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biological
system, includes
Absorption
Distribution
Metabolism
Excretion
In order to reach their site of action, drugs have to pass through several
membranes transmembrane transport
Mechanisms of transport
Passive diffusion: passage of drugs through the lipid surface (major
mechanism of drug absorption)
Lipid-soluble drugs
Small water-soluble drugs
Noncharged form of weak electrolytes
Membrane permeability versus lipid (olive oil):water partition coefficient
solubility
The greater the partition coefficient, the higher the lipid-solubility of the drug,
and the greater its diffusion across membranes.
Weak electrolytes and membrane permeability
Most drugs are small (MW < 1000) weak electrolytes (acids/bases). This
influences passive diffusion since cell membranes are hydrophobic lipid bilayers
that are much more permeable to the non-ionized forms of drugs.
The fraction of drug that is non-ionized depends on its chemical nature, its
Ingestion of a solid dosage form with a glass of cold water, fasting, lying
on the right side, hyperthyroidism accelerate gastric emptying
Ingestion with a fatty meal, acidic drink, or with another drug with
anticholinergic properties, lying on the left side, hypothyroidism,
sympathetic output (as in stress) retard gastric emptying.
First-Pass Metabolism
Extent of metabolism occurring before drug enters systemic circulation
Main site: Liver
Decrease in drug efficacy (orally) can be overcome by using a
greater dose
Example: Propranolol (5 mg vs. 100 mg)
Extensive metabolism may render oral admin. impossible
Example: Lidocaine
The fraction of drug eliminated from portal blood during absorption
hepatic extraction ratio (ERH)
ERH = ClH/ QH
Bioavaibilty (F) F = 1- ERH
Drug Absorption & Route of administration
Absorption describes the rate and extent at which a drug leaves its site of
administration.
Bioavailability (F) is the extent to which a drug reaches its site of action, or to
a biological fluid (such as plasma) from which the drug has access to its site of
action.
Important Properties Affecting
Drug Absorption
Chemical properties
acid or base
degree of ionization
polarity
molecular weight
lipid solubility or...
partition coefficient
Physiologic variables
gastric motility
pH at the absorption site
area of absorbing surface
blood flow
pre absorptive hydrolysis
ingestion w/wo food
Advantage
Relatively Fast
Painless (usually)
Easy
Safe
No need for equipment
or help
given orally
caffeine, alcohol
Disadvantage
Not very fast
Some drugs dont
withstand stomach/GI
conditions (insulin,
cocaine)
variable
uncooperative, vomiting,
unconscious
Liver
INJECTION
subcutaneous, intramuscular absorbed by diffusion and affected by
blood flow
intravenous, intraarterial injection avoids absorption
Other Injection types
Intraperitoneal = (I.P.) into stomach cavity (between organs). Faster than P.O.
Intense effects
Smoke Examples:
metapmphetamine
Vapor examples:
anasthetics
Disadvantage
Potential harm to lungs
Short term = pneumonia
Long term = cancer
Exacerbation of abuse
liability
Drug is sometimes
destroyed in proCESS
MUCOUS MEMBRANE
sublingual, buccal, nasal, vaginal or rectal mucosa: passive diffusion
Advantage
Quick absorption
Easy and discreet
Little chance of
infection or tissue
vasoconstrictors)
Disadvantage
Can taste bad or
irritate membranes
absorbed readily
exacerbate abuseliable
drugs potential
for abuse
SKIN
Transdermal
Advantage
Easy
Not painful
Slow, sustained
release
Bypasses GI tract
& first pass
Only have to change
every few days /
weeks
Disadvantage
Can fall off
Potential toxicity to
children and pets
Very few drugs
absorbed sufficiently,
low permeability of
skin
Local irritation possible
Toxicity if additional
drug consumed
Distribution
Only that fraction of drug which is non-protein-bound can bind to cellular
receptors and pass across tissue membranes, thus being distributed to
other body tissues, metabolized, and excreted.
The actual pattern of drug distribution reflects various physiological
factors and physicochemical properties of the drug.
Plasma protein
albumin
- binds many acidic drugs
a1-acid glycoprotein for basic drugs
The fraction of total drug in plasma that is bound is determined by its
concentration, its binding affinity, and the number of binding sites.
Phases of Distribution
first phase
reflects cardiac output and regional blood flow. Thus, heart, liver,
kidney & brain receive most of the drug during the first few minutes
after absorption.
next phase
delivery to muscle, most viscera, skin and adipose is slower, and
involves a far larger fraction of the body mass.
probenecid
benzodiazepines
streptomycin
bilirubin
sulfonamides
digotoxin
tetracycline
fatty acids
tolbutamide
penicillins
valproic acid
phenytoin
warfarin
phenylbutazone
Drugs Binding Primarily to
a1-Acid Glycoprotein
alprenolol
lidocaine
bupivicaine
methadone
desmethylperazine
prazosin
dipyridamole
propranolol
disopyramide
quinidine
etidocaine
verapamil
imipramine
amitriptyline
nortriptyline
Drug Reservoirs
Body compartments where a drug can accumulate are reservoirs. They have
dynamic effects on drug availability.
GIT
plasma proteins as reservoirs (bind drug)
cellular reservoirs
Adipose (lipophilic drugs)
Bone (crystal lattice)
Transcellular (ion trapping)
Bone Reservoir
Tetracycline antibiotics (and other divalent metal ion-chelating agents) and
heavy metals may accumulate in bone. They are adsorbed onto the bonecrystal surface and eventually become incorporated into the crystal
lattice.
Bone then can become a reservoir for slow release of toxic agents (e.g., lead,
radium) into the blood
Adipose Reservoir
Many lipid-soluble drugs are stored in fat. In obesity, fat content may be
as high as 50%, and in starvation it may still be only as low as 10% of
body weight.
70% of a thiopental dose may be found in fat 3 hr after administration.
GI Tract as Reservoir
Weak bases are passively concentrated in the stomach from the blood
because of the large pH differential.
Some drugs are excreted in the bile in active form or as a conjugate that
can be hydrolyzed in the intestine and reabsorbed.
In these cases, and when orally administered drugs are slowly absorbed,
the GI tract serves as a reservoir.
Redistribution
Termination of drug action is normally by biotransformation/excretion, but
may also occur as a result of redistribution between various
compartments.
Particularly true for lipid-soluble drugs that affect brain and heart.
Central nervous system: permeable to lipid-soluble drugs only; limited
permeability to water-soluble drugs when inflamed
Placental transfer: limited by blood flow, not by a "barrier
Penetrating into the Brain
Drugs that are small molecules
Lipid-soluble
Active transport systems (require energy:
mitochondria)
Carrier-mediated transport systems (dont need energy), Pinocytotic
vesicles
Other factors that affect absorption into the CNS
Drugs that are highly bound to plasma proteins are
less likely to penetrate the BBB
Drugs that are weak acids (are highly ionized at the
pH of blood, 7.4) are less likely to penetrate (have
low lipid-solubility)
Volume of distribution (Vd) relates the amount of drug in the body to the
plasma concentration of drug (C).