2.2 Pharmacokinetics Flashcards
What is AD(M)E?
Summary of pharmacokinetics:
Absorption
Distribution
Metabolism (excretion)
Elimination
Water v lipid solubility
Water:
~ must be aqueous for absorption, distribution, interation with target, passagein circulation
Lipid:
~cross cell membranes by passive diffusion
~ distribute into fatty tissue
~ easy access to action sites in cells
~easily re-absorbed from kidney
What happens to drugs in plasma?
Drugs in plasma available for distribution to sites of action, passage to organs of excretion, metabolism
Passage of drugs into/from circulation
Cross the vascular endothelium via gaps between cells packed with matrix of proteins that act to retain molecules of high molecular weight
How do drugs pass across cell membranes?
Passive diffusion
Active/facilitated diffusion
~ pinocytosis
~ aqueous pores
Factors effecting drug movement
Molecular weight
Lipid solubility
Chemical nature
How does molecular weight alter absorption of a drug?
High molecular weight compounds will remain at the site of administration
How does lipid solubility alter absorption of a drug?
Lipid soluble drugs can readily cross cell membranes
How does chemical properties alter absorption of a drug?
Weak acid/base: partially ionised so unionised fraction readily cross cell membranes
Neutral drugs: readily cross cell membranes
Strong acid/base: 100% ionised - polar molecules do not readily cross cell membranes
What is pKA
pH + log (conc. protonated species / conc. non-protonated species)
What affects the rate of absorption?
- drug properties
- physiological properties
- drug formulation (e.g. coating)
How does pH affect drug absorption?
pH varies at different parts of the body so drug pH effects how well it absorbs:
In plasma:
~ weak base (unionised) readily absorbed
~ weak acid (ionised) less readily absorbed
In acid conditions:
~ weak base (ionised) less readily absorbed
~ weak acid (unionised) readily absorbed
How does the area of absorbing surface affect absorption?
surface area
compromised surfaces
How does local blood flow effect absorption?
vasoconstriction reduces rate of diffusion of a drug from injection site
What is bioavailability?
The fraction of administered dose that reaches the circulation in active form
(expressed as a % of total amount)
How can bioavailability be determined?
By measuring the amount of drug in the plasma overtime.
What is first pass metabolism?
When the drug is extensively metabolised before it reaches the systemic circulation
Explain Cmax and Tmax
Cmax (maximal plasma conc. of a drug) at Tmax (time achieved at)
What is volume of distribution?
A measure of volume of fluid required to contain the total amount of drug at plasma conc.
How is volume of distribution calculated?
Vd = Q/Cp
Q = Dose (total amount of drug in the body) mg/Kg
Cp = Plasma conc ng/ml
Why is Vd important?
predicts if a drug is likely to reach target site at effective concs
Determines loadinh dose necessary to achieve target plasma conc
Why might drugs accumulate in target tissues?
High lipid solubility (accumulates in fate)
Ion trapping (pH difference across barriers)
Binding to unrelated site from target
How are drugs eliminated?
Drug enters, reaches peak, plasma conc falls
Which drugs are eliminated more quickly?
water soluble
lipid soluble (reabsorbed)
How are drugs metabolised?
Foreign substance so removed
Converted to water soluble form
Metabolised so biologically inactive
Main sites of drug metabolism
Liver, plasma, GIT wall, lung, kidney
How are lipid soluble drugs metabolised?
Liver - cross liver membrane to reach microsomal enzymes
Oxidation/reduction
Conjugation
What is enterohepatic recycling?
Liver cells transfer drugs to bile, delivers to intestines, conjugated, drug reformed (free drug reabsorbed)
What is half life?
Time taken for the conc in plasma to fall by 50%
Explain elimination by first order kinetics
Expenontial decrease over time
rate of removal proportional to conc.
elimination pathways not saturated - fixed proportion removed over time
Half life independant on dose
Explain elimination by zero order kinetics
Linear decrease in plasma drug conc. over time
Fixed amount of drug removed
Elimination pathways saturated
Half life increases with increase of dose
What is the important of half life?
Indicates time to reach steady state of plasma
Time taken for drug to be removed from the body and duration of action
Estimation of appropriate dose intervals
What are the 2 ‘groups’ of factors that affect of behaviour of a drug in the body?
Drug / product factors
Animal / human factors
What does drug pharmacokinetics depend on? (6)
Lipid and water solubility
Stability
Dose
Plasma protein binding
Chirality
Effect of drugs on liver enzymes
What will influence the pharmacokinetics of a drug?
Product formation
pH (renal excretion)
Other drugs being used
Effect of drugs on liver enzymes
Enzyme induction caused by repeated administration of drugs
Liver enzyme inhibition
Consequences of liver enzyme induction/inhibition (3)
Plasma conc. of the drug
Therapeutic efficacy
Time between doses need changing
What does drug formulation effect?
Cmax
Tmax
Time drug remains at therapeutic levels
How can food effect Cmax and Tmax?
↓ Cmax, ↑Tmax (Competition for absorption)
↓ Cmax, = Tmax (Reaction with food = excreted with food)
= Cmax, ↑Tmax (Delayed time for absorption)
↓ Cmax, ↑Tmax (Food required for absorption)
Explain the effect of pH and renal excretion on the fate of drugs in the body
Acidic urine animals eliminate weakly basic drugs most effectively
Alkaline urine animals eliminate weakly acidic drugs mist effectively
Effects of drug interaction (4)
Absorption
Plasma protein binding
Metabolism
Excretion
What are the animal/human factors affecting the fate of drugs?
Disease
Age
Species/breed
Feeding schedule
Admin route
Time of day
Physiological state
Gender
How does disease effect drug pharmacokinetics?
Changes in ggastric/intestinal motility
Damage to epithelial barrier
Reduced blood flow
Distribution
Inflammatory disease
Metabolism and excretion
How does age effect pharmacokinetics?
In neonates:
~reduced renal excretion
~reduced hepatic metabolism
~reduced plasma protein binding
~increased GIT absorption
~increased volume of distribution
In aged animals:
~decline in liver and kidney elimination
Define side effects
An unwanted action caused by a drug used at therapeutic dose
Define adverse drug reaction
(ADR)
Any unwanted vent associated with the use of a drug at therapeutic doses
What is type A ADR?
Augmented - expected but exaggerated response (predictable) dose dependant
What is type B ADR?
Bizzare - unexpected/abnormal responses (unpredictable) not dose dependant
What is type C ADR?
Chronic - only occurs after prolonged use
What is type D ADR?
Delayed - occur at remote time from the treatment
What is type E ADR?
End of treatment - occur when drug use is abruptly stopped
What is type F ADR?
Failure - expected response is not acheived (rarely due to primary failure of a drug)
What is the nocebo effect?
ADR reported isnt actually related to the drug
