Pharmacokinetics

Question 0

P450 Induction

Answer 0

Phenobarbitol
Carbazepine
Rifampin

Question 1

P450 Inhibition

Answer 1

Amiodarone
Cimetidine
Azole Antifungals (Ketoconazole)
Macrolide Abx (Erythromycin)
Ritonivir (HIV protease inhibitor)
Furocoumarins in Grape Fruit Juice

Question 2

P-Glycoprotien

Answer 2

Transporter that moves drugs back into the lumen. Decreases bioavailability Liver=pumps drugs to bile acid. Kidney=pumps into urine. Intestines=pumps into lumen. Brain=pumps back into blood, limiting access to brain.
targets: Digoxin, HIV protease inhibitors
Inhibited by: macrolide Abx
Transcriptionally regulated by: PXR (any drug that induces PXR will increase P glycoprotein activity)

Question 3

AhR (aryl hydrocarbon receptor)

*know Inducer and Gene Target

Answer 3

Inducer: PAHs,TCDD

Gene Target: CYP1A1,1A2,1B1

Question 4

PXR (pregnane X Receptor)

*know inducer and gene target

Answer 4

Inducer: Steroids, Hyperforin, rifampin, phenobarbitol, mifepristone
Gene Target: 3A4, 3A7

Question 5

CAR (constitutively active receptor)

*know inducer and Gene target

Answer 5

Inducer: Phenobarbitol, Phenytoin

Gene Target: 3A4, 2B6

Question 6

Xenobiotic receptors

• know specific ones and what binds to them
• know mechanism of action

Answer 6

AhR, PXR, CAR

Drugs, environmental polluntants, industrial chemicals, food stuffs

Binding to the receptor causes it to translocate to the nucleus and bind promoters of various enzymes

Question 7

P450 info

Answer 7

18 families, 43 subfamilies
metabolizes 75% of all drugs
3A4 metabolizes 50% of all drugs and is 33% of all enzymes
CYP 1-3 are for xenobiotic metabolism
CYP 4-18 are for endogenous functions

Question 8

Toxic Metabolism

Answer 8

Acetaminophen –> NAPQI by 2E1 –>cause cell death if GSH is used up. Most Acetaminophen is safely metabolized and excreted in the kidneys
*Antidote=N-acetylcysteine: it provides cysteine to make GSH and it also directly reacts with NAPQI

Question 9

Factors affecting drug metabolism

Answer 9

Genetic: affect pharmacokinetics (metabolism/transport variation), pharmacodynamics(target variation) and idiosyncratic drug effects. *most common Pharmacokinetic
Diet/Environment: Grapefruit juice inhibits 3A4 and pGlycoprotein (decrease in first pass effect), cigarette smoke induces ArH and they metabolize some drugs faster, charcoal food induce 1A enzymes…
Age: slower in young children and elderly
Diseases: hepatisis, cirrhosis, fat accumulation…affects the metabolism
Drug induced interactions

Question 10

Sites for Excretion of drugs

Answer 10

Mostly Renal

Small bile, fecal, breast milk, lung for anaestetic gases, sweat/saliva/tears, hair and skin

Question 11

Renal Excretion

Answer 11

Glomerular Filtration: normal is about 125mL/min or 20% of RPF=600mL/min. Free drugs not bound flow through bowman space slits. Must have MWt affect GFR
Tubular secretions: 80% of drugs pass by to be secreted through 2 transport systems. one for organic anions and one for organic cations
Tubular Reabsorption: high liposoluble drugs get reabsorped easily Polar drugs easily excreted

Question 12

Biliary and Fecal Excretion

Answer 12

Drugs can be secreted into bile through ABC transporters. Some will be excreted in feces but most will be reabsorbed into the blood to be excreted in urine.
Ex: steriods hormones, digoxin and some cancer drugs are largely excreted in bile

Question 13

Drug elimination

*know 4 biotransformations

Answer 13

metabolized in the liver or excreted. excreted better when polarized and hydrophilic

1. active drug converted to inactive drug
2. unexcretable drug converted to excretable metabolite
3. active drug converted to toxic metabolite
4. inactive prodrug converted to active drug.

Question 14

Phase I reaction

Answer 14

oxidations, reductions, decarboxylations, deaminations, hydrolytic reactions
*turns drug into more polar metabolite. usually=inactive

Question 15

Prodrugs

Answer 15

pharmacologically inactive compounds converted active compounds
often by hydrolysis of ester or amide linkage.
Ex: cyclophosphamide (activated to anticancer metabolite)

Question 16

Phase 2 reactions

Answer 16

consist of conjugation reactions which leads to covalent linkage between functional group on drug and glucoronate, acetate, glutathione, amino acids or sulfate.
*usually inactive and excreted. exception is Morphine 6 glucuronide (more potent than parent drug)

Question 17

Phase reaction order

*know an exception

Answer 17

Usually Phase I and then Phase 2

Exception: isoniazid is acetylated first then it is hydrolysed to isonicotinic acid

Question 18

First Pass Effect/metabolism in cell

Answer 18

Orally taken drugs pass through the liver first and are metabolized, limiting bioavailability of the drug.
Phase I metabolism=ER
Phase 2 Metabolism=cytosol
*things can also occur in mitochondria, nuclear envelope, plasma membrane

Question 19

Drug Distribution

Answer 19

rate is determined by CO, regional blood flow, capillary permeability, tissue volume, binding capability, hydrophobicity

Question 20

Binding of Drugs to plasma proteins

Answer 20

plasma albumin bind to acidic drugs
Alpha1 acid glycoprotein bind to basic drugs
*only unbound drugs are active
**Many drugs compete for plasma proteins. Sulfonamides displace lots of drugs and molecules. Like Bilirubin in newborns to cause kernicterus and Warfarin. There is very little free warfarin so even little amounts of increase can cause severe bleeding

Question 21

Tissue Binding

Answer 21

Drugs can accumulate in tissues causing a prolonged effect of the drug
Ex: Liposoluble barbiturate thiopental can be found in fat when its undetectable in blood

Question 22

The Blood Brain Barrier dilemma

Answer 22

Made of Endothelial cells with no pores or pinocytosis
Tight junctions
Astrocytes (endfeet)
* very hard for molecules to cross, depends on transcellular movement. Drugs need to be more liposoluble Highly ionized molecules don’t cross. P-glycoprotein present to pump drugs out.
*Levodopa can cross the BBB if you give Dopadecarboxylase inhibitors.
**Bypass the BBB by intrathecal drug administration

Question 23

Placental barrier

Answer 23

Drugs that are liposoluble and nonionized will cross easily. Be careful because any drugs can cause congenital deformities. Movement across is by simple diffusion.

Question 24

Bioavailability (F)

Answer 24

the fraction of administered dose that makes it to systemic circulation
*compare oral to IV and measure area under the curve
F=AUCoral/AUCiv x 100

Drug formulation, chemical instability, food and drug interactions (most tetracylcines impaired absorption when dairy, Al OH, Ca, Mg, Fe, Zn, Bismuth subsalicylate.), high fiber may bind the drug

Contact time affects it. Ex: diarrhea=little contact time and qiuck movement.

Question 25

Ion Trapping

*know the Henderson hasselbach equation

Answer 25

manipulation of drug excretion by the kidney. most drugs filtered but the liposoluble are reabsorbed by simple diffusion. you can adjust urine pH to ionize drug so its excreted.
Weak acid drugs excreted in basic urine (give bicarb)
Weak base drugs excreted in acidic urine (give ammonium chloride)
pH-pK=log(unprotonated/protonated)
*for each unit pH above pK the unprotonated will be 10x the protonated
*for each unit pH below pK the protonated will be 10x the unprotonated