Week 5 Al-Mehdi ILAs

Question 1

What are the major causes of relative and absolute hypovolemia?

Answer 1

relative- third space loss (fluid changes places), sepsis, edema states (heart failure, cirrhosis); nephrotic syndrome

absolute- hemorrhage, GI fluid loss (diarrhea, etc), fluid loss from skin (burns, sweating) ; diuretics, endocrine diseases

Question 2

Why is 5% glucose in water (D5W) ineffective for replacement of lost fluid?

Answer 2

if 1000mL is given, ~70mL will be intravascular and the rest will be added to ICF or ECF

Question 3

Why is 3 L of normal saline (NS) or Ringer’s lactate needed to replace 1 L of blood loss?

Answer 3

they are isotonic solutions of electrolytes in water and they distribute rapidly through ECF compartment, they contain NaCl and lactate, K+ and Ca2+

Question 4

Why is lactate better than bicarbonate in solution to replace plasma bicarbonate?

Answer 4

bicarbonate is unstable in solution. Once lactate is metabolized, it results in bicarbonate

Question 5

How does administration of hypertonic NaCl solution reduce brain edema?

Answer 5

induces a shift of fluid from ICF to ECF –> reducing brain water and Inc intravascular volume

Question 6

Why are colloids NOT used frequently for volume resuscitation despite their theoretical advantages over crystalloids?

Answer 6

HES in particular appears associated with a risk of renal failure when used for resuscitation in patients with septic shock

Question 7

What are the major phases of drug metabolism?

Answer 7

Phase 1- OXIDATION, REDUCTION, AND HYDROLYSIS, of the parent molecule
goal: WATER SOLUBILITY + drug activation sometimes

Phase 2- CONJUGATION
Goal: DRUG INACTIVATION + water solubility

Phase 3: EXCRETION INTO BILE

Question 8

Which cell is the major site for drug metabolism?

Answer 8

Hepatocytes

Question 9

What are the goals of phase 1 of metabolism?

Answer 9

make water soluble for urine excretion; activate prodrugs, inactivate some drugs

Question 10

What are the major reactions in phase 1?

Answer 10

OXIDATION, REDUCTION, HYDROLYSIS
bile acid oxidation by specific CYPs
testosterone –> estrogen by CYP 19 (aromatase)
CYP2E1 catalyzes ACETAMINOPHEN to NAPQI –> hepatotoxicity

Question 11

How do the cytochrome P450 enzymes metabolize drugs?

Answer 11

inducers - DEC effectiveness
inhibitors- INC toxicity

Question 12

What are the typical reactions in phase 2 metabolism?

Answer 12

conjugation

Question 13

What is the goal of phase II?

Answer 13

inactivation of drugs and glucuronidation

Question 14

List drugs and other products that inhibit or induce cytochrome P450 enzymes. How can they affect the effectiveness or toxicity of other drugs?

Answer 14

CYP3A4 inducers (DEC effectiveness) - St. Johns Wort, Rifampin, Griseofulvin

CYP3A4 inhibitors (INC toxicity) - grapefruit juice, Cimetidine, Ciprofloxacin, Erythromycin, Ketoconazole

Question 15

Where is the subcellular location of CYPs?

Answer 15

within the endoplasmic reticulum and mitochondria of liver cells

Question 16

What happens to smooth ER after barbiturate treatment?

Answer 16

induce the proliferation of the smooth ER and its associated detoxification enzymes, thus increasing the rate of detoxification

Question 17

What is the mechanism of CYP induction by drugs?

Question 18

What 2 drugs metabolize/inactivates CYP2C9 that leads to bleeding

Answer 18

WARFARIN + CIMETIDINE

Question 19

What 2 drugs metabolize/inactivates CYP3A4 that leads to bleeding

Answer 19

WARFARIN + ERYTHROMYCIN

Question 20

What 2 drugs inhibit CYP3A4 = metabolized by CYP3A4, and prolongs QT leading to arrhythmia and cardiac arrest? and what is it called just before the heart goes into ventricular fibrillation?

Answer 20

ERYTHROMYCIN + KETOCONAZOLE

Torsades de Pointes

Question 21

What 2 drugs are activated/inactivated by CYP2C19 leading to platelet aggregation

Answer 21

CLOPIDOGREL + OMEPRAZOLE

Question 22

What drugs metabolize and inhibits CYP3A4 leading to myopathy, including rhabdomyolysis

Answer 22

STATINS + Grapefruit juice

Question 23

What 2 drugs induce/ degrade CYP34A that leads to a baby?

Answer 23

RIFAMPIN + Oral contraceptive

Question 24

What 2 drugs compete for UDP-glucuronosyltransferase for inactivation (phase 2 metabolism) leading to myoglobinuria

Answer 24

GEMFIBROZIL + SIMVASTATIN

Question 25

What is the substrate for CYP2C9?

Answer 25

WARFARIN

Question 26

What is the substrate for CYP2C19

Answer 26

OMPRAZOLE

Question 27

What is the substrate for CYP2D6

Answer 27

CODEINE

Question 28

What is the substrate for CYP3A4

Answer 28

AMIODARONE

Question 29

What is the scope of pharmacokinetics and pharmacodynamics?

Answer 29

Pharmacokinetics- what happens to dose before reaches Cp
Pharmacodynamics- how does effect happen when it hits Cp

Question 30

What is ADME?

Answer 30

determinants of plasma concentration
Absorption, Distribution, Metabolism, Elimination

Question 31

Why can the effective (active) fraction of a drug be very low compared to its administered dose?

Answer 31

obstacles of drug absorption include size of drug, hydrophobicity, charge, pH trapping, and area of absorption

Question 32

How can pH affect drug absorption by cells?
Can you calculate the effect of extracellular pH on drug distribution (knowing its pKa) inside and outside a cell? (hint: can you use Henderson-Hasselbalch equation?)

Answer 32

charged don’t readily cross cell membranes

pH= pKa + log (base/ acid)

Question 33

What is first pass metabolism? How does it relate to bioavailability?

Answer 33

drug gets metabolized at a specific location in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation
(hepatic first pass= first TRUE pass)

REDUCES bioavailability

Question 34

How does buccal/sublingual administration help avoid first pass metabolism?

Answer 34

completely bypasses the liver by draining into the SVC then right atrium

Question 35

Why can a delay in absorption be helpful?

Answer 35

to produce a local effect and to prolong systemic action

Question 36

What role does binding to albumin and other plasma proteins play in drug effect?

Answer 36

slows drug elimination

Question 37

How does distribution of drugs relate to the notion of apparent volume of distribution?

Answer 37

when you use the eqn Vd= D/ Cp, you get a large volume of plasma, but the patient does not actually have that much because most of it is distributed in tissues and some has been eliminated

Question 38

Can you calculate Vd, Cp, or administered dose (D), if two of these three values are given?

Answer 38

Vd= D/ Cp

Question 39

What is therapeutic index and therapeutic window?

Answer 39

therapeutic index = LD50 / ED50 (lethal andeffective dose for 50% of patients)

therapeutic window- dose range of a drug that provides safe and effective therapy with minimal adverse effects (desired and right before adverse effect)