Block 1 Pharmacokinetics

Question 1

Pharmacokinetices domains

Answer 1

Absorption
Distribution
Metabolism (biotransformation)
Excretion

Question 2

Enteral administration

Answer 2

GI tract: oral (PO), sublingual (SL), rectal (PR)

Question 3

Pros & cons to enteral drug administration routes

Answer 3

PO: most convenient, safe, economical; variable absorption, irritation of GI, first-pass effect
SL: bypasses hepatic portal vein
PR: bypasses hepatic portal vein

Question 4

Parenteral administration

Answer 4

Intravenous (IV), intramuscular (IM), subcutaneous (SC)

Question 5

Pros & cons to parenteral drug admin routes

Answer 5

IV: immediate, emergency use, bypass GI, large volume; risk of adverse effects, training
IM: prompty, bypass GI, self-admin; limited volume, pain
SC: same as IM

Question 6

Other routes of drug admin

Answer 6

Topical, transdermal (into systemic circulation), intra-arterial, intrathecal (into CNS), inhalation

Question 7

Absorption of drugs

Answer 7

Lipid bilayer = polar/ionized harder to get across
*Passive diffusion (depends on conc grad)
Active transport (link transport proteins)

Question 8

Transport proteins

Answer 8

Across epi -> intestine; OATP, p-glycoprotein (prevents absorption)

Question 9

Ion trapping & gastric and plasma pH

Answer 9

Only non-ionized can pass lipid membranes
GI: 1.4
Plasma: 7.4

Question 10

pKa of a drug

Answer 10

pH value at which ½ drug is ionized

Question 11

Weak acid vs. weak base

Answer 11

WA: low pKa, diffusion at low pH, blocked at high pH
WB: high pKa, diffusion at high pH, blocked at low pH

Question 12

Factors affecting oral absorption

Answer 12

Dosage formulations: enteric coating (dissolves at high pH), controlled release (for short T½)
Blood flow: poor absorption with shock, short bowel syndrome
GI motility: inc or dec contact time with drugs
First pass effect: metabolism by liver

Question 13

Causes of inc and dec GI motility

Answer 13

Inc: diarrhea, laxative
Dec: diabetes, anticholinergic drugs

Question 14

Bioavailability

Answer 14

F = fraction entering systemic circulation (100% for parenteral drugs)
Low oral F for drugs subject to first-pass effect

Question 15

First-pass effect

Answer 15

Drugs absorbed from GI metabolized by liver before reaching systemic circulation, decreases F for oral drugs

Question 16

Factors affecting drug distribution

Answer 16

Organ blood flow: fast to highly perfused organs (liver, kidney, heart, lungs) vs. slow to less perfused (skin, fat, bone)
Plasma protein binding: inactive if bound to e.g. albumin, varying affinities for plasma proteins
Lipid solubility: soluble = greater Vd, can pass BBB

Question 17

Volume of distribution

Answer 17

Vd; indirectly measured by plasma concentration
Vd = amount in body/plasma conc
Useful for calculating loading dose, elimination rate, T½

Question 18

Fluid volumes in L per kg: plasma, extracellular fluid, intracellular fluid, total body water

Answer 18

P: 0.04 L/kg
Ex (plasma, interstitial): 0.25 L/kg
In: 0.35 L/kg
TBW (ex + in): 0.6 L/kg

Question 19

Calculating loading dose

Answer 19

Vd = dose/Cp (desired plasma conc)
Dose = Vd x Cp x kg

Question 20

Drug metabolism: phase 1 and 2 reactions

Answer 20

To activate or inactivate and make easily excreted compounds

1: add small polar group by redox or hydrolysis, makes polar and H2O soluble
2: form water soluble conjugates that is inactive & easily eliminated

Question 21

Cytochrome P450

Answer 21

Bound to membrane, contains heme, absorb 450 nm light with CO exposure
Primarily in liver, also intestine, lung, brain, placenta
Responsible for most phase 1 reactions
Makes chol, steroids, PCs, detoxes
*Changes = most drug interactions

Question 22

Pro drug

Answer 22

Needs to be metabolized to become active; if dependent on P450 in short supply or inhibited, little or no clinical effect

Question 23

Pro drug examples

Answer 23

Hydrocodone -> hydromorphone
Tramadol (Ultram) -> metabolite
Enalapril -> enalaprilat for HTN
Vyvanse (lisdexamfetamine) -> dextroamphetamine

Question 24

Excretion of drugs

Answer 24

Biliary: conjugated metabolites, large molecular weight compounds, ? reabsorbed by enterohepatic cycling
Renal: most parent/metabolite, filtration depends on protein binding, active secretion, passive reabsorption (ion, lipid)

Question 25

Clearance

Answer 25

Volume of plasma from which drug is eliminated per unit time (L/hr or ml/min)
Elimination rate = Cl x Css (plasma conc at steady state)

Question 26

Creatinine clearance

Answer 26

Estimate of renal function, constant rate by-product of muscle, decreased GFR = rise of Scr until new steady state reached; must know sex, age, IBW, Scr
CrClest = [(140-age) x IBW (kg)] / (scr x 72) * x 0.85 for women

Question 27

Zero order elimination & examples

Answer 27

Constant elimination rate, nonlinear/capacity limited, clearance inversely proportional to drug conc; phenytoin (Dilantin), aspirin (high doses), ethanol

Question 28

First order elimination

Answer 28

At normal doses, rate of elimination proportional to plasma drug concentration

Question 29

Elimination rate constant (Ke)

Answer 29

Fraction of drug eliminated over set period of time
Ke = clearance of drug (L/hr) / volume distribution (L)
= slope of semi-log conc curve

Question 30

Half life relation to Ke

Answer 30

T½ = ~0.7/Ke
T½ = ~(0.7 x Vd)/Cl

Question 31

Steady state relation to half life

Answer 31

Take ~5 half lives to reach steady state after starting drug without loading dose
*Also 5 to eliminate after last dose

Question 32

Predicting serum concentration at any time

Answer 32

Cp = (Cp^0)(e^-Ke.t)
Cp = plasma conc at time t
Cp0 = initial plasma conc
Ke = elim rate constant
t = time