Comprehensive Drug Effects, Reactions, and Pharmacogenetics

How does the lecture classify drug effects into therapeutic vs adverse?

Therapeutic effect = the clinically desirable effect of a drug.
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Adverse effect/reaction = any undesirable action of a drug.

Characterize a side effect.

An undesired effect that is often tolerable, generally reversible upon drug discontinuation, and dose-related.

Differentiate a side effect from a toxicity reaction.

Side Effect → undesired but usually tolerable, dose-related, and reversible on stopping the drug.

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Toxicity Reaction → causes actual permanent cell/tissue damage (microscopic to macroscopic) and is intolerable.

What is a drug monograph, and how does the FDA require adverse reactions to be listed in it?

The monograph is the package insert that must accompany prescription drugs.

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• The FDA requires all observed adverse effects to be listed, organized by the body/organ system affected and reported as the percentage of the population affected.

How are FDA monograph categories of adverse drug reactions organized, and what are some example systems? (dont need to memorize specific examples)

Organized by body system / organ system →

1) .g., body as a whole,

2) cardiovascular

3) respiratory

4) digestive

5) endocrine

6) reproductive

7) genitourinary

8) skeletal muscle

9) nervous

10) hematologic (anemia, leukopenia, thrombocytopenia, agranulocytosis),

11) special senses (tinnitus, metallic taste),

12) hypersensitivities, and skin.

Define a drug hypersensitivity (allergy) reaction, and what must occur first?

An immune-mediated reaction in a susceptible individual producing allergic manifestations (rash, asthma, rhinitis, anaphylaxis).

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The person must have had a previous exposure (sensitization) to the drug to later react.

Walk through the mechanism of a Type I (immediate) drug hypersensitivity reaction.

1) The drug or metabolite acts as an antigen that bridges (cross-links) two adjacent IgE antibodies on the surface of mast cells / basophils

2) → Then cell degranulates, releasing histamine and other mediators

3) → allergic manifestations.

What is anaphylaxis, and what drug counteracts it?

The most severe form of hypersensitivity; a systemic Type I reaction with angioneurotic edema (lip/tongue/throat swelling), wheals (urticaria), GI symptoms, bronchospasm, and dropping blood pressure.

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• Epinephrine can override the histamine reactions.

Name the three drug-associated allergic reaction types with their antibody and key manifestation.

Type I — IgE — anaphylaxis, asthma, rhinitis, dermatitis (most severe).

Type II — IgG/IgM — hemolysis of red blood cells.

Type III — IgG — arthralgia, fever, lymphadenopathy.

What makes a hypersensitivity reaction so "frightening" clinically?

It is unpredictable and NOT dose-related — someone could take a drug (e.g., penicillin) 100 times without incident, then react. It occurs frequently with penicillins (~10% of the population is penicillin-allergic).

Define a teratogenic effect (and when is risk highest)?

The ability of a drug/agent to cause defects in a developing embryo (teratogen, from Greek teratos = "monster").

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• Risk is greatest early in pregnancy (organogenesis).

What is the significance of thalidomide in the 1960s

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What is isotretinoin (Accutane)'s teratogenic risk?

Thalidomide was a sedative for morning sickness; offspring were born with major limb defects (phocomelia).

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• Isotretinoin (for cystic acne) is ~99% teratogenic.

List modern-day medical/dental uses of thalidomide, and why can a teratogen still be FDA-approved?

Uses: AIDS-related mouth/throat ulcers, multiple myeloma and blood dyscrasias, leprosy sores, and reversing AIDS "wasting."

• A teratogen can be approved when therapeutic benefit outweighs risk.

Under the FDA's PLLR, what happened to the pregnancy letter categories, and what replaced them?

The PLLR removed letter categories A, B, C, D, X.

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It replaced them with three narrative subsections:

8.1 Pregnancy (incl. labor/delivery),

8.2 Lactation (incl. nursing mothers)

8.3 Females and Males of Reproductive Potential.

Define a drug interaction, and what three general outcomes are possible?

When 2+ drugs are taken together, the resultant effect may differ from each drug alone (can also involve food, supplements, or a condition).

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Outcomes:

1) enhancement of an effect,

2) new effects not seen alone,

3) inhibition of one drug's effect.

Name the four types of interaction effects with their "math" shorthand.

Synergistic: 2+2=20;

Additive: 2+2=4;
Potentiating: 0+2=10;
Antagonistic: 2+2=1.

Contrast a synergistic vs a potentiating drug interaction.

Synergistic: two active drugs together produce an effect far greater than the sum (2+2=20).

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Potentiating: a drug with no effect on its own greatly increases the second drug's effect (0+2=10).

List the four basic mechanisms of drug interactions.

(1) Drugs with similar effects (additive/synergistic/potentiation);
(2) Absorption effects (altered pH/binding in the stomach);
(3) Displacement from plasma proteins (more free active drug);
(4) Metabolism effects (altered CYP → induction or inhibition).

Classify drug interactions as pharmacokinetic vs pharmacodynamic.

• Pharmacokinetic: absorption, distribution, metabolism (CYP induction/inhibition), excretion.

• Pharmacodynamic: synergistic and antagonistic interactions.

List the seven factors that influence the effectiveness and safety of drugs.

1) Biological variation,

2) hypersusceptibility,

3) drug idiosyncrasy,

4) age,

5) pathological state

6) tolerance,

7) Tachyphylaxis.

Define biological variation.

The range of response per dose; an individual may need a higher or lower dose than average to produce the desired effect.

Define hypersusceptibility.

A greater-than-normal reaction to a drug — e.g., a small tranquilizer dose expected to give mild sedation instead causes major motor incoordination.

Define drug idiosyncrasy.

A genetically determined abnormal/unusual response to a drug (often a genetic deficiency); the response is qualitatively different from the expected one.

How does age affect drug handling in children?

Children need smaller doses; increased skin/mucous-membrane permeability speeds absorption. Dose by weight (and BSA/age). OTC meds are typically ~half the adult dose, with the adult dose as the upper limit.

How does age affect drug handling in geriatric patients, and what's the dosing rule?

↓ absorption (↑ gastric pH), ↓ liver function (more active drug), ↓ lean mass, ↑ body fat (drug storage), ↓ total body water (drug more concentrated), ↓ plasma proteins (more free active drug). These push normal doses toward overdose levels → give a lower dose.

How does a pathological state (liver vs renal disease) affect dosing?

Liver disease: metabolism reduced (diminished CYP-450) → reduce dose.

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Renal disease: excretion impaired → modify dose based on the drug's renal clearance.

Define drug tolerance.

Increasing amounts of a drug are required to produce a consistent effect; usually associated with drugs causing physical dependence (addiction).

Define tachyphylaxis and give the dental example.

A rapid development of tolerance after only a few doses given in quick succession.

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• Dental example: if you wait too long to re-inject a local anesthetic, the second injection won't produce adequate anesthesia.

What is polypharmacy?

The use of multiple medications — generally 5 or more — including excessive/unnecessary use; usually discussed in older adults. (Herbal analog: polyherbacy.)

What are the Beers Criteria?

Lists of medications whose potential risks outweigh benefits for people 65 and older.

List the five main categories of the Beers Criteria.

(1) Potentially inappropriate meds in older adults;

(2) meds to avoid with certain conditions;

(3) meds to use with considerable caution;

(4) combinations that may cause harmful interactions;

(5) meds to avoid or dose differently in poor renal function.

Give representative Beers Criteria "avoid" examples and their reasons. (4)

Digoxin > 125 mcg/day in HF/Afib → ↑ toxicity, no benefit;

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Anticholinergics (diphenhydramine) → ↓ clearance, dry mouth, confusion;

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TCAs → confusion, orthostasis;

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1st-gen antipsychotics → ↑ stroke/mortality in dementia.

Define the field of pharmacogenetics, including polymorphisms.

The study of the genetic variability of drug effects.

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Polymorphisms = differences in genetic sequences that influence pharmacokinetics (plasma levels) and occur in target genes mediating a drug's therapeutic effect (pharmacodynamics).

What is the purpose of pharmacogenetic screening?

To prevent adverse effects/ineffectiveness → "misspelled" genes encoding altered drug receptors or CYP enzymes can cause adverse reactions or lack of response.

Give the "misspelled gene" examples where metabolism/response is altered. (3)

Isoniazid (TB) — metabolized so rapidly it's ineffective.

Prozac (fluoxetine) — metabolized so slowly it reaches toxic levels

Albuterol — ineffective at dilating bronchiole smooth muscle

Give the two genetic-deficiency examples affecting drug safety.

• Plasma cholinesterase altered form (~2% of the population) alters drug metabolism

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• G-6-PD deficiency lowers glutathione and can cause hemolytic anemia (~200 million people worldwide).