Lecture 2: ASM Interactions and Kinetics

PDAT 507

What are some reasons for frequent occureence of ASM drug interactions?

• Chronic administration

• Narrow therapeutic indices

• Elimination via hepatic metabolism

• Hepatic enzyme induction/inhibition

What are the two main categories of ASM drug interactions?

• 1) Pharmacodynamic

  • a. Enhanced neurotoxicity

  • b. Lower seizure threshold

• 2) Pharmacokinetic

  • Interference with absorption

  • Reduction in plasma protein binding

  • Enhancement/inhibition of hepatic metabolism

C_ss-total refers to…?

The total steady-state plasma drug concentration

• C_ss-total = C_ss-bound + C_ss-free

C_ss-free refers to…?

Free (or unbound) steady-state plasma drug concentration

Pharmacological effect is directly related to…?

C_ss-free

_____ is the level measured during routine plasma concentration monitoring

C_ss-total

What are the clinical consequences of reduced absorption (F) of a drug?

• Change in C_ss-total? → Reduced C_ss-total

• Change in C_ss-free? → Reduced C_ss-free

• Change in pharmacologic effect? → Decreased/less pharmacologic effect

• Is clinical action required? Yes

What are the clinical consequences of inhibiting hepatic metabolism (decreased CL_intrinsic)?

• Change in C_ss-total? → Increased C_ss-total

• Change in C_ss-free? → Increased C_ss-free

• Change in pharmacologic effect? → Greater pharmacologic effect

• Is clinical action required? Yes

What are the clinical consequences of inducing hepatic metabolism? (Increased CL_intrinsic)?

• Change in C_ss-total? → Reduced C_ss-total

• Change in C_ss-free? → Reduced C_ss-free

• Change in pharmacologic effect? → Decreased/less pharmacologic effect

• Is clinical action required? Yes

What are the clinical consequences of drug displacement/decrease in plasma binding proteins?

• Change in C_ss-total? → Reduced C_ss-total

• Change in C_ss-free? → No change

• Change in pharmacologic effect? No change

• Is clinical action required? No

If a drug interaction causes a change in bioavailability (F) or hepatic metabolism (CL_intrinsic), what is the effect on C_ss-total and C_ss-free?

C_ss-total and C_ss-free change to the same extent

• Monitoring C_ss-total provides accurate reflection of change in pharmacological effect of a drug

If a drug interaction causes a change in the protein binding (f_u), what is the effect on C_ss-total and C_ss-free?

• C_ss-total changes in proportion to the change in f_u

  • Change in C_ss-total no longer reflects change in pharmacologic effect

• C_ss-free (pharmacological effect) is unchanged

Drugs such as aspirin (salicylates) displace…?

Phenytoin and valproic acid

Valproic acid acid displaces…?

Phenytoin

Phenytoin and valproic acid displace…?

Warfarin

Other than drug displacement of other drugs, what is a condition that can cause protein binding displacement?

HypoalbuminemiaW

What are three things that can affect the oral absorption of ASMs?

1) Food

• Slows rate of absorption, but no effect on bioavailability

• May be beneficials for AEDs with rapid half life

2) Antacids

• Ex: reduces phenytoin, gabapentin bioavailability

3) Enteral feedings via NG tubes

• Ex: reduces phenytoin bioavailability

How does hepatic metabolism affect ASMs? (drug interaction)

• Occurs from induction or inhibition of metabolism of a co-administered drug

  • Interactions involving hepatic metabolism affect all ASMs except a few…

Which ASMs are not affected by drug interactions related to hepatic metabolism?

Gabapentin, Levetiracetam, and Pregabalin

• They are renally eliminated

Describe hepatic enzyme inhibition as a ASM drug interaction

• There is competition at active site on enzyme between the substrate & inhibitor

• Inhibition-based Interactions are:

  • Enzyme-specific and substrate dependent

  • The extent of extent determined by Ki (affinity constant) & C_inhibitor

  • Generally, the inhibited pathway must contribute to >50% of the drug’s overall elimination

What are the clinical consequences of Hepatic Enzyme Inhibition?

• Decreased CL intrinsic (decreased metabolism)

• Increased elimination t1/2

• Increased C_ss-total and C_ss-free

• Increased pharmacological effect (if there is no active metabolite, aka not a prodrug)

  • If the drug is an active metabolite → decreased pharmacological effect

What are the clinical consequences of Hepatic Enzyme Induction?

• Increased CL_intrinsic (increasing metabolism)

• Decreased elimination t ½

• Increased C_ss-total and C_ss-free

• Decreased pharmacological effect (if not an active metabolite)

  • If it is an active metabolite → Increased pharmacological effect

                                                                                                                                                                                                                                                  What are the metabolic pathways involving Carbamazepine?

• CYP3A4: ~85%

• CYP1A2/2C: minor

What are the metabolic pathways involving Phenytoin?

• CYP2C9: major pathway

• CYP2C19: minor

What are the metabolic pathways involving Valproic acid?

• Glucuronidation: 30-50%

• Beta-oxidation: 30-40%

• CYP2C9/2C19: 10-20%

Which ASMs are hepatic enzyme inducers? & which enzymes?

• Carbamazepine & Phenytoin → Inducers of:

  • CYP1A, 2C, and 3A

  • Glucuronidation

Which ASMs are hepatic enzyme inhibitors? & which enzymes?

Valproic acid inhibits:

• Gluronidation

• CYP2C19

• Epoxide hydrolase

What are some PPIs have DDIs with ASMs?

Omeprazole and Lansoprazole

How is omeprazole eliminated? What does it inhibit?

• Eliminated: hepatic metabolism via CYP2C19 and CYP3A4

• Omeprazole inhibits CYP3A4 and 2C19

How is lansoprazole eliminated? What does it inhibit?

• Eliminated: hepatic metabolism via CYP2C19

  • Lansoprazole is a weak inhibitor of CYP1A2

Which ASMs induce metabolism and reduce effectiveness of hormonal contraceptives? (focus only on the meds that Habibi pointed out)

• Carbamazepine

• Oxcarbazepine

• Phenytoin

• Topiramate

What effect does Carbamazepine have on other drugs?

It is an inducer of:

• Glucuronidation

• CYP1A, 2C, 3A