Pharmacokinetics

What the body does to the drug. (absorption, distribution, metabolism, excretion)

Metabolism

Excretion

Concentration gradient

Always moves down.

ONLY free unionized drug.

Surface area & vascularity

Larger the SA and > the vascularity = more absorption.

Muscles (IM) > Fat (SQ)

Weak Acid

Only nonionized crosses membranes (lipid soluble)

R-COOH --> R-COO- + H+

                nonionized          ionized

Place acidic drug in acidic environment can move!

ASA, PCN, cephalasporins, loops, thiazide diuretics

Weak Base

R-NH3+ --> R-NH2 + H+

                   ionized       nonionized

Weak base in the stomach wouldn't be absorbed b/c most would be in ionized form!

Morphine, Local anesthetics, amphetamines, PCP  

Ionization & Renal Clearance

Ionized and nonionized are filtered but ionized unable to be secreted or reabsorbed.

Acidify urine --> increase ionization of weak bases

(NH4Cl, vit. C, cranberry juice)

Alkalinize urine -->increase ionization of weak acid

(NaHCO3)

Bioavailablity (f)

Fraction of a dose that reaches systemic circulation

IV doses = 100%

Protein binding

usu. to albumin

Bound to protein = inactive drug(affects distribution)

Competition

warfarin + sulfonamides --> warfarin toxicity

sulfonamides + unconjugated bilirubin --> kernicterus in neonates

Volume of Distribution

does the drug stay in the bood or get out?

Vd = Dose/C^o (L)

C^o = [plasma] at zero time

Vd LOW = HIGH % of drug bound to plasma protein

Vd HIGH = HIGH % of drug in tissues  

Biotransformation

Metabolic transformation of the drug to H2O soluble metabolites

Drug --> inactive metabolite

Drug --> active metabolite (ie benzo's :diazepam)

Prodrug --> drug

Type I biotransformation

Oxidation, reduction or hydrolysis of the drug

Microsomal metabolism:  

Done by CYP450 isozymes (found in smooth ER of liver cells, and GI/lungs/kidney)

Nonmicrosomal metabolism:  

Hydrolysis done by adding H2O (ex:local anesthetics)

Monoamine oxidases for amine NT's (ex: tyramine containing foods like beer, wine, cheese, fish)

CYP450 Inducers

Drugs that stimulate liver to make more of these enzymes :. plasma levels of the drug will be LESS

Examples: anticonvulsants (barbs, phenytoin, carbamazepaine) ATBX's (rifampin) EtOH use, glucocorticoids,

CYP450 Inhibitors

Drug stimulates liver to make LESS enzymes so plasma levels of the drug are HIGHER --> SE's!

Examples: antiulcer meds (cimetidine, omeprazole), ATBX's (chloramphenicol, macrolides, ritonavir, ketoconazole) acute EtOH use, grapefruit use, haloperidol & quinidine (w/ CV or CNS drugs)

Type II biotransformation

Attach something to the drug via transferases

Glucuronidation: glucose-like mol. attached (morphine, chloramphenicol) neonates have ↓ ability

Acetylation: fast vs. slow metabolizers (slow = drug induced SLE & hydralazine > procainamide > isoniazid)

Glutathione conjugation: Tylenol depletes levels in liver

Half life

Zero-order elimination

Constant AMOUNT is eliminated per unit of time

Half-life is variable

Examples (EtOH, phenytoin & ASA at HIGH levels)

1st order elimination

Constant FRACTION is elimated per unit of time

Half-life is constant not amount elimated

Renal Elimination

Rate of elimination = GFR + active secretion - reabsorption

Cl = GFR (w/ NO secretion/reabsorption/protein binding)

GFR = 120ml/min

Steady State

Rate in = rate out

Have peaks and troughs for plasma levels

Clinical steady state reached in 4-5 half lives

(rate of infusion doesn't affect amt of time to steady state just that the [drug] will be higher once reached) 

Loading dose

Given to put amt into body that should be there at a steady state

LD usu 2X the maintenance dose

Half life calculation

t_1/2 = 0.7 X Vd/Cl

If renal Cl ↓ then 1/2 life ↑

If Vd goes ↑ than 1/2 life ↑

Loading dose calculation

LD = Vd X C^ss

(target plasma level aka steady state concentration)

Maintenance dose calculation

MD = Cl X C^ss X τ

(tau = dosing interval)