Pharm Flashcards
What is the pathway for isoniazid metabolism
So isoniazid is unique in that phase 2 reaction occurs before phase 1. So first step is acetylation (conjugation).
The second reaction is a hydrolysis which exposes a carboxyl group.
Yielding isonicotinic acid and acetylhydrazine.
Acetylation of acetylhydrazine leads to macromolecules that are hepatotoxic. Pyrimidine B6 is what acts to counter.
So slow metabolizers (acetylation) have build up of isoniazid
What is the pathway for tylenol?
Acetaminophen
So usually it undergoes a phase 2 reaction (glucuronidation), becoming acetyl glucuronide and its done.
Sometimes it undergoes a phase 1 hydroxylation to become a reactive electrophilic compound.
From there it can undergo two reactions. A glutathione conjugation to GS- AC and then to a nontoxic metabolite.
OR.
Undergo conjugation with macromolecule (protein) which causes hepatic cellular damage.
So if you OD, you will run out of glutathione and that will shunt it down the toxic pathway.
The antidote is Cysteamine and N-acetylcysteine which are analogs of glutathione.
DrugX is a weak acid with pka of 4.8 What percentage of the drug will be in a form that can be absorbed into the plasma from the intestinal lumen. Assuming ambient pH of 5.3 at the intestinal villi.
25%
Drug A has bioavailability of 35%. Total body clearance of 2.7 mL/min x kg, a Vd of .2 L/kg and safe effective plasma concentration of 100 microgram/mL. Drug A is eliminated 60% unchanged in urine. What would be the approriate single oral dose of drug A to generate a safe and effective plasma concentration in a 70 kg patient
Ab = Vd x Cpl = .2 L/kg x 70 kg x 100 mg/L = 1,400 mg = 1.4 g
But only 35% of the oral dose makes it in as 1.4 g. So 1.4/.35 = 4.0
What is ER in CL organ = OPF x ER
ER is fractional decline in drug concentration from arterial to venous side of the organ.
Drug X is 85% bound to albumin. A drug that completely displaced drug R from plasma albumin will?
Increase volume of distribution of drug R.
This frees drug R to move out of the plasma into extraplasma spaces thereby resulting in a decrease in Cpl and increase in Vd.
t1/2 would increase as a result of increased Vd. Displacement of drug R from albumin will have no effect on the fraction of the drug excreted unchanged. Displacement of drug R will have no effect on CL body
What happens in a phase 1 clinical trial?
2
3?
- evaluate a small number of individuals (20-100) with regard to tolerability (maximum tolerated dose and pharmacokinetic properties.
Learn: absorption, metabolism
Effects on organ and tissues - Study in a modest number (100- 1,000) of patients with the target disease to determine its efficacy as well as the doses to be used in any follow on clinical trials.
- evaluated for safety and efficacy in a large number (thousands) of patients with the target disease.
What is the major enzymatic system for Phase 1 reactions and their characteristic
How about Phase 2?
So Phase I is CYP and they are promiscuous enzymes with low substrate specificity.
High lipid solubility is the only common structural feature between substrates.
They are sluggish catalysts and their drug biotransformation reactions are slow.
Phase 2 reactions are conducted by transferases which add a highly polar conjugate which promotes excretion in urine or bile.
Ex. glucuronidation, glutathione conjugation and N-acetylation
What are examples of acute and chronic diseases that affect liver function and diminish metabolism of some drugs?
- alcoholic or viral hepatitis
- Alcoholic or biliary cirrhosis
- Cancer - hepatic
- Cardiac disease - limiting blood flow to the liver
- also impairing metabolism of drugs that are flow dependent (morphine and lidocaine) - Heavy metal poisoning & porphyria (rare genetic disease where heme production in liver is defective) can impair hepatic drug metabolism by impairing enzyme activity or defective formation of metabolic enzymes. P450’s have a heme in them.
How do age and gender effect drug metabolism.
- very young and old are more sensitive, both pharmalogically and toxic
- phase 1 and 2 reactions occur in newborns but much slower in adults
- age decreases liver mass, hepatic enzymes, and flow which decreases overall metabolic activity (particularly CYP in the elderly)
- pregnancy induces certain metabolizing enzymes (what douche was talking about) so need to adjust dosage
- some oral contraceptive agents are potent irreversible inhibitors of CYP enzymes
What do these Vd’s say about a drug?
Vd = 3 Vd= 14 Vd = 42 Vd= 300
Vd = 3, can only take residence in the plasma so likely high molecular weight drugs or if they have high plasma protein binding, even if they are small, hydrophobic
**hydrophilic drugs do not bind well to albumin, anionic hydrophobic drugs do.
Vd= 14, can swim in interstitial fluid also, so has to be a small drug
Vd = 42, can swim in all pools, must be small and of hydroPHOBIC variety to enter a cell.
Calculate the rate of infusion for Drug x (t1/2 = 8 hours) to establish an effective dose of 250 mg in the body.
kd = .693/t1/2
=.086
R0 = kd x Vd x Cp
Ab = Vd x Cp
R0 = .86 x 250 = 21.5 mg/hr
Describe a variable discontinuous drug regimen
Loading dose of 2 x ED50.
Then every half life repeat ED.
Start with 500, lose 250 every half life so add 250 every half life.
What is ED50?
The effective dose at which 50% of individuals exhibit the desired quantal response
In a 70-kg patient, drug X has a total body clearance of 2.4 L/hr, an oral bioavailability of 74%, and is safe and effective at a plasma concentration of 10 mg/L. Following an initial loading dose, drug X is to be administered orally twice a day.
389 mg
