DDI Pt 1

what is a drug-drug interaction?

An alternation in one drug’s effect due to the presence of another drug, potentially leading to preventable adverse outcomes

What is a pharmacodynamic DDI?

One drug modifies the effect of another at the site of action (receptor/effector pathway) or at the physiologic system level. Drug concentrations may remain uncharged

what is a pharmacokinetic DDI?

An interaction in which one drug changes the concentration (exposure) of another drug, altering its effects

what phrase distinguishes PD DDIs from PK DDIs?

• PD DDI: “same levels, different effect”

• PK DDI: “different levels, different effect”

what does pharmacokinetics describe?

what the body does to the drug

what does pharmacodynamics describe?

what the drug does to the body

Where can PD DDIs occur?

1. same receptor/target

2. same signaling pathway/effector

3. same organ system output(BP, respiration, platelet formation)

what is an additive DDI?

the combined effect equals the sum of the individual effects

give an example of an additive DDI

NSAID + acetaminophen

What is a synergistic DDI?

The combined effect is greater than expected from the sum of individual effects

give an example of a synergistic DDI

alcohol + benzodiazepine

what is potentiation?

a drug with little or no effect alone increases the effect of another drug

give an example of potentiation

carbidopa + levodopa

what is antagonism?

one drug reduces the effect of another drug

give an example of antagonism

benzodiazepine + flumazenil

what is competitive antagonism?

an antagonist competes for the same receptor binding site as the agonist and decreases apparent agonist affinity

what happens to the dose-response curve with competitive antagonism?

• ↑ EC50 (right shift)

• Emax unchanged

• Can be overcome by increasing agonist dose.

what is noncompetitive antagonism?

an antagonist reduces agonist effect such that increasing agonist concentration cannot restore the full response

what mechanisms produce noncompetitive antagonism?

• irreversible orthosteric binding

• negative allosteric modulation

what happens to Emax during noncompetitive antagonism?

Emax decreases

what is partial agonist antagonism?

a lower-efficacy ligand competes with a full agonist and decreases the overall response at a given agonist concentration

what is convergent physiology?

two drugs act on different targets but produce effects on the same physiologic output or toxicity endpoint

what is physiologic antagonism?

two drugs act through different pathways and produce opposing physiologic effects on the same variable

why are shared toxicity endpoints important?

multiple drugs affecting the same endpoint can produce severe toxicity even if they act through different mechanisms

what high-risk DDI occurs with alcohol and benzodiazepines

synergistic CNS and respiratory depression

what happens when propranolol is given with albuterol?

propranolol competitively blocks β₂ receptors, reducing albuterol's bronchodilator effect. More albuterol may be required to achieve the same response.

why is propranolol + albuterol considered a PD DDI?

it is a same-target receptor-level interaction involving competitive antagonism at β₂ receptors.

what is the risk of lisinopril + sprinolactone?

hyperkalemia due to reduced renal potassium excretion by both drugs

why is CKD a major risk factor when ACE inhibitors and sprinolactone are combined?

reduced physiologic reserve increases risk of severe hyperkalemia and cardiac conduction abnormalities

how can NSAIDs interact with hypertensives?

NSAID-induced sodium retention can oppose antihypertensive efficacy

what is step 1 of the PD DDI prediction checklist?

define the toxicity endpoint

What is Step 2 of the prediction checklist?

determine whether the drugs share a toxicity endpoint

What is Step 3 of the prediction checklist?

Identify the mechanism:

• Same target

• Convergent physiology

• Physiologic antagonism

What is Step 4 of the prediction checklist?

Assess risk modifiers:

• Therapeutic index

• Physiologic reserve

• Comorbidities

• Age

• Electrolytes

What is Step 5 of the prediction checklist?

Decide on mitigation:

• Avoid

• Substitute

• Adjust dose

• Monitor

• Educate patient

What factors make PD DDIs more dangerous?

• Narrow therapeutic index

• Low physiologic reserve

• Endpoint stacking

• Time-course mismatch

• Polypharmacy/comorbidities

What are the core management strategies for PD DDIs?

• Avoid high-risk combinations

• Substitute safer alternatives

• Minimize dose and duration

• Monitor appropriate endpoints

• Educate patients

• Document monitoring plan

What should be monitored for lisinopril + spironolactone?

Potassium (K⁺) and serum creatinine.

What should be monitored in patients at risk of QT-related DDIs?

ECGs and QT interval.

What should be monitored in CNS depressant combinations?

Sedation level and respiratory rate.

What are the major red-flag PD DDI syndromes?

• Respiratory depression

• Bleeding

• QT prolongation/Torsades de Pointes

• Serotonin toxicity

• Hyperkalemia

• Bradycardia/Hypotension

Why is respiratory depression a dangerous endpoint?

It can cross a threshold into apnea and respiratory failure

Why is QT prolongation a dangerous endpoint?

: It increases the risk of Torsades de Pointes, a potentially fatal arrhythmia

What ECG changes suggest severe hyperkalemia?

• Tall peaked T waves

• PR prolongation

• Widened QRS complexes

What is the key exam takeaway for PD DDIs?

The most dangerous PD DDIs involve endpoint stacking, where multiple drugs affect the same toxicity endpoint

PD DDI = change in ______, not necessarily change in ______.

Effect; drug concentration

Competitive antagonism causes what two classic changes?

↑ EC50 and rightward shift of the dose-response curve. Emax is unchanged

Noncompetitive antagonism causes what classic change?

↓ Emax.

What is the easiest way to predict a serious PD DDI?

Identify whether both drugs affect the same toxicity endpoint

What four words summarize prevention of PD DDIs?

Define → Classify → Assess → Mitigate.