Lecture 24

Question 1

PK

Answer 1

ADME, alters drug concentrations in the blood

Question 2

PD

Answer 2

Toxicity and effectiveness, alters drug effect at a given drug concentration

Question 3

Drug interaction

Answer 3

• When the administration of a drug alters the pharmacological activity of 1+ other drugs
• Can increase or decrease activity or toxicity

Question 4

Multiple Drugs

Answer 4

• Necessary for many or concurrent disease states
• Multifocal disease states like cardiac failure (vasodilation, diuretic, cardiac glycosides)
• Combo therapy for additive or synergistic effects (Chemotherapy for complex infections or cancer)

Question 5

Types of Drug Interactions (4)

Answer 5

1. Additive
2. Synergistic
3. Indifferent
4. Antagonistic

Question 6

PD Mechanisms

Answer 6

• Can be based in receptors of physiology
• Two drugs acting on different sites on a receptor OR two drugs targeting linked targets within a single pathway may be synergistic (EX: Bactrim)
• One drug can cause desensitization and decrease the action of the second drug

Question 7

Combined Toxicity

Answer 7

-Organ based - concurrent administration of two nephotoxic drugs can cause kidney damage, even though the dose of either alone may have been insufficient to produce toxicity

Question 8

Different Mechanisms Colliding

Answer 8

• Warfarin has decreased TI with potential for bleeding complications
• NSAIDs can cause GI ulcers and co-administration with Warfarin increases the risk of GI bleeding 4x than Warfarin alone
• Antibiotics alter intestinal flora and decrease the bacterial synthesis of vitamin K and therefore increase the effect of warfarin

Question 9

Low TI

Answer 9

• Increased risk of drug interaction
• For Low TI drugs, small variations in clinical plasma concentrations of a drug (or its metabolites) may result in serious clinical manifestations of adverse effects
• Other risks: Age, renal/hepatic disease, chronic drug therapy, polypharmacy

Question 10

What is layered in with drug interactions?

Answer 10

Factors of individual variation

Question 11

Are most drug interactions PK or PD based?

Answer 11

PK

Question 12

Absoprtion + Drug Interactions

Answer 12

• Binding or chelate
• Altering gastric pH
• Altering GI motility
• Affect transport proteins such as P-glycoprotein and organic anion transporters
• Effects on extent of absorption are more clinically relevant than the rate of absorption itself (greater impact on serum drug levels)

Question 13

Examples of Altered Absorption (3)

Answer 13

1. Iron and calcium - bind to drugs and decrease absorption (like tetracycline)
2. Antacids - bind drugs and/or increase gastric emptying
3. PPIs and H2RAs - increase gastric pH (may alter distribution and absorption of drugs)

Question 14

Transporters

Answer 14

-Saturated or inhibited
-Include uptake and efflux transporters
EX: Probenecid (gout) - inhibits organic acid transport proteins (OATP), prevents excretion of penicillin and other drugs using transporters, increase AUC

Question 15

Distribution/Transport

Answer 15

• Mechanism that alters drug distribution from drug interactions
• Saturated or inhibited
• Competition for plasma protein binding
• Displacement from tissue binding sites
• Alterations in local tissue barriers (ex: P-glycoprotein inhibition in BBB)

Question 16

Membrane Transporters

Answer 16

• Play multiple roles in PK pathways
• Absorption, distribution, metabolism, and excretion
• Sets systemic drug levels

Question 17

Excretion

Answer 17

• Competition for anion carrier sites (ex: probenecid decreases excretion of penicillin/methotrexate)
• Competition for cation carriers (ex: cimetidine decreasing the excretion of procainamide)
• Altering sodium transport, indirectly altering reabsorption of charged drugs (Ex: Li+ lowering the clearance by diuretics from causing decreased volume, OR NSAIDs increasing proximal tubular sodium reabsorption)
• Change in urine pH

Question 18

Metabolism

Answer 18

• Competition and induction
• Competition - two drugs compete for metabolism by same enzyme
• Induction: 1 drug induces the synthesis of enzyme that metabolizes itself or another co-administered drug

Question 19

Drug Interaction Summary

Answer 19

• Drug interactions can occur based on PK and/or PD
• Multiple mechanisms can cause drug interactions between two drugs.
• Drug interactions more common with low TI drugs