(6B) Drug-drug interactions: Pharmacodynamics

 Four Pharmacodynamic Interaction Patterns

• three increase an effect and antagonism decreases an effect

• Additive

• Synergistic

• Potentiation

• Antagonistic

Additive

• Combined effect

  • E(A+B) = E(A)+E(B)

  • combined effect equals the two individual effects added together.

• Usual relationship

  • Often similar mechanism; same receptor/site and role

• Example

  • NSAID + acetaminophen

Synergistic

• Combined effect

  • E(A+B) > expected effect

  • The combined effect is greater than expected.

• Usual relationship

  • Often different mechanisms/targets; may use different sites on one receptor

• Example

  • Alcohol + benzodiazepine

Potentiation

• Combined effect

  • E(B) ≈ 0, but E(A+B) > E(A)

  • Drug B has little or no relevant effect alone, but it increases Drug A’s effect.

• Usual relationship

  • N/A

• Example

  • Carbidopa + levodopa

Antagonistic

• Combined effect

  • E(A+B) < E(A)+E(B)

  • Combined effect is less than expected because one drug reduces or opposes the other’s effect.

• Usual relationship

  • N/A

• Example

  • Benzodiazepine + flumazenil

Synergistic

Alcohol + benzodiazepine

• Both interact with the GABA-A receptor, but at different sites and in different ways; alcohol has an allosteric role.

• Their synergistic sedation may cause coma or death.

Potentiation

Carbidopa + levodopa

• Levodopa can enter the brain. Once inside, it is changed into dopamine, which produces the desired effect.

• Carbidopa does not produce a dopamine effect by itself.

• Carbidopa protects levodopa from being broken down before it reaches the brain.

• Therefore, more levodopa reaches the brain, producing a stronger and longer dopamine effect.

Antagonistic

Benzodiazepine + flumazenil

• Flumazenil antagonizes/reverses benzodiazepine effects.

• The professor described overdose reversal as the main reason to intentionally use antagonism; unintended antagonism may occur with polypharmacy.

What are the main Pharmacodynamic interactions?

• Same-Target Mechanisms

• Different Targets → Same or Opposing Output

What are the Same-Target Mechanisms?

• Competitive antagonism

• Noncompetitive antagonism

• Partial-agonist antagonism

Same-Target Mechanisms

Competitive antagonism

• Reversible antagonist competes with agonist at the same orthosteric site; can be overcome by more agonist if safe

• ↑EC50, right shift, Emax unchanged

Same-Target Mechanisms

Noncompetitive antagonism

• Irreversible orthosteric binding or allosteric negative modulation; more agonist cannot restore full response

• ↓Emax

Same-Target Mechanisms

Partial-agonist antagonism

• Lower-efficacy ligand competes with a full agonist at the same receptor

• Lower net response at a given full-agonist concentration

Same-Target Mechanisms

Partial-agonist antagonism - example

• Methadone was referenced as competing with a full opioid agonist while producing a lower response and not causing as strong a withdrawal syndrome.

Same-Target Mechanisms

Competitive antagonism - example

• Albuterol tries to activate the β₂ receptor, while propranolol blocks it.

• Therefore, the patient’s usual albuterol treatment does not work as well.

Different targets may converge on…

• one physiologic/toxicity endpoint

• Combined effects may cross a dangerous threshold even when each isolated effect seems small.

Different Targets → Same or Opposing Output

physiologic/toxicity endpoint -examples

• respiratory depression

• bleeding

• QT/TdP

• BP/HR

• AV-nodal conduction

• serotonin toxicity

• hyperkalemia

Different Targets → Same or Opposing Output

example

1. Lisinopril + spironolactone

• Lisinopril and spironolactone work through different mechanisms.

• Both cause the kidneys to excrete less potassium.

• Different targets → same physiologic effects

2. NSAID + antihypertensive

• The antihypertensive is trying to lower BP, while the NSAID pushes BP back up by retaining sodium and water

• Different targets → opposing physiologic effects

Why PD DDIs Become Dangerous?

• Narrow therapeutic index: small margin between benefit and harm.

• Steep response near toxicity: small added effect → large increase in harm.

• Endpoint stacking: multiple drugs affect one toxicity endpoint.

• Low physiologic reserve: age, frailty, CKD, COPD, CHF, liver disease.

• Polypharmacy/comorbidity: more opportunities for convergent effects.

• Time-course mismatch: long-half-life drug + short-acting add-on → persistent toxicity.

Five-step prediction checklist -

1. Define endpoint: sedation, bleeding, QT, K⁺, BP/HR, etc.

2. Check for a shared toxicity endpoint.

3. Identify mechanism: same target, convergent physiology, or physiologic antagonism.

4. Assess risk modifiers: therapeutic index, reserve, age, comorbidities, renal function, electrolytes.

5. Mitigate: avoid/substitute, adjust dose/titrate, monitor, educate, or use reversal/removal when appropriate.

Management strategies

• Avoid high-risk endpoint stacking when alternatives exist.

• Substitute a drug with a different mechanism or lower endpoint burden.

• Minimize dose and duration; avoid simultaneous up-titrations.

• Monitor the correct variable: ECG, K⁺/creatinine, sedation/respiratory rate, or bleeding markers.

• Educate patients about specific warning signs and actions:

  • Severe drowsiness

  • Black stools or blood in urine

  • Gum bleeding/bruising

  • Palpitations

• Document intentional combinations, why both drugs are needed, and the monitoring plan