Lecture 30 Flashcards
4 Mechanisms of drug permeation
- paracellular pathway (aqueous diffusion)
- transcellular pathway (lipid diffusion)
- special carriers
- transcytosis (endocytosis & exocytosis)
What exactly is absorption of drug?
transfer of a drug from its site of administration to bloodstream.
EX) IV = 100% Absorption
other route = partial absorption
3 types of enteral routes and extent of first-pass effect on each
- oral
- sublingual (bypass first-pass effect)
- rectal (partial avoidance of the first-pass effect)
first-pass effect
a fraction of the drug is metabolized in the gut wall and liver before reaching systemic circulation
4 types of parenteral routes
- IV
- IM (intramuscular)
- Subcutaneous
- Intradermal
5 factors that influence drug absorption
- effect of pH on drug absorption
- surface area available for absorption
- blood flow to absorption site
- contact time at absorption surface
- P-Glycoprotein
For weak acid, which will permeate through membrane: protonated or unprotonated?
protonated form = uncharged = HA
- Due to Chatlier principle, as conc of HA decrease outside the cell, equilibrium shift to left, thus A- gets protonated into HA, thus all drug eventually enters membrane but slow.
For weak base, which will permeate through membrane?
upprotonated form = uncharged = B
Henderson-hasselbalch equation
pH-pK = log ([unprotonated form]/[protonated form])
When pH=pK what happens to concentration of unprotonated and protonated?
[unprotonated] = [protonated]
When pH-pK is 1,-1,2,-2 what is % of unprotonated and protonated
When 1, ratio is 10 so % unprotonated = 90 , %protonated = 10
When -1, ratio is 0.1 so %unprotonated = 10, %protonated = 90
When 2, ratio is 100 so %unprotonated = 99 , %protonated = 1
When -2, ratio is 0.01 so %unprotonated = 1, %protonated = 99
What is ion trapping and its relationship to H-H equation?
In kidney, if a drug is in a liposoluble form during its passaage down the renal tubule, a significant fraction will be reabsorbed by passive diffusion. So by manipulating pH of urine, drug excretion can be manipulated. To accelerate excretion of drug, pH should be adjusted to ionize the drug so that drug can be trapped in urine.
- Weak acid excreted fast in alkaline urine
- Weak base excreted fast in acidic urine.
What does it mean by contact time at absorption surface affect drug absorption
if a drug moves through GI tract very quickly i.e, diarrhea, it is not well absorbed.
What is P-glycoprotein?
P-glycoprotein (MDR1) is a transporter protein responsible for transporting several drugs across cell membrane into lumen for excretion. Thus it reduces drug absorption.
What is bioavailability?
fraction of administered dose of a drug that reach systemic circulation.
How is bioaviliability of a drug is determined?
by comparing area under the curve (AUC) after a particular route of administration with AUC after IV injection
*AUC reflects extent of absorption of drug
Bioavailability equation
F= (AUC oral) / (AUC IV) *100
What is drug distribution?
the process by which a drug leaves the bloodstream and enters extracellular fluid and/or the cells of the tissue.
4 factors that determine drug distribution
- blood flow (well-perfused organ receive more drug eg liver, brain etc)
- drug binding to plasma and tissue proteins (drug biniding to plasma protein such as albumin slows distribution)
* Many liposoluble drugs accumulate in fat prolonging drug action. - capillary permeability
- drug hydrophobicity
Features of blood-brain barrier
- continuous tight junction of endothelial cells of brain capillaries
- astrocytic “end feet” surround outside of capillary endothelial cells which reduce blood flow to brain
- P-glycoprotein actively transport drug back into systemic circulation.
Why is metabolism of drug into hydrophilic metabolites essential?
for termination of their biological activity
and their elimination from the body
Which organ is actively involved in drug metabolism?
Liver the most
- GI tract, kidney, skin and lungs
Which system in hepatocyte is responsible for 80% of drug metabolism?
cytochrome p450
How can activity of cytochrome p450 induced?
drugs can enter hepatocytes and bind to xenobiotic receptor, activated receptor would translocate to nucleus and bind to promoter of enzymes (p450), thus increasing transcription.
What are the drugs that induce p450 activity?
rifampin, phenobarbital, carbamazepine
3 clinical consequences of enzyme induction
- a drug can increase its own metabolism
- a drug can increase the metabolism of a coadministered drug
- This may reduce drug plasma concentrations below therapeutic levels.
4 drugs that inhibit cytochrome p450
Cimetidine
Erythromycine
Chloramphenicol
Grapefruit juice
What could be the result of inhibiting enzyme involved in metabolism?
drug level may reach toxic concentration.
2 ways of drug excretion
- renal excretion (major)
2. bile excretion (small number of drugs)
