Lecture 2: ASM Interactions and Kinetics

PDAT 507

What are some reasons for frequent occurence 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 equations for C_ss-total and C_ss-free?

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 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?

Hypoalbuminemia

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

• Separate administration by 2 hours

3) Enteral feedings via NG tubes

• Ex: reduces phenytoin bioavailability

• Delay feedings 1-2 hrs before and after PHT, flush tubing, increase dose, or use alternative route

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 and how is relates to ASMs

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

• Inhibition-based interactions are:

  • Enzyme-specific and substrate dependent

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

  • The inhibitor does not need to be a substrate of the enzyme

  • 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 (prodrug) → 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

• CYP2C9

• Epoxide hydrolase

What are some PPIs have DDIs with ASMs?

Omeprazole and Lansoprazole

How is omeprazole eliminated? What does it inhibit?

Elimination: 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 of + reduce effectiveness of hormonal contraceptives? (focus only on the meds that Habibi pointed out)

C-O-P-T!

• Carbamazepine

• Oxcarbazepine

• Phenytoin

• Topiramate

How does Carbamazepine affect other drugs?

Carbamazepine is an inducer of:

• Glucuronidation

• CYP1A, 2C, 3A

What effect do other drugs have on Carbamazepine?

They can impact Carbamazepine’s:

• Metabolic pathways (CYP3A4, epoxide hydrolase)

• Some drugs inhibit 3A4/inhibit epoxide hydrolase

• Some drugs induce 3A4

Which enzyme converts carbamazepine to carbamazepine-10,11-epoxide (active metabolite)?

CYP3A4

Which enzyme converts carbamazepine-10,11-epoxide into its inactive metabolite?

Epoxide hydrolase

• Converts into carbamazepine-10,11-diol (inactive)

What drugs specifically affect Carbamazepine?

Clarithromycin → Inhibits 3A4

Valproic acid → Inhibits epoxide hydrolase

Phenytoin → Induces 3A4

How does phenytoin affect other dugs? (hint: inducer or inhibitor of what?)

Phenytoin is an inducer of:

• Glucuronidation

• CYP 1A, 2C, 3A subfamilies

What effect do other drugs have on Phenytoin? (hint: clearance of drug)

• Clearance can be decreased by inhibitors of CYP2C9 and CYP2C19

• Clearance can induced by carbamazepine

How long does it take for enzyme induction to take full effect?

1-3 weeks

Is there an interaction between phenytoin and warfarin?

Yes

• Phenytoin alters warfarin kinetics in two ways

  • 1) Initially, there is competitive inhibition between the two (competes for CYP2C9)

    • This doesn’t allow for warfarin to metabolized normally (expect INR to go up, increased risk of bleeding)

  • 2) Later, phenytoin starts inducing hepatic metabolism

If a patient is on warfarin and phenytoin gets added to the regimen, what changes need to be made?

Initially requires a reduction in warfarin (because of competition of CYP2C9 enzyme) thus reducing warfarin clearance.

After phenytoin reaches steady state, we must increase warfarin dose because of the induction of hepatic metabolism.

• Greater clearance → reduced warfarin levels → need to increase dose for therapeutic effect.

What effect does valproic acid have on other drugs? (what does it inhibit?)

Inhibits:

• CYP2C9

• Glucuronidation

• Epoxide hydrolase

What effect do other drugs have on valproic acid?

• Impacts glucuronidation, beta-oxidation, and CYP2C9/19

• Felbamate → Inhibits glucuronidation and beta-oxidation

• Carbamazepine, Phenytoin, Lamotrigine → induce glucuronidation

What effect does Lamotrigine have on other drugs? (inducer of…)

It is an (weak) inducer of glucuronidation

What effect do other drugs have on lamotrigine?

• Impacts Glucuronidation (Major), oxidation via CYP (minor pathway)

  • Valproic acid inhibits glucuronidation (major interaction)

  • Carbamazepine and phenytoin→ induce glucuronidation