Pharmacology 2 (Drug Distribution and Biotransformation)

plasma proteins
bone
CNS
placenta

Drug + Protein <-> Drug-Protein complex

upon excretion or metabolism, the equilibrium is shifted to the left liberating free drug

drugs can be adsorbed onto bone crystal surface

more of a dead end than a reservoir

I) endothelial junctions in capillaries are very tight
II) no pinocytosis

only very lipid-soluble drugs can cross the capillaries in the brain to an appreciable extent

with meningitis the blood-brain barrier can become leaky

placenta is not a barrier - eventually even very hydrophilic drugs will cross

there are more biological membranes to cross before entering fetus - drug will reach fetus in a question of time and concentration

must be lipophilic to be transported across membranes to any great degree

must be hydrophilic to be transported in plasma to any great degree

the higher the dissociation constant, the more easily the drug dissociates from proteins

at some point, the slope steepens, and at this point there is a saturation of binding (at this point you may see toxic rxns at therapeutic total drug concentration)

at lower concentration of protein, drugs can saturate the protein more easily, so a lower percent of drug is protein bound

may see toxic reactions at therapeutic total drug concentrations

adding a drug X that binds to proteins at the same site as Drug Y forces more of Drug Y to be free; the increased concentration of Drug Y can lead to toxicity

redistribution
excretion
biotransformation

brain and viscera have a large amount of blood supply and therefore get a large portion of the drug initially

fat has a low blood flow, therefore it takes longer for drug to find its way there

lungs (anesthetics)
sweat
tears
saliva
breast milk
feces (MAJOR)
urine (MAJOR)

free drug concentration

important for hydrophilic drugs because of low protein binding

degree depends upon drug concentration in plasma

it is an active mechanism

I) drug has to have COO- or NH3+ group to be a candidate for secretion

II) there is competition among drugs for secretion (anions with anions; cations with cations)

III) protein binding is irrelevant; drug's affinity for pump protein is what's important for tubular secretion

anions can compete with anions; cations can compete with cations; anions cannot compete with cations

there is one transporter for anions and a different one for cations

70% of filtered water is reabsorbed in the proximal convoluted tubule, increasing the drug concentration and creating a gradient

to hasten the elimination of:
an organic acid -> sodium bicarbonate
an organic base -> dilute hydrochloric acid

increase the percent of ionized drug within the tubule so that less of the drug will undergo tubular reabsorption

lipophilicity refers to how lipid soluble a drug is; if concentration and lipid solubility are sufficient the drug will be reabsorbed

drug concentration in tubular fluid

urinary pH

lipophilicity of the drug

fluid flow rate through the nephron

as flow rate is increased, contact time with the tubular wall is decreased, therefore less of the drug is reabsorbed

enzymatically converted from one thing to another

enter bile by either passive diffusion and secretion

blood -> liver (conjugated) -> bile -> intestines (unconjugated by bacteria) (organic acids in unionized form b/c of lower pH) -> blood

increases the half-life of some drugs

take a lipid soluble substance and make it not so lipid soluble

synthetic reactions (conjugation)

nonsynthetic reactions

glucuronidation

glucuronidation
amino acid conjugation
acetylation
sulfate conjugation
methylation
glutathione conjugation

-OH group on the drug

-COOH group on the drug

-NH2 group on the drug

-OH group on the drug

N atom on the drug

cysteine - sulfur is the nucleophile that shares electrons

cysteine (glycine and glutamic acid are spared)

acetylation

to form a more easily excretable compound

Fe2+ > Fe3+

NADPH via cytochrome P450 reductase

oxidize drugs so that they become candidates for glucuronidation

OXIDATIVE REACTIONS
N-Dealkylation
O-Dealkylation
Aliphatic hydroxylation
aromatic hydroxylation
N-Oxidation
S-Oxidation
Deamination
Reduction

HYDROLYSIS REACTIONS

phase 1 - nonsynthetic reaction
phase 2 - synthetic reaction

CYP2 is the family

CYP2C is the subfamily

CYP2C19 is the particular enzyme in the subfamily

they have inhibitors - if inhibitors are administered to the patient at the same time as a drug requiring these enzymes, the concentration of the drug can be raised to potentially dangerous levels because it isn't being metabolized

liver has the richest supply

kidney has second richest supply

other tissues have enzymes for some or all of these reactions but are of lesser importance

location: Endoplasmic Reticulum

substrates: lipid soluble (mostly foreign, few endogenous)

glucuronide conjugation only

catalyze virtually all oxidation/reduction

Really where liver metabolism occurs

location: cytoplasm

substrate: both foreign and endogenous

catalyze fewer reactions than microsomal enzymes

all conjugations except glucuronidation

body has enzymes to biotransform endogenous and exogenous compounds; the same enzymes can do both

conjugation pathways (glucuronidation and sulfate conjugation) are saturated

undergoes cytochrome P450 oxidation, followed by glutathione conjugation until cysteine reserves are depleted

acetaminophen electrophile is attached to protein, causing cell death when enough are bound up

acetylcysteine

replenishes cysteine stores so that acetaminophen can be conjugated to glutathione