ASM Drug Interaction Kinetics (L2)

_________ slows the rate of absorption, but has no effect on bioavailability and may be beneficial for ASMs with rapid t1/2

food (able to decreases SEs without having to decrease dose)

____________ (medication class) reduce PHT bioavailability by 20-30% and should therefore be separated by 2 hours

antacids

antacids reduce ___________ (ASM) bioavailability by 20-30% and should therefore be separated by 2 hours

PHT (Phenytoin)

enteral feedings via NG tube reduce __________ (ASM) bioavailability and should therefore be delayed 1-2 hours before and after ___________ dose

PHT (Phenytoin)

__________ reduce PHT bioavailability and should therefore be delayed 1-2 hours before and after PHT dose

enteral feedings (via NG tube)

interactions involving hepatic metabolism observed with all ASMs, except those eliminated renally like ___________

LEV (Levetiracetam)

onset of hepatic enzyme inhibition: initial effect within ________

24 hours (immediate)

onset of hepatic enzyme induction: meaningful effect within ________

1-3 weeks (longer)

clinical consequences of hepatic enzyme inhibition

_________ CL intrinsic (metabolism)

decreased (less drug getting metabolized and peed out= t1/2 will increase= drug will work longer)

clinical consequences of hepatic enzyme induction

_________ CL intrinsic (metabolism)

increased (more drug getting metabolized and peed out= t1/2 will decrease= drug will not work as long)

clinical consequences of hepatic enzyme inhibition

__________ elimination half-time (t1/2)

increased (less drug getting metabolized and peed out= t1/2 will increase= drug will work longer)

clinical consequences of hepatic enzyme induction

__________ elimination half-time (t1/2)

decreased (more drug getting metabolized and peed out= t1/2 will decrease= drug will not work as long)

clinical consequences of hepatic enzyme inhibition

_________ Css-total and Css-free, and therefore a _________ pharmacological effect (unless its a prodrug)

increased

clinical consequences of hepatic enzyme induction

_________ Css-total and Css-free, and therefore a _________ pharmacological effect (unless its a prodrug)

decreased

clinical consequences of hepatic enzyme inhibition

increased Css-total and Css-free

if it is a prodrug this means a __________ pharmacological effect

decreased (less drug being metabolized into its active metabolite form)

clinical consequences of hepatic enzyme induction

decreased Css-total and Css-free

if it is a prodrug this means a __________ pharmacological effect

increased (more metabolism= more working/active drug is made)

CBZ is 85% metabolized by CYP____ and CYP1A2/2C (minor)

3A4

__________ is 85% metabolized by CYP3A4 and CYP1A2/2C (minor)

CBZ (Carbamazepine)

PHT major metabolism pathway is CYP____ and CYP2C19 (minor)

2C9

________ major metabolism pathway is CYP2C9 and CYP2C19 (minor)

PHT (Phenytoin)

VPA 30-50% metabolized via ____________, 30-40% by beta-oxidation, 10-20% by CYP2C9/2C9

glucuronidation

_____ 30-50% metabolized via glucuronidation, 30-40% by beta-oxidation, 10-20% by CYP2C9/2C9

VPA (Valproic Acid)

Erythromycin is eliminated by hepatic metabolism via CYP3A4 and it inhibits CYP3A4 and 1A2

consequences of co-administration with CBZ= _________ [CBZ]

increased (inhibited CYP3A4= decreased hepatic metabolism of CBZ= less CBZ peed out)

Erythromycin is eliminated by hepatic metabolism via CYP3A4 and it inhibits CYP3A4 and 1A2

consequences of co-administration with PHT= _________ [PHT]

no change (since CYP3A4 does not effect PHT)

Erythromycin is eliminated by hepatic metabolism via CYP3A4 and it inhibits CYP3A4 and 1A2

consequences of co-administration with VPA= _________ [VPA]

no change (since CYP3A4 does not effect VPA)

Omeprazole is eliminated by hepatic metabolism via CYP2C19 and CYP3A4 and it inhibits CYP2C19 and 3A4

consequences of co-administration with CBZ= _________ [CBZ]

increased (inhibited CYP3A4= decreased hepatic metabolism of CBZ= less CBZ peed out)

Lansoprazole is eliminated by hepatic metabolism via CYP2C19 and it inhibits CYP1A2 (weak)

consequences of co-administration with CBZ= _________ [CBZ]

no change

the 4 ASMs that increase metabolism and therefore decrease effect of OCPs are

CBZ, PHT, OXC, TPM

Css-________ is the total steady-state plasma drug concentration

total (not the same as pharmacological effect)

Css-_______ is the unbound steady-state plasma drug concentration

free (same as pharmacologic effect)

f_u is the fraction unbound, fraction of drug in plasma not bound to plasma proteins (ratio of Css-____:Css-_____ drug concentration)

free:total

this is the equation for Css-________ (which includes f_u in the denominator)

total (therefore f_u does not affect the pharmacological effect)

this is the equation for Css-_______ (which does not include f_u in the denominator)

free (this is the same as the pharmacological effect)

should we decrease this patients dose

NO

(the Css-free did not change and therefore the pharmacological effect did not change)

(only the f_u changed, meaning the Css-total changed, which has no effect on pharmacologic effect)

pharmacologic effect is directly related to changes in Css-_______, which (looking at the equation) is NOT affected by ______

free, fu

an interaction causing a change in bioavailability (F) or hepatic metabolism (CLintrinsic)

the change in Css-total is _________ (same or different) as Css-free (pharmacologic effect)

same (i.e. monitoring Css-total does provide an accurate reflection of change in pharmacological effect)

an interaction which alters protein binding (f_u)

the Css-_________ is unchanged

free (therefore the pharmacological effect is unchanged)

an interaction which alters protein binding (f_u)

the Css-free is __________ (changed or unchanged)

unchanged

an interaction which alters protein binding (f_u)

the Css-total is __________ (changed or unchanged)

changed (Css-total changes proportional to change in f_u)

an interaction which alters protein binding (f_u)

the Css-_______ changes proportional to changes in f_u

total

an interaction which alters protein binding (f_u)

the change in Css-total is _________ (same or different) as Css-free (pharmacologic effect)

different (monitoring Css-total does NOT provide an accurate reflection of changes in pharmacologic effect)

if F (absorption) is decreased

change in Css-total: _____

change in Css-free: _____

change in pharmacologic effect: ________

clinical action required: __________ the dose

decreased, decreased, decreased, increase

(Css-total and Css-free change the same= Css-total does accurately reflect pharmacologic effect)

if F (absorption) is increased

change in Css-total: _____

change in Css-free: _____

change in pharmacologic effect: ________

clinical action required: __________ the dose

increased, increased, increased, decrease

(Css-total and Css-free change the same= Css-total does accurately reflect pharmacologic effect)

if CL intrinsic (hepatic metabolism) is inhibited (less being metabolized= less being peed out)

change in Css-total: _____

change in Css-free: _____

change in pharmacologic effect: ________

clinical action required: __________ the dose

increased, increased, increased, decrease

(Css-total and Css-free change the same= Css-total does accurately reflect pharmacologic effect)

if CL intrinsic (hepatic metabolism) is induced (more being metabolized= more being peed out)

change in Css-total: _____

change in Css-free: _____

change in pharmacologic effect: ________

clinical action required: __________ the dose

decreased, decreased, decreased, increase

(Css-total and Css-free change the same= Css-total does accurately reflect pharmacologic effect)

if displacement occurs/ there is a decrease in plasma proteins (increased f_u)

change in Css-total: _____

change in Css-free: _____

change in pharmacologic effect: ________

clinical action required: __________ the dose

decrease, unchanged, unchanged, do NOT change

(since Css-free is not effected by changes in f_u, then pharmacologic effect does not change)

displacement of ASMs from their binding site causes a ___________ in pharmacologic effect

no change (since f_u does not effect Css-free= does not effect pharmacologic effect) (f_u only effects Css-total)

displacement of ASMs from their binding site causes a ___________ in Css-free

no change (f_u only effects Css-total)

displacement of ASMs from their binding site causes a ___________ in Css-total

decrease (due to an increased f_u)

displacement of ASMs from their binding site causes a ___________ in f_u

increase (less bound to their site= more unbound) (increased f_u= decreased Css-total)

ASMs that are highly protein bound (>90%) are ______ and _______

PHT, VPA (Phenytoin and Valproic Acid)

ASMs that are highly protein bound (>90%) are PHT and VPA

drugs such as ___________ (class) can displace PHT and VPA

salicylates (ASA, Aspirin)

ASMs that are highly protein bound (>90%) are PHT and VPA

_____ (ASM) can displace PHT

VPA

ASMs that are highly protein bound (>90%) are PHT and VPA

VPA can displace ______ (ASM)

PHT

ASMs that are highly protein bound (>90%) are PHT and VPA

PHT and VPA can displace __________

warfarin

hypoalbuminemia can happen d/t malnutrition, renal failure, or pregnancy

we should adjust the observed Css-total _________ (ASM) for patients with low albumin or renal disease

PHT (Phenytoin)

CBZ effects onto other drugs: it is an inducer of ____________ and CYP______

glucuronidation, 3A4

________ effects onto other drugs: it is an inducer of glucuronidation and CYP3A4

CBZ

effects of other drugs on CBZ: drugs like __________ inhibit CYP3A4

clarithromycin, erythromycin

effects of other drugs on CBZ: ______ (ASM) inhibits epoxide hydrolase

VPA (prevents breakdown of active CBZ-10,11-epoxide into the inactive CBZ-10,11-diol= more active CBZ-10,11-epoxide is around= increase [active CBZ])

effects of other drugs on CBZ: drugs like Clarithromycin and Erythromycin inhibit ________

CYP3A4

effects of other drugs on CBZ: VPA inhibits _______ ________

epoxide hydrolase (prevents breakdown of active CBZ-10,11-epoxide into the inactive CBZ-10,11-diol= more active CBZ-10,11-epoxide is around= increase [active CBZ])

effects of other drugs on CBZ: ________ (ASM) induces CYP3A4

PHT (Phenytoin)

effects of other drugs on CBZ: drugs like Clarithromycin and Erythromycin ______ CYP3A4

inhibit

effects of other drugs on _____: drugs like Clarithromycin and Erythromycin inhibit CYP3A4

CBZ

effects of other drugs on CBZ: VPA _________ epoxide hydrolase

inhibits (prevents breakdown of active CBZ-10,11-epoxide into the inactive CBZ-10,11-diol= more active CBZ-10,11-epoxide is around= increase [active CBZ])

effects of other drugs on ______: VPA inhibits epoxide hydrolase and prevents breakdown of the active _____-10,11-epoxide into the inactive form

CBZ

effects of other drugs on CBZ: PHT _______ CYP3A4

induces

effects of other drugs on CBZ: PHT induces ________

CYP3A4

effects of other drugs on _______: PHT induces CYP3A4

CBZ

effects of other drugs on CBZ: VPA induces epoxide hydrolase, which _________ breakdown of active CBZ-10,11-epoxide into the inactive CBZ-10,11-diol

prevents (decreases)

PHT displays ________ kinetics

non-linear

PHT effect on other drugs: it is an inducer of __________ and CYP_____

glucuronidation, 3A4

PHT effect on other drugs: it is an _______ of glucuronidation and CYP3A4

inducer

______ effect on other drugs: it is an inducer of glucuronidation and CYP3A4

PHT

PHT time-dependent effect on other drugs (ex: _________): initial competitive inhibition, then enzyme induction next 1-3 weeks

warfarin

PHT time-dependent effect on other drugs (ex: Warfarin): initial __________, then enzyme _________ next 1-3 weeks

inhibition, induction

PHT alters Warfarin kinetics by:

initial competitive inhibition (CYP_____)

induction of _________ __________

2C9, hepatic metabolism

PHT alters Warfarin kinetics by:

initial competitive inhibition via CYP2C9 (less metabolism= less being peed out), then induction of hepatic metabolism (more metabolism= more being peed out)

after adding PHT, Warfarin initially __________ the efficacy and then __________ its efficacy

increase, decrease

PHT alters Warfarin kinetics by:

initial competitive inhibition via CYP2C9 (less metabolism= less being peed out), then induction of hepatic metabolism (more metabolism= more being peed out)

after adding PHT, Warfarin initially requires a ___________ in dose and then a __________ in dose

decrease, increase

VPA effect on other drugs: inhibits CYP_______, ___________, and ________ _________

2C9, glucuronidation, and epoxide hydrolase

VPA effect on other drugs: _______ CYP2C9, glucuronidation, and epoxide hydrolase

inhibits

_______ effect on other drugs: inhibits CYP2C9, glucuronidation, and epoxide hydrolase

VPA

effects of other drugs onto VPA: induction from _______, ________ (ASMs via multiple pathways), and _________ (ASM via weak glucuronidation only)

CBZ, PHT, LMT

effects of other drugs onto ____: induction from CBZ, PHT (via multiple pathways), and LTG (via weak glucuronidation only)

VPA

effects of other drugs onto VPA: ________ from CBZ, PHT (via multiple pathways), and LTG (via weak glucuronidation only)

induction

effect of LTG on other drugs: induction of __________ (weak)

glucuronidation

effect of LTG on other drugs: ________ of glucuronidation (weak)

induction

effect of other drugs onto LTG: inhibition from _______ (ASM) via glucuronidation

VPA

effect of other drugs onto LTG: ______ from VPA via glucuronidation

inhibition

effect of other drugs onto LTG: induction from _______ and ________

CBZ and PHT

patient is 33 y/o female with refractory epilepsy

currently on CBZ XR 400mg BID and VPA ER 750mg BID

during the clinic visit she says she is very sedated and reports double vision and problems with balance (ataxia)

what could be causing her symptoms?

VPA inhibiting epoxide hydrolase= increasing [active CBZ] (d/t prevention of active CBZ-10,11-epoxide breakdown into the inactive CBZ-10,11-diol)