ICPP 10 Pharmacokinetics Flashcards
How to calculate oral availability
F = Fa x Fg x Fh
Fa - fraction of dose absorbed
Fg - fraction of drug passing through gut wall w/o metabolism
Fh - fraction of drug passing through liver w/o metabolism
Is a fraction or percentage
What are the four main processes in drug therapy?
What do each of these mean?
- Absorption: site of administration > bloodstream
- Distribution: bloodstream > body tissues
- Metabolism: drug is chemically modified
- Excretion: drug is eliminated from body
What processes allow drugs to enter?
Absorption
Distribution
What processes allow drugs to exit?
Metabolism
Excretion
What is enteral drug administration?
Delivery into internal environment of body - GI tract
What is parenteral drug administration?
Delivery via all routes that are not in GI tract
difference between pharmacodynamics and pharmacokinetics
pharmacodynamics - what the drug does to the body
pharmacokinetics - what the body does to the drug
what are the 4 main process of drug therapy?
- pharmaceutical - is the drug getting into the patient?
- pharmacokinetics - is the drug getting to its target site?
- pharmacodynamics - is the drugs producing the required pharmacological effect?
- therapeutic - is the pharmacological effect being translated into a therapeutic effect?
what are the types of drug administration
paraentral - intrathecal, intramuscular, transdermal, inhalation, intravenous, subcutaenous
enteral - rectal, oral, sublingual
how are drugs absorbed?
drug mixes with chyme + enters small intestine
where does most drug absorption occur?
small intestine
why is there little drug absorption in the stomach
thick layer of mucosa layer
what process facilitates drug absorption?
- passive diffusion
- facilitated diffusion
- primary/secondary active transport
- pinocytosis
what drug absorption is via passive diffusion?
lipophilic drugs e.g. steroids
weak acids/bases
what drug absorption is via facilitated diffusion?
outline the process
- molecules with net ionic charge
- based on electrochemical gradients through solute carrier transporters - OATs (-) or OCTs (+)
what mechanisms do solute carrier transporters enable drug transport by?
facilitated diffusion
secondary active transport
describe drug absorption by secondary active transport
- via solute carrier transporters
- electrochemical gradient needed
- no ATP
physicochemical factors affecting drug absorption
- surface area (GI length)
- drug lipophilicity (pKa)
- density of SLC expression in GI
physiological factors affecting drug absorption
- blood flow - increases after meal
- GI mobility - decreases after meal
- food
- pH - low pH can destroy some drugs
what factors affect drug absorption in terms of first pass metabolism by GI and liver?
gut lumen - enzymes can denature drugs
gut wall/liver - some drugs can metabolised by cytochrome p450s and conjugating enzymes (phase I + II enzymes)
what in the gut wall/liver affects drug absorption?
cytochrome p450s + conjugating enzymes
metabolised some drugs
what is bioavailability?
the fraction of the drug which gets to a specific body compartment
what is the most common reference compartment for bioavailability?
CVS - circulation
what is the bioavailability reference for CVS compartment and why?
IV bolus = 100%
no physical/metabolic barriers to overcome
how to calculate bioavailability
amount reaching systemic circulation orally/total of SAME drug given IV
AUCoral/AUCiv
outline the first stage of drug distribution
bulk flow
diffusion
what factors affect drug distribution?
drug molecule hydrophilicity:
- lipophilic drugs move freely across cell membrane
- hydrophilic drugs need EC gradient
drug binding to plasma and/or tissue proteins
describe drug binding to plasma and/or tissue proteins
- only free drug molecules can bind to target sites
- binding to plasma/tissue decreases the free drug available for binding
what is Vd?
apparent volume of distribution
how to calculate Vd
Vd = drug dose/[plasma drug] at time 0
in litres
what do smaller and larger Vd values indicate?
Smaller - less penetration of interstitial/intercellular fluid compartment
Larger - more penetration of interstitial/intercellular fluid compartment
what factors affect Vd?
- changes in regional blood flow
- pregnancy
- paediatrics/neonates
- geriatrics
- cancer patients
what is drug elimination?
where does it occur mainly
metabolism - liver
excretion - kidneys
outline hepatic drug metabolism
via phase I + II enzymes (cytochrome p450s and cytosolic enzymes)
cytochrome P450 - generalists > metabolise wide range of molecules
cytosolic enzymes - generalists but faster kinetics
what is action of phase I and II enzymes
metabolism drugs
increase ionic charge > enhances renal elimination
what factors affect drug metabolism?
- age
- sex
- general health/disease
- other drugs which induce or inhibit CYP450s
What does HRH stand for?
Hepatic
Renal
Heart diseases
what effect can grapefruit juice have on drug metabolism?
inhibits CYP450 > less drug is metabolised
What are the three processes in renal excretion
- glomerular filtration
- active (proximal) tubular secretion
- passive (distal) tubular reabsorption
describe drugs in glomerular filtration
unbound drugs enter glomerulus via Bowman’s capsule for filtration - 20% of renal blood flow
describe drugs in proximal tubular secretion
- remaining 80% of blood via peritublar capillaries
- charged + polar molecules actively transported back by OATs or OCTS
what is clearance?
the volume (Vd) of plasma that is completely cleared of the drug per unit time (ml/min)
rate of elimination of drug from body
what is drug half life (t1/2)?
time it takes for drugs plasma conc to decrease by half
what is the relationship between half life, Vd and clearance?
t1/2 is dependent on Vd and CL
- if CL increases + Vd stays the same > t1/2 decreases
- if CL stays the same + Vd increases > t1/2 increases
what happens if the DCT is acidic?
weak acids pronate > become neutral charge > reabsobed
what happens if DCT is basic?
weak bases lose protons > become neutral charge > reabsorbed
what effect does acidic vs alkaline urine have on weak acids?
Acidic - increase absorption
Alkaline - decreases absorption
what effect does acidic vs alkaline urine have on weak acids?
acidic - decreases absorption
alkaline - increases absorption
what is linear elimination kinetics
rate of elimination is proportional to plasma drug conc. per unit time
what happens when the elimination process becomes saturated?
rate limited
becomes zero order kinetics
what are zero order kinetics?
- drugs near therapeutic dose with saturation kinetics
- elimination is constant
what is the clinical importance of zero order kinetics?
small dose changes can:
- produce large increase in drug plasma conc.
- lead to serious toxicity
Outline phase I reactions of metabolism
Introduce more polar groups on drug e.g. OH or NH2 by:
- oxidation
- hydrolysis
.
Carried out by cytochrome P450s
What do OATs and OCTs transport?
- OATs: deprotonated weak acids A-
- OCTs: protonated weak bases BH+
