SEIZURES AND EPILEPSY 2

Question 1

DISTRIBUTION
 Volume of distribution (Vd)

Answer 1

Vd is the “apparent” volume in which the drug
distributes
 It reflects the extent of drug distribution in the body
Clinical relevance: it is helpful in determining the
loading dose (LD)

loading dose = desired css x Vd
part loading dose = [(desired Css - current Css) x Vd] / FS

So if I give it another drug that interacts with the other agent, that kicks out the, the highly protein bound drug from the protein binding. So the free fraction of that drug will increase, right? So what will happen? This free drug will distribute the other tissues to the volume distribution will increase. And also we’ll go to the elimination organs, liver and kidney. And if the clearance will increase

And also in the free fraction increases. The pharmacologically active agent. So efficacy will increase and side effects would also increase. So this is like a major interaction. But because clearance and VD actually increase at the same time, sometimes that interaction becomes insignificant later on

Usually they counteract each other and half-life will stay the same.

The protein binding displacement levels in the immediate period post to starting the medications. You see that also with warfarin. But later on, everything will stabilize and things will go back to semi normal or could be normal. But the patient need to be monitored at the area at the time line where these drugs are started.

Three to five half-lives to reach a steady-state, three to five half-lives to get kicked out.

If pt still seizing, dmeasure a level of concentration and Do what we call a part loading dose

Question 2

DISTRIBUTION
 Volume of distribution (Vd)
 Phenytoin partial loading dose:

Answer 2

Phenytoin’s Vd = 0.7 L/kg
Phenytoin reference range 40-80 umol/L (in
metric units it is 10-20 mg/L)
 F ≈ 1
S ≈ 1

d I might ask you questions about a TDM during the in the exam. So remember just two numbers, 0.7 liters per kilogram. And the reference range is 40 to 80.

Question 3

DISTRIBUTION
 Protein Binding

Answer 3

Drugs can bind to plasma albumin, alpha acid
glycoprotein or lipoproteins
The higher the extent of protein binding the smaller
the volume of distribution i.e. restricted to plasma
 Factor affecting protein binding can alter the
percentage of free fraction and so can alter
efficacy, clearance and volume of distribution

Question 4

DISTRIBUTION
 Drug Levels
 Reference range:

Answer 4

 It is the range of drug concentrations below which the drug
is most probably ineffective and above of which is most
probably toxic
 Important – It is not carved in stone
 Reference ranges mainly based on retrospective studies
and expert opinions
 Can be used as a tool rather than an ultimate target -Treat
the patient not the level
 Reported in total drug concentration (bound and unbound)
 Concentration-dependent adverse reactions

Question 5

DISTRIBUTION
 Drug levels
 Routine levels are not recommended
 Drug levels can be beneficial in situations such as:

Answer 5

 Change in seizure frequency
 Suspected dose related adverse reactions/toxicity
 Administration of multiple interacting drugs
 Checking adherenece
 Formulation/route change
 Conditions of altered pharmacokinetics e.g. elderly,
pregnancy
 Determination of individual therapeutic range
 Measure steady state
 Pre-steady state levels can be beneficial in some situations
to determine the adequacy of the dosage e.g phenytoin

Question 6

DISTRIBUTION
 Free drug level
 Phenytoin:

Answer 6

 Highly bound (~90%) to plasma proteins mainly albumin
 Target free level 4-8 umol/L (10 % free)
 Factor altering protein binding can alter phenytoin free
fraction and hence efficacy and toxicity.
 Corrected phenytoin concentration can be calculated
based on patient’s serum albumin (g/L)

Question 7

DISTRIBUTION
 Saturable protein binding
Valproic acid:

Answer 7

Concentration-dependent protein binding
At low concentration, the unbound fraction is 7-
10%
At higher concentrations, the unbound fraction is
15-20%
 Less than proportional increase in drug level

Question 8

DISTRIBUTION
 Drug interactions

Answer 8

Displacement from protein binding
Phenytoin

Question 9

METABOLISM AND EXCRETION
clearance

Answer 9

 Clearance (Cl)
 It is the volume of the blood cleared from the drug
per unit time
Determinants of clearance:
Drug dependent
Drug metabolizing enzymes e.g. Cytochrome
P450s
Renal function - Creatinine clearance
 Liver function - Child Pugh Score
Clinical relevalnce: determines drug half life, drug
interactions, dose adjustment in organ impairment

Question 10

METABOLISM AND EXCRETION
 Half life (t1/2)

Answer 10

Clearance and volume of distribution
determine drug’s half life:
↑Cl ↔ Vd ↓t1/2
↔ Cl ↑Vd ↑t1/2
↑Cl ↑Vd ↔ t1/2
Clinical relevance: determines the time to
reach steady state, drug accumulation, rate
of decline of drug concentration if the drug
is stopped

Question 11

METABOLISM AND EXCRETION
 Saturable metabolism

Answer 11

Phenytoin:
Phenytoin metabolism is saturable and follows
Michaelis-Menten kinetics (nonlinear
pharmacokinetics)
Proportional increase in phenytoin dose is not
accompanied by a proportional increase in drug
concentration as in most drugs that follow linear
kinetic profile.
Due to saturable kinetics, dose adjustments
should not exceed 50-100 mg/d

Question 12

METABOLISM AND EXCRETION
 Auto-induction of metabolism

Answer 12

Carbamazepine:
 It induces its own metabolism
Half-life at initiation of therapy ranges between
25-65 h and with chronic dosing is 12-17 h
The more you increase the dose, the half-life will get shorter and shorter and shorter and shorter

Question 13

SATURABLE PHARMACOKINETICS

Answer 13

slide 59

Question 14

METABOLISM AD EXCRETION
 Active Metabolites

Answer 14

Primidone:
 Primidone partly metabolized to Phenobarbital (1-8%)
 Phenobarbital have longer half life (2-6 days) than
primidone (3-22h)
 On chronic dosing, phenobarbital:primidone ratio >1
 Oxcarbazepine:
 It is metabolized to the equipotent monohydroxymetabolite
(MHD)
 MHD is found in concentrations much higher than the
parent drug

Question 15

METABOLISM AD EXCRETION

drug interactions

Answer 15

Phenytoin, phenobarbital, primidone,
carbamazepine and topiramate are liver
microsomal enzyme inducers
Valproic acid is a liver microsomal enzyme inhibitor
Always consult a drug interaction reference when
above drugs are initiated or a new drug added to
existing regimens containing above drugs

Question 16

ADVERSE DRUG REACTIONS

Answer 16

 Acute
 Concentration-dependent: do a level
 Could be resolved with dose reduction

 Idiosyncratic
 Ranges from mild to life-threatening
- must stop the drug

 Chronic

Question 17

CONCENTRATION-DEPENDENT ADVERSE
REACTIONS/ TOXICITY

When you take too much of these agents, what will happen to the CNS? Depression

Answer 17

Phenytoin Nystagmus (nystagmus is actually the, the eyeball will actually keep shaking), dizziness, slurred speech, blurred
vision, ataxia, decreased mental status,
confusion, coma
Valproic acid GI upset, tremors, thrombocytopenia, CNS
depression, increased LFT and serum ammonia
Carbamazepine Nausea, vomiting, decreased WBC, lethargy
dizziness, drowsiness, blurred vision, diplopia
Phenobarbital Sedation, ataxia, cognitive impairment,
respiratory depression, coma
Lacosamide PR-interval prolongation

Question 18

DIOSYNCRATIC ADVERSE REACTION

Answer 18

Carbamazepine
* blood dyscrasias, (Carbamazepine: because of the blood dyscrasias you see like sometimes the bone marrow depression. So you need to monitor CBC at least every six months and then every year and so on)
*rash: Increased SJS, high risk Asian population, recommend screening before tx

Lamotrigine
* rash
Levetiracetam
* Behavioural
adversereactions
* psychosis
Phenytoin
* rash, blood
dyscrasias
Valproic acid
* acute hepatic
failure, pancreatitis
Valproic: mild elevation of transaminases like ASH or other liver chemistry tests, ALT and AST. Ast and ALT. Bilirubin. Mild elevation is not an indication for stopping

Question 19

CHRONIC ADVERSE REACTIONS

Answer 19

Gabapentin
* weight gain

Pregabalin
* weight gain

Topiramate
* weight loss
* Cognitive SE

Valproic acid
* hyperammone mia, weight gain

Carbamazepine
* hyponatremia

Oxcarbazepine
* hyponatremia u(more than CBZ)

Phenobarbital
* osteomalacia, mood change

Vigabatrin
* permanent vision loss

Phenytoin
* gingival hyperplasia, hirsutism, acne, coarsening of facial feature, cognitive mpairment

Question 20

OSTEOMALACIA

Answer 20

 ASMs might increase the risk of bone loss and vitamin D
turnover
 Older agents more implicated
 Phenytoin, carbamazepine, phenobarbital, valproic acid
 Newer agent unknown or no effect
 Risk factors
 Higher doses
 Longer duration
 Exposure to multiple ASMs
 Enzyme-inducing ASMs (?) but what about valproic acid?
 Prevention
 Regular bone density monitoring
 Calcium and vitamin D supplementation

Question 21

ASM HYPERSENSITIVITY SYNDROME

Answer 21

 Drug Rash with Eosinophilia and Systemic Symptoms
(DRESS)
 Presentation: fever, rash, lymphadenopathy, eosinophilia
and hepatosplenomegaly
 Incidence: 1/1000 – 1/10 000
 Implicated ASMs: Phenytoin, carbamazepine, primidone and
phenobarbital
 DRESS attributed to arene oxide reactive metabolites
 Cross-reactivity: ~75%

It looks like it’s related to the one of the metabolites of those aromatic anti-seizure meds.
Look at the cross sensitivity is huge.
o it’s absolute contraindication
STOP DRUG RIGHT AWAY

 Most reactions occur within 2 month of initiation of therapy
 Re-initiation of culprit ASM could induce the reaction
immediately (less than 24h)
 Management:
 Immediate ASM withdrawal
 Supportive therapy
 Alternative ASMs: valproic acid, levetiracetam

Question 22

SUICIDAL BEHAVIOR

Answer 22

 A warning on suicidal behavior and ideation accompanies all
ASMs.
 Patients on an ASM had double the risk of suicidal thinking or
behavior compared to placebo.
 Based on pooled analyses of almost 200 RCTs of 11 ASMs
(incidence < 0.5% of patients on ASMs compared to 0.24% of
patients on placebo).
“While some believed that this risk is nonsignificant, responsible
providers must carefully assess this risk when evaluating their
patients for ASM therapy, especially as depression and anxiety
are common comorbid conditions in epilepsy. Patients and
caregivers should be informed that ASMs increase the risk of
suicidal thoughts and should be advised to be on the alert for
any unusual changes in mood or behavior.”