?
1) If it is a poorly-absorbed drug
2) To limit off-target effects in other tissues
Systemic routes that require drug to be absorbed
Oral, skin, lungs, nose, rectum, injectable
Systemic route of administration that doesn’t require absorption of drug
Intravenous
Manner in which most drugs are eliminated from the bldy
At a rate proportional to the concentration in plasma
Name for when drugs have distributed in body as if body were a single compartment
Drug equilibrium
Aspects of drug distribution
1)
2)
3)
1) Rarely uniform
2) Driven by circulation
3) Generally rapid (when reaches distribution equilibrium)
Factors affecting drug distribution
1)
2)
3)
1) Molecular size
2) Ability to bind plasma proteins
3) Lipid solubility
Effect of drug binding plasma proteins
Plasma proteins are much harder for kidneys to excrete, harder to transport across vascular endothelium
Effect of high lipid solubility of a drug
Leads to sequestration in lipid
Only type of drug able to cross blood brain barrier
Lipid soluble
Drug reservoirs in the body effects
1)
2)
3)
1) Can prolong action of drug (if released from store as concentration falls)
2) Can quickly terminate action (if stored drug has high capacity)
3) Can lead to slow distribution (if store has high capacity)
Places where drugs can find a reservoir
1)
2)
3)
1) Plasma proteins (only get into tissues if displaced from protein)
2) Cells (accumulation due to active transport or specific binding)
3) Lipids (blood supply is poor and capacity large, so may lead to slow distribution)
Volume of distribution
Volume of water that the total amount of drug administered would occupy if it had the same concentration as that in the plasma.
Equation for volume of distribution (Vd)
Vd = Amount of drug in body/Drug concentration in plasma
Effect on Vd if drug binds plasma protein
Lowers Vd, as more drug is retained in plasma
Effect on Vd if drug binds tissues, is taken up by cells
Increases Vd, as less drug is in plasma
What does Vd tell us clinically?
How much drug to give to get a particular amount of drug in plasma
Excretion
Drug elimination by kidney
Metabolism
Drug elimination by liver
Places from which excretion can occur
1)
2)
3)
1) Bowman’s capsule/glomerular capillary - Glomerular filtration
2) Tubule - Tubular secretion
3) Tubule - Tubular reabsorption
Is tubular secretion an active or passive process?
Active
Is tubular reabsorption an active or passive process?
Passive
Glomerular filtration rate
~120mL/minute.
Takes drugs out of blood through leaky glomerulus.
Can’t take plasma-protein-bound drugs
Tubular secretion
Takes drugs out of blood.
Active process.
Can take plasma-protein-bound drugs out of the blood.
Can be competitively inhibited
Tubular reabsoption
Takes drugs back into blood
Passive movement across cell membranes of of tubule and peritubular capillary
pH-dependent
How is lipid solubility affected by pH?
Acidic drugs are uncharged at low pH (A-H), charged at higher pH (A- + H+).
Basic drugs are charged at low pH (BH+), uncharged at higher pH (B + H+)
Example of how tubular reabsorption can be manipulated therapeutically
Aspirin overdose.
Administer NaHCO3, make urine basic.
Increases amount of ionised aspirin, which reduces reabsorption, increases excretion
Renal clearance
Amount of drug removed by kidneys/time
Maximum renal clearance rate
800mL/minute
Clearance
Total amount of drug cleared from body/time.
Clearance(kidney)+clearance(liver)+clearance(other)
Drug metabolism
Biotransformation in most tissues, but mainly in liver.
Enzyme-catalysed reactions to increase water-solubility of drug to facilitate excretion
Phase I metabolism
Create a new functional group on drug (EG: -OH, -NH2, -COOH)
Enzyme superfamily responsible for many phase I drug metabolism actions
Cytochrome p450
Phase II metabolism
Conjugation of a water-soluble molecule to drug (EG: glucuronyl transferase conjugating UDP-glucuronic acid to drug)
Effect of phase II metabolism
Methyl, acetyl, sulphate, glutathione often attached
Products almost always inactive
More water-soluble products
Equation to calculate drug clearance
(Drug concentration in - drug concentration out)/drug concentration initial * blood flow
