Transcript 9-13-04 Factors Affecting Action of Drugs

Absorption/Distribution
• Drug effects are affected by Absorption and
Distribution
– Absorption refers to the entrance of drug into
the blood stream
– Distribution refers to distribution to the various
tissues once in the blood
Drug Forms
• Aqueous
– Water and sugar and added
drug
• Alcoholic
– Drug dissolved in EtOH (520%)
• Solid
• Capsules
– Gelatin dissolves in
stomach releasing drug
• Delayed –release
– 2-3 single doses released over
time
• Enteric coated
– Acid resistant covering
prevents digestion in stomach
• Suppositories
– Self explanatory
• Ointments
– Petrolatum or lanolin for topical
absorption
• Transdermal
– Bandage or patch and absorbed
through skin for up to 24 h
Routes of Administration
• Oral (PO)
– Safest and most convenient
– Typically takes 30-60 min for appearance in
blood
– Can be removed by gastric lavage or induced
vomiting
• Parenteral
– Any route that does not involve GI tract
Parenteral Administration
• IM
– Intramuscular injections- short action (min)
• Gluteals or deltoids
– Gluteals and sciatic nerve
• IV
– Intravenous injection – immediate action
• Directly into bloodstream
• Drug cannot be withdrawn once administered
• Inhalation – short action
– Nose, mouth into lungs during inspiration
The Five Rs
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Right patient
Right drug
Right dose
Right route
Right time
Absorption
• Drug must be dissolved in body fluids
• Drugs must pass through membranes
(except IV administration)
– GI
– Blood vessels
– Many drugs rely on passive diffusion to be
absorbed (concentration gradient)
• Absorption affected by
– Lipid solubility
• More fat soluble compounds diffuse easily across membranes
– Drug ionization
• Like Na+ and Cl- ions do not diffuse readily across membranes
• Basic drugs (aspirin) are un-ionized in the stomach and more
readily absorbed
• Acidic drugs (morphine, streptomycin) un-ionized in lower GI
and more readily absorbed
• Liquid formulations are typically absorbed
more quickly
• Solid tablets or capsules must dissolve in
body fluids before they can be absorbed
– Slows down the absorption process
Drug Distribution
• Distribution of drug to tissues affected by
factors such as
– plasma protein binding
– Blood flow
– Blood brain barrier
Plasma Protein Binding
• Primarily albumin and globulins
– Proteins help regulate osmotic balance
• Many drugs attracted to proteins
– Some are bound to proteins
– Some are unbound (free to circulate)
– Only unbound drugs exert effect
Blood Flow
• Various organs receive different blood flow
• Liver, kidneys and brain have largest supply
– These organs exposed to largest amounts of
drugs
• Adipose has poor supply
– Does not receive large amounts of drugs
– Lipid soluble drugs can accumulate
Blood Brain Barrier
• An extra layer of lipid membrane that protects
the brain
– Water soluble compounds do not cross blood brain
barrier effectively
– Drugs that are intended to act on the brain must
have a lipid soluble chemistry
• E.g benzodiazepines treat anxiety and convulsions
• Some antibiotics are not lipid soluble and cannot treat
infections of the brain
Drug Metabolism
• Conversion of foreign substances to chemical
forms that can be eliminated (biotransformation)
– Renal, intestinal, respiratory
• Main organ of transformation is liver
• Drug microsomal metabolizing system or
cytochrome P450 system
• Converts lipid soluble compounds to water soluble
– Easily eliminated in the urine
• Metabolic conversions can inactivate drugs
by converting to more easily excretable
form
– Also typically less active at receptor
• Conversions can also activate “pro-drugs”
– E.g. codeine is metabolized to morphine a more
potent form of opiates
Phase I and Phase II reactions
• Phase I
– Drug is oxidized or reduced to more polar form
• More readily excreted
• Phase II
– Drug is conjugated to glutathione
• Increases the polarity of the drug even more
• Phase II is not dependent on phase I although often
happens after I
Induction
• Liver P450 system responsible for Phase I
reactions
• P450 can be induced by consistent drug
administration
– E.g. chronic alcohol use
• Increases metabolism and excretion of drug
resulting in tolerance
Inhibition
• Co-incidental administration of two drugs
metabolized by same P450 system will
result in inhibition of conversion of each of
the drugs
– Can result in increased potency, duration of
action of drug
– May often result in adverse effects
First Pass Metabolism
• Drugs that are orally administered are
absorbed and pass into portal circulation
• These drugs pass through liver prior to
distribution
• Many of these drugs are metabolized
(activated or inactived) extensively
• Protective mechanism
Excretion
• Three primary routes of excretion
– Renal – urine
– GI – feces
– Respiratory – exhaled gases
• Kidney is primary organ of excretion
Renal Excretion
• Blood is filtered through the glomerulus of
the kidneys
– Most filtered substances are eventually
reabsorbed
– exceptions- urinary waste products
• Waste products are water soluble and usually
ionized
• So, .. Excreted drugs must be water soluble and
ionizable
The Kidney
The Nephron
Urine Formation
1) Filtration
2) Reabsorption
3) Secretion
Movement of materials across
the filtration membrane into
Bowman’s capsule
Solutes are reabsorbed across
the wall of the nephron into
the interstiial fluid
Solutes are secreted across the
wall of the nephron into the
filtrate
Water is reabsorbed across the
wall of the nephron by osmosis
GI Excretion
• After oral administration, unabsorbed drug
passes through GI tract and is excreted in
feces
• Some drugs can be reabsorbed in the
intestinal tract
Respiratory Excretion
• Typically, general anesthetic gases are not
totally absorbed
– Remnants exhaled
• Some drugs are metabolized to products
that can leave exchange with blood and air
in lungs
– Exhaled also
Half Life
• Time required for the concentration of a
drug in the blood to fall to half of its
original level
• Dependent on ADME
• Affected by liver or kidney disease
• Necessary to determine dosing regimen
Bioavailability
• Amount of drug that is actually absorbed
into the blood stream
• Dependent on route of administration
– E.g. drugs with high First Pass metabolism will
not have good oral bioavailability
– Necessary to administer parenterally
Patient Profile
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Age
Pregnancy
Smoking and drinking
Liver or kidney desease
Pharmacogenetics
Drug interactions
Psychological factors
Age
• Drug metabolism (P450) enzymes
– Underdeveloped in young
– Compromised in elderly
– Adult dosages may not be extrapolated to
children or elderly
Pregnancy
• Drug effects in pregnant women can have
drastic effects on unborn, or no effects at all
– FDA pregnancy categories
– Teratogenic drugs
– Drugs affecting breast feeding
Smoking and Drinking
• Both induce P450 enzymes
• Can effectively lower effective drug
concentration in blood
• Can more activate pro-drugs more
effectively
Liver or Kidney Disease
• A damaged liver will metabolize drugs to a
lesser extent
– Can result in greater or lesser active drug
• Damaged kidneys excrete less drug
metabolites