CHAPTER 11
FACTORS AFFECTING DRUG ACTIVITY
CHAPTER OUTLINE
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Human Variability
Disease States
Adverse Drug Reactions
Drug-Drug Interactions
Drug-Diet Interactions
Review
HUMAN VARIABILITY - AGE
• Neonates and infants
– drug distribution, metabolism, and excretion slower
• Children (age range from 1-12 years old)
– metabolize certain drugs more rapidly, e.g., clindamycin,
valproic acid, theophylline, ethosuximde and theophylline
• The elderly
– changes in gastric pH and emptying, intestinal motility, slow
the rate of absorption
– decreases in cardiac output, liver enzymes, and kidney
function
HUMAN VARIABILITY
• Gender
– Women and men handle drugs differently.
• Pregnancy
– Delayed gastric emptying.
• Pharmacogenomics
– Hereditary basis of differences in ADME.
• Body weight
– Important in dosing medication to children.
• Psychological factors
– Influences patients responses to drugs, e.g., placebo effect.
DISEASES THAT AFFECT DRUG DISPOSITION
- HEPATIC
• The disposition and effect of some drugs can be influenced
by the presence of disease.
– Cirrhosis
• A chronic and potentially fatal disease.
– Obstructive jaundice
• Obstruction of the bile duct causing hepatic waste
products and bile to accumulate in the liver.
– Acute viral hepatitis
• An inflammatory condition of the liver caused by
viruses.
DISEASES THAT AFFECT DRUG
DISPOSTION - RENA
• Reduced renal function can affect the elimination and
plasma protein binding of many drugs.
• As renal function decreases, the dosage of a drug that is
eliminated by the kidney should be reduced.
Atenolol
Piperacillin
Digoxin
Ranitidine
Gentamicin
Vancomycin
Lithium
• Decrease in renal function is measured by the amount of
creatinine in the blood.
DISEASES THAT AFFECT DRUG DISPOSITION CARDIAC
• Circulatory disorders diminish blood flow to one or more organs.
• Effects on absorption
– delayed gastric emptying
– decreased intestinal motility
– changes in GI pH
• Effects on metabolism
– decreased movement of drugs into hepatic cells
– decreased metabolism of blood flow sensitive drugs
• Effects high renal clearance drugs
DISEASES THAT AFFECT DRUG DISPOSITION
- THYROID
• Changes are in one direction with hypothyroidism
(under active thyroid) and in the other direction with
hyperthyroidism (over active thyroid)
– changes in bioavailability
– activity of metabolizing enzymes
– changes in renal blood flow
ADVERSE DRUG REACTIONS
• Any undesired symptom involving any organ
– common or rare
– localized or widespread
– mild or severe
• Some occur at normal doses (sometimes called side
effects).
• Some occur only at elevated doses.
COMMON ADVERSE DRUG REACTIONS
• Central nervous system effects
– CNS stimulation: agitation, confusion, disorientation
– CNS depression: dizziness, drowsiness, sedation, coma
• Hepatotoxicity
– occurs with acetaminophen, isoniazide, nitrofurantoin
• Gastrointestinal effects
– occur with nonsteroidal anti-inflammatory drugs (aspirin)
• Nephrotoxicity
– occurs with aminoglycosides, NSAIDs
• Hematological effect
– blood coagulation, bleeding, and bone marrow disorder
COMMON ADVERSE DRUG REACTIONS
• Teratogenicity
– substance that causes abnormal fetal development.
• Carcinogenicity
– substance that causes cancer.
• Drug dependence
– physiological dependence – physical symptoms
– psychological dependence – emotional fixation
• Idiosyncrasy
– unexpected reaction to a drug
• Hypersensitivity
– generally antibody mediated
– anaphylactic shock
DRUG-DRUG INTERACTIONS
• Two types:
– One drug affects how another drug is absorbed,
distributed, metabolized, or excreted.
– One drug affects how another drug accesses a
receptor or interferes with a normal physiological
process.
• called additive, synergistic, potentiation
• Time of reaction varies
DRUG–DRUG
INTERACTIONS – ALTER ADME
• Absorption
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Complexation
Gastric emptying
Gastric pH
Intestinal metabolism
• Distribution
– Displacement - one drug removes another drug from a
plasma protein binding site
– The displacement is significant if the percent bound is high.
DRUG-DRUG
INTERACTIONS – ALTER ADME
• Metabolism
– enzyme induction – much slower time course
– enzyme inhibition – generally within 24 hours
• Urinary excretion
– drugs compete for renal secretory system
– drugs that alter renal reabsorption
DRUG-DRUG
INTERACTIONS – AFTER SITE OF ACTION
• Additive Effects - when two drugs result in an effect
equal to the sum of the individual effects
• Synergism - when two drugs with similar
pharmacological actions produce greater effects than
the sum of individual effects
– e.g., vancomycin + gentamicin = increased
antibacterial effect from gentamicin
DRUG-DRUG
INTERATIONS – ALTER SITE OF ACTION
• Potentiation - when one drug with no inherent activity
of its own increases the activity of another drug that
produces an effect
– e.g., amoxicillin + clavulanic acid.
• Antidote – a drug given to block or reduce the toxic
effect of a drug
– naloxone + morphine
DRUG-DIET INTERACTION
• Absorption
– interacts chemically
– improves solubility
– alters drug release from formulation
– alters gastric emptying, intestinal motility, liver blood
flow
• Distribution
– high fat meals can increase fatty acid levels
– nourishment state
DRUG-DIET INTERACTION
• Metabolism
– high protein diets accelerate metabolism
– high carbohydrate diets decrease metabolism
– decreased calories decrease metabolism
• Excretion
– high protein diets increase glomerular filtration,
decrease reabsorption, and decrease secretion
• Most drug-diet Interactions can be avoided by
separating the administration of drug and food about 2
hours.