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The study of what a drug does to the body
Recognition molecule for chemical mediator
Physiological mediators (endogenous): hormones, neurotransmitters, inflammatory mediators
Drug molecule (external source): Acute regulation of physiological & biochemical functions. Do not create effects but modulate ongoing function or an action that your body is already or should already be doing.
Drug is usually described b it's more prominent effects: targets specific receptors, rarely sufficiently selective to be described as specific.
Multiple subtypes of receptors exist within classes
Goal: increased efficacy and minimization of adverse effects
Receptor Sites/Drug Receptor Interaction
- The "strength" of the interaction between a ligand and a receptor
- Efficacy (Intrinsic Activity)
- Ability of a drug to initiate a physiologic response, activate the receptor.
- Has both affinity and efficacy
- Full Agonist
- Can produce maximal response obtainable
- Mimics endogenous neurotransmitter
- Partial Agonist
- Affinity but intermediate efficacy
- Sub-maximal response
- Affinity but no efficacy
- Competitive Antagonist
- “Competes” for same binding site
- Inhibition can be overcome by increasing the concentration of the agonist
- Irreversible Antagonist
- Noncompetitive antagonist
- Binds to different site on same receptor
- Blocks agonist binding
- Tolerance (desensitization, down-regulation)
- Continued stimulation by agonist
- Same dose = diminished effect. Gradual decrease in responsiveness (days or weeks). Cross tolerance within classes of drugs.
- Occurs rapidly (often within minutes)
- Hyperreactivity (not hypersensitivity)
- An increase in receptor density
- “Up regulation” often because an antagonist has been around fro a long time.
Factors that may influence drug response:
- Receptor density, signal transmission
- Interpatient and intrapatient variation
- Pregnancy status
- Disease states
- Ethnicity, genetic factors
- Concomitant drug use
- The power of an agent to produce the desired effect.
- Often related to dose of a drug.
- Drugs are more meaningful compared in terms of relative potency (ratio of equi-effective doses).
- 50% effective concentration.
- Drug with lower EC50 would be more potent .
- e.g. Drug whose EC50 is 4 mg is 10X more potent than a drug whose EC50 is 40 mg.
- The maximal effect produced by a drug.
- Ceiling effect.
- Efficacy and potency of a drug are not necessarily correlated.
- More potent drugs may not always be the most efficacious.
- Greater clinical importance than potencyIf undesired effects of a drug limit its dose, its efficacy will be correspondingly limited.
Adverse Drug Reaction (ADR)
A “response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the modification of physiological function.”
Causal link between drug and ADR.
Harm directly caused by the drug at normal doses, during normal use.
- Predictable ADRs: 70-80%
- Usually dose-related and generally preventable
- Unpredictable ADRs: 20-30%
- Hypersensitivity: Mediated by immune response
- Idiosyncratic: Abnormal reactivity to a chemical that is peculiar to a given individual. Extreme sensitivity to low doses or insensitivity to high doses. Could also be paradoxical response (not expected reaction).
Adverse Drug Event (ADE)
- Any injury resulting from the use of a drug.
- Adverse drug reaction (ADR)
- Medication errors: Preventable ADR
Allergic Drug Reactions
- FIRST exposure:
- Drug (hapten) + protein = antigenic complex →Ab synthesis
- LATER exposure = allergic response
Dose-response relationships usually not applicable.
Immediate (Type I) vs. delayed (Types II, III, IV)
Type I: Immediate or Anaphylactic
- Drug-specific IgE antibodies
- Surface receptors on mast cells or basophils
- Re-exposure Antigen-Ab release vasoactive mediators
- Targets: GI tract, skin, eye, respiratory system, vasculature, ex: Urticaria – rash/skin reaction
- Systemic Anaphylaxis
- Most severe presentation of IgE-mediated drug reaction = Acute, life-threatening
- General vasodilation and smooth muscle contraction
- Severe bronchiole constriction, GI (n/v/d), sudden loss of blood pressure, massive edema
- Anaphylactoid reactions
- Release of the mast-cell mediators without IgE-allergen interaction
- Not a hypersensitivity reaction although produce same symptoms & treated the same way
- e.g., radiopaque contrast dyes
Type II: Tissue Specific (Cytotoxic)
- IgG (rarely IgM) antibodies
- Major target = cells in circulatory system
- “Delayed” (5-8 days)
Type III: Immune Complex
- Drug (antigen) binds IgG → complexes precipitate in vessels or tissues → destructive inflammatory response
- Serum sickness (urticarial skin eruptions, arthralgia/ arthritis, lymphadenopathy, fever), drug fever, vasculitis
- “Delayed” (one or more weeks)
Type IV: Cell-Mediated
- Memory T-cells
- Exposed to antigen, become activated and produce an inflammatory response
- Tissues killed by release of soluble factors
- “Delayed” 48-72 hrs
- Tuberculin reaction, contact dermatitis (poison ivy, topical meds), Stevens-Johnson syndrome
- Response elicited by combined drugs is EQUAL TO combined responses of individual drugs
- 1 + 1 = 2
- Response elicited by combined drugs is GREATER THAN combined responses of individual drugs
- 1 + 1 = 3
- A drug which has no effect enhances the effect of a second drug
- 0 + 1 = 2
- Drug inhibits the effect of another drug
- 1 + 1 = 0
Pregnancy Categories for Drug Use
Well controlled studies -no fetal risks
- B: Animal studies have not shown fetal risk
- No adequately controlled trials in women
- C: Animal studies revealed adverse fetal effects
- No adequately controlled trials in women
- D: Some fetal risk, benefits may outweigh risk
- Warn patient
- X: Fetal abnormalities in animal or human studies, risk outweighs any benefit