Lectures 10-11: Introduction to ADME

pharmacodynamics (PD)

effect of drug on the body

pharmacokinetics (PK)

effect of body on the actions of a drug

ADME

major cause of attrition in the clinic

effective responses

require dose high enough + appropriate route of administration

advantages of subcutaneous route

slow onset, may be used to administer oil-based drugs, rate of absorption controlled by vasculature

disadvantages of subcutaneous

slow onset, small volumes, irritation

advantages of intramuscular

intermediate onset, may be used to administer oil-based drugs, slow release from repository

disadvantages of intramuscular

can affect lab tests (creatine kinase), intramuscular hemorrhage, painful

advantages of intravenous

rapid onset, controlled drug delivery, least dependent on absorption processes, can be large volumes, can dilute irritating solutions

disadvantages of intravenous

peak-related drug toxicity, not for oily solutions or suspensions

advantages of intrathecal

bypasses blood-brain barrier by directly injecting into cerebrospinal fluid

disadvantages of intrathecal

infection, highly skilled personnel required

rectal route

local application to colon

sublingual route

vasodilators, angina

inhalation

gases

regional perfusion

delivery to certain organs

intraperitoneal

vaccines, chemo

physiological factors

• gastric motility and residence time

• pH of the gastrointestinal tract

• intestinal surface area and transit time

• intestinal microfllora

physiochemical properties of drugs

• hydrophilicity and lipophilicity

• ionizability and charge

• chemical stability

• molecular size

• particular size

Lipinski’s Rule of Five

• >5 H-bond donors

• molecular weight >500

• octanol/water partition coefficient: logP >5

• >10 H-bond acceptors

bioavailability (F)

fraction of drug available to the systemic circulation

F = 1

bioavailability of IV

presystemic elimination

entry of orally (po) administrated drug

first pass effect

excretion and metabolism in enterocytes and hepatocytes to reduce amount of drug delivered to systemic circulation

heart

IV inserts almost directly to this part of the body

GI system

oral dosing goes from this part of the body to distribute drug

extraction ratio (ER)

(C in - C out) / C in

0-1

interval of extraction ratio (ER)

clearance rate

Q x ER

Q (blood flow)

~90 L/h or 1.5 L/min

maximum hepatic clearance

~1.5 L/min

lower rectum

suppository drugs are absorbed into vessels that drain into the inferior vena cava (bypass liver) here

upper rectum

suppository drugs are absorbed into veins that lead to the liver here

layers from outside to inside

1. serosa

2. longitudinal muscle

3. circular muscle

4. sub-mucosa

5. mucosa

parts of muscularis mucosa

longitudinal muscle, circular muscle, sub-mucosa

Myenteric plexus

• control GI motility

• sympathetic & parasympathetic

• within muscularis mucosa

submucosal (Meissner’s) plexus

• control GI secretion

• parasympathetic primarily

• nearest lumen

vagus nerve

supplies the parasympathetic nervous system

cranial nerves

innervate upper and lower most portions of GI tract: esophagus, stomach, pancreas, large intestine in parasympathetic nervous system

sacral nerves

innervate lower most portions of large intestine in parasympathetic nervous system

increases

stimulation of parasympathetic fibers ___ most activities of GIT

all

sympathetic nerves __ portions of the GI tract

inhibits

stimulation of sympathetic fibers ___ most activities of the GIT

mixing movements

local constrictive contractions of small segments of the gut walls

luminal fluid

increase ___ to mucosal surface to promote absorptive action of colon

propulsive movements

contractile ring appears in a segment of GI tract and then moves forward, material in front moves forward too

mass action contractions

another name for propulsive movements

peristalsis

main mechanism of propulsive movements

sucralfate, some milk products, antacids, and oral iron preparations

block absorption of quinolones, tetracycline, and azithromycin

omeprazole, lansoprazole, H2 antagonists

reduce absorption of ketoconazole, delavirdine

didanosine

reduce ketoconazole absorption

cholestyramine

binds raloxifene, thyroid hormone, and digoxin

plasma membrane

bilayer of amphipathic lipids with hydrocarbon chains inward and hydrophilic heads outward

plasma membrane

• cholesterol

• membrane proteins

• highly ordered domains

• charged chemicals cannot pass through by diffusion

diffusion

drug molecule penetrates by ___ along a concentration gradient by virtue of solubility in the lipid bilayer

transfer is proportional

__ is proportional to:

• magnitude of concentration gradient

• lipid-water partition coefficient

• membrane surface area exposed to drug

paracellular transport

filtration in glomerulus

tight

paracellular transport cannot occur if CNS capillaries are ___

active transport

• used when proteins with drug molecules bound are too large and polar for crossing membrane

• unbound drug crossing membrane

• blow flow transfer of drugs with water through membrane up to 100-200 Da

• energy is required (ex. ATP)

• frequently occurs for endogenous metabolites like glucose

pKa

pH at which ½ drug is in its ionized form

acids

release protons

bases

acquire protons

uncharged

only ___ forms pass through the membrane by diffusion

weak acid

pH = pKa + log [RCOO-]/[RCOOH]

weak base

pH = pKa + log [RNH2]/[RNH3+]