ADME Liu

the standard drug dose works for _____% of pts

80

which drugs need to cross cell membranes easily? which ones work better if they do not?

easy= most PO drugs

dont cross= GI drugs (bc thats their site of action)

transcellular vs paracellular drug passage

transcellular:

- goes through cell

- only way to pass BBB

paracellular:

- goes btwn cells

- non existent in brain

drugs entering the brain use

a. paracellular transport

b. transcellular transport

b. transcellular

tight junctions dont let drugs get btwn cells

primary vs secondary active transport

Primary - transport w ATP

Secondary- symport and antiport

ABC vs SLC active transport

ABC= atp binding cassette

- uses ATP to drive transport of drugs OUT OF cells

SLCs: solute carriers

use symport or antiport w ions to move drugs (usually into cell)

how does the following affect how a drug crosses a membrane

size:

degree of ionization:

l/w coeff:

protein binding:

size: smaller is better

degree of ionization: only unionized form crosses

l/w: larger/ more lipid soluble is better

protein binding: less protein binding is better. if highly protein bound it doesnt reach target, it stays in plasma

-> small, unionized, lipophilic, free

which would you expect to more easily cross a cell membrane for absorption?

drug A: l/w=1

drug B: l/w= 5

drug C: l/w= 580

drug c. it is the most lipid soluble and will more easily cross membranes to be absorbed

explain the concept of ficks law of diffusion

used for passive diffusion until concentration gradients are equal on both sides

faster diffusion if drug is smaller, membrane area is larger, concentration gradient is larger, and membrane is thinner

pH of blood

about 7.4

what is pKa

the pH when 50% of a drug is ionized

only the __________ form of a drug can diffuse across membranes and be absorbed

non-ionized

when are acids absorbed better?

bases?

acids:

- in acidic environments (stomach)

- weak acid, high pKa is better

bases:

- in basic environments (intestines)

- weak base, low pKa is better

explain ion trapping

drugs are trapped when they become ionized

an acidic drug will be trapped in basic environment

a basic drug will be trapped in acidic environment

acid vs base:

what ph-pka value is better for absorption

acid:

more negative pH-pKa is better

[remember pH-pka= A-/HA, so you want a more neg number (larger pKa) to have more unionized]

base:

more positive pH-pKa is better

[pH-Pka= base/BH+ so you want your top number to be bigger, so you want a smaller pka]

for weak acids, there is better absorption if pH ___ pKa

pH < pKa is better

which drug would be absorbed most readily from the stomach (pH=1)

a. weak acid, pKA=2

b. weak acid, pka=3.5

c. weak base, pka=3

d. weak base, pka=9

b

stomach is acidic, we need acidic drug.

higher pka= weaker acid

which drug would be absorbed most readily from gut

a. weak acid, pKA=2

b. weak acid, pka=3.5

c. weak base, pka=3

d. weak base, pka=9

gut is basic. we want a basic drug with the smaller pka (pH- pka= B/BH+)

so c

which would be more readily absorbed

acid with ____ pka

base with _______ pka

(larger or smaller)

acid with LARGER pKa (weaker)

base with SMALLER pKa (weaker)

explain why PK studies are important (not just ionization) using quinidine and warfarin as examples

1. when quinidine weak base was added to stomach WITH ppis its absorption DID NOT increase

- shows that it depends on solubility too. it decreased the solubility of quinidine

2. when warfarin (weak acid) was acid to stomach with a PPI, its absorption increased

- more basic pH increased its solubility

what happens to soluble vs non soluble drugs in the stomach

soluble= rapidly reach intestines and are absorbed

non soluble= stay in stomach for a longer time or excreted in feces

what is absorption defined as

movement of drug from site of administration into the blood

what is bioavailability

F

the Fraction of a drug reaching blood

(for IV, F=100)

what is the hepatic extraction ratio

the fraction of drug removed by the liver from the blood

E= (Cin - Cout)/ Cin

100mg of Drug A is orally taken and 80mg is absorbed into portal circulation. the hepatic extraction ratio is 0.75. whats the bioavailability

E= (Cin-Cout)/Cin

0.75= (80-Cout)/80

Cout=20mg

If Eh=0.6 and 40% is absorbed into the gut, what is the bioavailability?

E= (Cin-Cout)/Cin

Assume start with 100mg. Only 40% is absorbed so 100 x 0.4= 40mg.

Then 60% is extracted so 40mg x 40%= 16%

which routes of administration have no first pass metabolism? which do?

none:

parenteral

sublingual

pulmonary

transdermal

first pass:

oral

rectal (50%)

sublingual route pros and cons

pro:

rapid, no first pass

con:

drug must be highly LIPOphilic

rectal route pros and cons

pros:

rapid, only 50% first pass effect, good for vomiting pts

cons:

incomplete absorption, irritation

which routes of administration bypass first pass metabolism but require highly lipophilic drugs

sublingual

transdermal

types of parenteral drug administration

pros and cons

1. subQ

- constant and slow rate of absorption; can use w oil

- infection risk

2. IM

-intermediate onset, large volumes ok

-infection

3. IV

-rapid onset, controlled

- infection

4. Intrathecal/ epidural

-bypasses BBB

-infection, highly skilled personel

which route of parenteral administration bypasses the BBB

intrathecal/epidural

compare IM vs SC route in terms of plasma drug concentration over time

IM: has a higher peak (all of drug is absorbed before elimination occurs) and faster elimination

SC: lower peak (less high drug concentration) but also longer duration

what affects drug stability in the GI tract

1. pH= can inactivate drug

2. digestive enzymes (like insulin-> destroy)

3. drug chelation (ex: tetracycline and calcium)

t/f: a large part of drug absorption occurs in the intestines regardless of pH

true.

SI has the largest surface area and also the most blood flow. drug absorption happens regardless

what can cause a DECREASED gastric emptying rate

pharm:

AGAIN

Anticholinergics (block rest&digest)

Ganglionic blockers

Aluminum OH

Isoniazid

Narcotic

what can cause a DECREASED gastric emptying rate

foods:

patho:

solids, acids, fat

patho:

gastric ulcer

acute abdomen

intestinal obstruction

paralytic ileus

what can cause a INCREASED gastric emptying rate

foods:

patho:

liquids, gastric distention, lying on right side

patho:

chronic cholecystitis

gastroenterostomy

what can cause a INCREASED gastric emptying rate

drugs:

RAMS (like "ramp" it up)

Reserpine

Anticholinesterases (increase Ach-> rest and digest)

Metoclopramide

Sodium bicarb

what is PGP?

type of transporter?

where is it expressed?

P-glycoprotein

moves drugs back out into lumen (lowers absorption)

ABC transporter (uses ATP)

found in intestines, kidney, BBB, testes

compounds that block PGP will _____ drug absorption and ______ elimination

block pgp means

increase drug absorption

decrease elimination (toxicity)

ex: digoxin, verapamil

what is bioequivalence

when 2 drugs or routes are equal in rate and extent to which the API becomes available at the site of drug action

(same time vs concentration graph)

examples of tissues with high blood flow (and therefore more amounts of a drug received)

liver, kidney, muscles

_______ drugs are more likely to accumulate in the extracellular space

water soluble drugs

edema alters drug distribution

where do drugs most often accumulate

-fat-> slowly released

-liver

-bone (ex: tetracyclines, abx, metals)

albumin mostly binds ___ drugs

alpha1 acid glycoprotein mostly binds ______ drugs

albumin= acidic

alpha1 acid glycoprotein= basic

describe how an acidic drug binding to albumin changes its availability

(more or less free drug available?)

it stays in plasma for longer

-> not excreted

-> but also cant exert action

=== less free drug available

if drug a and drug b both bind to albumin but drug b has higher affinity for it, how does that affect the activity of both drugs

drug b gets trapped on albumin= lesser effect at target site

drug a cant get on albumin= more at target site but also more in blood= potentially toxic

all organs (except the lungs) eliminate ___ drugs better than ______ drugs

a. polar, lipophilic

b. lipophilic, polar

a. polar, lipophilic

think of drug being eliminated in urine. polar drug will easily dissolve and leave; lipophilic drugs must be metabolized and made more polar

summarize the following drug eliminating steps in the kidney

1. filtration

2. active secretion

3. passive reabsorption

1. filtration= glomerulus

-free unbound drug passes through; depends on GFR and if protein bound

2. active secretion= proximal convoluted tubule

-drug from the peritubular capillaries is ACTIVELY (atp) secreted into tubular fluid.

carriers: anion (acidic drugs) and cation (basic) transporters

3. passive reabsorption= PCT and DCT

- drug moves from tubular fluid BACK into blood

- pH dependant

where in the kidney do the following take place

1. filtration

2. active secretion

3. passive reabsorption

filtration= glomerulus

active secretion= prox convoluted tubule

passive reabsorption= prox,straight, & distal tubules

how can you alter tubular pH to increase drug excretion? which substances can you use?

ion trap it by making the substance ionized for excretion (needs to be unionized to diffuse back)

acidic drugs: make urine basic so it becomes ionized A- == sodium bicarb

basic drugs: make urine acidic so that it becomes ionized HB+ == citric acid

what would you add to the urine to lower excretion of an acidic drug

a. citric acid

b. sodium bicarb

a. citric acid

LOWER excretion means you want the drug to diffuse back. make urine more acidic

what would you add to urine to INCREASE excretion of the following:

1. acidic drug

2. basic drug

1. acidic= add base like bicarb (ion trapped)

2. basic= add acid like citric acid

what factors can alter renal excretion?

blood flow:

- increase blood flow by drinking/exercising

- lower blood flow by less water, kidney disease, heart disease. also FEMALES and AGE

what factors can alter renal excretion?

pharm:

probenecid

PGP

probenecid= lowers excretion of others (like penicillin)

PGP transporters= verapamil, digoxin

how can you determine the state of renal excretion

creatinine clearance-> creatinine is a muscle waste product that is filtered by the kidney. it is not actively secreted

this gives u glomerular filtration rate

how is creatinine clearance calculated

rate of creatinine excretion/ serum creatinine concentration

higher renal clearance of a drug than CrCl indicates that

active secretion is involved

(ex: metformin)

how can you test if a drug is more actively secreted than filtered through glomerulus?

add competitors that will compete for the transporters that usually secrete the drug

-probenicid for acidic drugs

-cimetidine for basic drugs

renal clearance of the drug will DECREASE in the presence of competitors if it uses active secretion

-If clearance didn't change, secretion is not important-> drug mostly cleared by filtration only

how would you test if an acidic drug uses active secretion or gfr

1. compare it to CrCl. if its about the same probs GF

2. test: add probenecid for acidic drugs (cimetidine for basic). probenecid will compete for active transporters and LESS of the drug will be excreted indicating that it uses active transport

how would you test if a basic drug uses active secretion or gfr

add cimetidine for basic drugs. cimetidine will compete for active transporters and LESS of the drug will be excreted indicating that it uses active transport

how can you test if a drug is reabsorbed in the kidneys

change the pH of urine

- making urine more basic will increase excretion of acidic drugs (ion trapped and excreted)

the renal clearance of a lipophilic weakly acidic (pka=5) drug is likely to be

a. reduced by citric acid

b. reduced by sodium bicarb

c. increased by acidifying urine

d. increased by alkalizing urine

a. reduced by citric acid

d. increased by alkalizing urine

less of weak acid will be excreted if its in an acidic environment since it will be unionized and diffuse back

a drug is given 100mg TID. Target is 5mg/L. Drug is 40% eliminated by the liver and the rest through GFR. The pt has a CRCl of 30% of the normal amount. What should the adjusted dose be?

300mg given total-> 40% is eliminated and 60% is kept

300 x 0.6 = 180mg will reach kidney [120 eliminated]

-we need only 30% of that to reach kidney since they have lower gfr

180 x 0.3 = 54mg needed to reach kidney

120 [was eliminated] + 54= 174mg

sites of biotransformation

stomach

GI

kidneys

lungs

liver (MOST)

which parts of a cell play an active roll in biotransformation of drugs

Smooth ER= phase 1

Cytosol= phase 2

others: nuclear envelope, mitochondria, plasma membrane

phase 1 vs phase 2 metabolism reactions

phase 1: functionalization rxns (expose functional group)

- oxidation, reduction, hydrolysis

phase 2: conjugation rxns (add endogenous compound to parent drug)

- glucuronic acid, acetic acid, amino acid