NTA Level 5 • Semester 1 • PST05104

Pharmacodynamics of Anticonvulsants

Pharmacology and Therapeutics • Source Session/Topic 28

Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability.

Session 28: Pharmacodynamics of Anticonvulsants

Total Session Time: 120 minutes

Prerequisites

None

Learning Tasks

By the end of this session students are expected to be able to:

Describe mechanism of action of Anticonvulsants

Describe drug interactions associated with Anticonvulsants

Describe side effects of Anticonvulsants

Describe contraindications of Anticonvulsants

Resources Needed:

Flip charts, marker pens, and masking tape

Black/white board and chalk/whiteboard markers

Computer and projector

SESSION OVERVIEW

Step

Time

Activity/

Content

Step

Time

Activity/

Content

Step

Time

Content

Step

Time

Method

Content

Method

05 minutes

Presentation

Introduction, Learning Tasks

45 minutes

Presentation/

Mechanism of Action of Anticonvulsants

45 minutes

Buzzing

Mechanism of Action of Anticonvulsants

Buzzing

20 minutes

Presentation/

Drug Interactions Associated With

20 minutes

brainstorming

Anticonvulsants

brainstorming

Anticonvulsants

20 minutes

Presentation

Adverse Effects of Anticonvulsants

20 minutes

Presentation/

Contraindications of Anticonvulsants

20 minutes

Brainstorming

Contraindications of Anticonvulsants

Brainstorming

05 minutes

Presentation

Key Points

05 minutes

Presentation

Evaluation

PST 05104 Pharmacology & Therapeutics

218

NTA Level 5 Semester 1 Facilitator Guide

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing.

STEP 2: Mechanism of Action of Anticonvulsants Drugs (45 minutes)

Activity: Buzzing (5 minutes)

ASK students to pair up and buzz on the following question for 2 minutes

How do drugs acting on the CNS produce their pharmacological effects?

ALLOW few pairs to respond and let other pairs add on points not mentioned

WRITE their response on the flip chart/board

CLARIFY and SUMMARIZE by using the content below Anticonvulsants

Sodium channel blockers (Phenytoin, Carbamazepine,)

o Carbamazepine stabilizes the inactive form of the Na+ channel, which slows the rate of channel recovery from the inactivated state. This increases the threshold for action potentials and prevents repetitive firing.

o Carbamazepine and other Na+ channel blockers bind to the Na+ channel when it is open. Because rapidly firing neurons, such as those found in seizure disorders are open a greater percentage of the time, these drugs tend to be selective for abnormal electrical activity found in a seizure focus and do not suppress normal neuronal activity. This is referred to as use-dependent blockade and is essential for limiting the toxicity of these agents.

o Valproic acid may also reduce reduces the propagation of abnormal electrical discharge in the brain. It may enhance GABA action at inhibitory synapses.

Calcium channel blockers (Ethosuximide)

o Ethosuximide is used clinically for its selective effect on absence seizures. The mechanism of action is due to inhibition of T-type calcium channels, which may play a role in generating the 3/second firing rhythm in thalamic relay neurons that is characteristic of absence seizures

Barbiturates: (Phenobarbital, Secobarbital, pentobarbital, mephobarbital, butabarbital, amobarbital)

PST 05104 Pharmacology & Therapeutics 219 NTA Level 5 Semester 1 Facilitator Guide

Binding of GABA to GABA A receptors leads to the opening of the chloride (Cl−) channel, facilitating Cl− influx and cellular hyperpolarization (making the inside more negative).

Hyperpolarization of a cell decreases the probability that the cell can be subsequently depolarized by other incoming excitatory signals; this will have a net inhibitory effect.

Barbiturates increase the binding of GABA to GABA A receptors and increase the influx of Cl− into the neuron, resulting in hyperpolarization and decreased neuronal

activity.

Barbiturates also potentiate the binding of benzodiazepines to GABAA receptors. The overall net effect of this binding is a global reduction in CNS activity; barbiturates are CNS depressants.

GABA-transaminase inhibition (vigabatrin )

Vigabatrin inhibit transaminase enzyme thus preventing the metabolism of GABA to its metabolites resulting to an increase in GABA concentration.

GABA-reuptake inhibitors (Tiagabine )

Tiagabine Inhibits GABA transporter (GAT-1) hence reducing reuptake of GABA by neurons and glial cells.

γ-Aminobutyric acid (GABA) Analogues (Gabapentin, Pregabalin)

GABA analogues are primarily used in the treatment of seizures and management of neuropathic pain.

The structure of gabapentin is derived from GABA; therefore it has long been thought of as simply a GABA agonist. However, gabapentin does not appear to bind to GABA receptors. Instead, it may promote the release of GABA.

Benzodiazepines

BDZ like Diazepam (Valium), lorazepam, clonazepam, clorazepate have anticonvulsant activity. Not all BDZ are used as anticonvulsants.

These drugs increases the frequency of GABAA-activated Cl- channel opening as discussed in Pharmacodynamics of Hypnotics and Anxiolytics

STEP 3: Drug Interactions Associated with Anticonvulsants (20 minutes)

Activity: Brainstorming (5 minutes)

Ask students to brainstorm on the following question:

What are drug interactions associated with anticonvulsants?

ALLOW few students to respond

WRITE their responses on the flip chart/ board

CLARIFY and SUMMARISE by using the content below

PST 05104 Pharmacology & Therapeutics 220 NTA Level 5 Semester 1 Facilitator Guide

The following are drug interactions of Anticonvulsants

Sodium channel blockers (Phenytoin, Carbamazepine, Valproate )

o Carbamazepine: should not be combined with monoamine oxidase inhibitors. It is a potent enzyme inducer and, in particular, it accelerates the metabolism of warfarin, theophylline and the oral contraceptive.

o Carbamazepine: The hepatic metabolism of carbamazepine is inhibited by cimetidine, isoniazid, diltiazem and erythromycin. Toxic symptoms may arise if the dose is not adjusted.

o Phenytoin:

Inhibition of phenytoin metabolism: Inhibition of microsomal metabolism of phenytoin in the liver is caused by chloramphenicol, dicumarol, cimetidine, sulfonarnides, and isoniazid. When used chronically, these drugs increase the concentration of phenytoin in plasma by preventing its metabolism.

A decrease in the plasma concentration of phenytoin is caused by carbamazepine,

which enhances phenytoin metabolism

Increase in metabolism of other drugs by phenytoin: Phenytoin induces the P-450 system which leads to an increase in the metabolism of other antiepileptics, anticoagulants, oral contraceptives, quinidine, doxycycline, cyclosporine, mexiletine, methadone, and levodopa.

Valproic acid: Valproate is a CYP2C9 enzyme inhibitor and can interfere with the metabolism of other antiseizure medications such as phenytoin and phenobarbital.

Barbiturates

All barbiturates are liver enzyme inducers; they increase the activity of CYP2A and CYP3A enzymes, which results in faster metabolism (and thus reduced effect of) other, coadministered drugs that are also hepatically metabolized.

Barbiturates are an example of autoinducers: a drug that induces the same enzymes

that metabolize it.

This results in increased dose requirements over time, compared with initial dose requirements.

STEP 4: Adverse Effects of Anticonvulsants (20 minutes)

The following are adverse effects of Anticonvulsants;

Sodium channel blockers (Phenytoin, Carbamazepine, Valproate, Lamotrigine)

o Lamotrigine: Rash: Rashes can range from mild to severe, including Stevens-Johnson syndrome and toxic epidermal necrolysis.

These rashes can be fatal in patients who are otherwise compromised, or if treatment is not discontinued and/or if the rash is not treated.

The exact mechanism behind these severe reactions is not known.

Carbamazepine: Dermatologic reactions may occur, including Stevens-Johnson

syndrome and toxic epidermal necrolysis, which are both very severe reactions with possible fatal outcomes.

Valproic acid: Hepatotoxicity: Elevations in liver enzymes and bilirubin are relatively common; however, severe hepatotoxicity leading to liver failure and death is rare.

PST 05104 Pharmacology & Therapeutics 221 NTA Level 5 Semester 1 Facilitator Guide

Infants are at highest risk of developing severe hepatotoxicity.

The mechanism has not been established; however, depletion of carnitine is believed to play a key role.

Barbiturates

o Sedation: Anti-seizure effects occur at a lower dose than sedation; however, some patients will need higher doses of treatment to suppress seizure activity, and the dose can approach a sedating dose.

Therefore the therapeutic index between the anti-seizure dose and the sedating

dose is small.

Addiction: Barbiturates are highly addictive.

Hypotension may occur when barbiturates are given intravenously for anesthesia, especially in patients at risk (cardiac disease or trauma).

CNS: Barbiturates cause drowsiness, impaired concentration, and mental and physical sluggishness.

Drug hangover: Hypnotic doses of barbiturates produce a feeling of tiredness well after the patient awakes.

This drug hangover leads to impaired ability to function normally for many hours after waking.

Occasionally, nausea and dizziness occur.

o Addiction: Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, restlessness, nausea and vomiting, seizures, delirium, and cardiac arrest.

Withdrawal is much more severe than that associated with opiates and can result in death.

Poisoning: Barbiturate poisoning has been a leading cause of death among drug overdoses for many decades.

Severe depression of respiration is coupled with central cardiovascular depression, and results in a shock-like condition with shallow, infrequent breathing.

Treatment includes artificial respiration and purging the stomach of its contents if the drug has been recently taken.

Haemodialysis may be necessary if large quantities have been taken.

Alkalinization of the urine often aids in the elimination of phenobarbital.

STEP 5: Contraindications of Anticonvulsants (20 minutes)

Activity: Brainstorming (5 minutes)

Ask students to brainstorm on the following question:

What are the contraindications of drugs acting on the CNS? ALLOW few students to respond?

WRITE their responses on the flip chart/ board

CLARIFY and SUMMARISE by using the content below

PST 05104 Pharmacology & Therapeutics 222 NTA Level 5 Semester 1 Facilitator Guide

Anticonvulsants

Sodium channel blockers (Phenytoin, Carbamazepine, Valproate, Lamotrigine)

o Valproic acid: Pregnancy: As is the case with a number of other antiseizure drugs, valproate is teratogenic, and its use in pregnancy should be considered only after a careful risk-benefit assessment.

o Valproic acid is contraindicated in significant hepatic disease or dysfunction.

Barbiturates

o Porphyria is a rare group of diseases caused by enzyme deficiencies resulting in accumulation of porphyrins, which are precursors to heme.

Barbiturates can increase activity through these biochemical pathways and

exacerbate accumulation of porphyrins.

Significant hepatic disease or dysfunction.

Pregnancy: As is the case with a number of other antiseizure drugs, valproate is teratogenic, and its use in pregnancy should be considered only after a careful risk-benefit assessment.

STEP 6: Key Points (5 minutes)

The choice of antiepileptic drugs depends on the type of seizures

Anticonvulsants exhibit different mechanisms of action

Anticonvulsants use is associated with a lot of significant drug interactions

Anticonvulsants have serious adverse effect when used

STEP 7: Evaluation (5 minutes)

What is the mechanism of action of phenytoin?

Anticonvulsants are contraindicated in which conditions?

Which drugs should be avoided to be co-administered with carbamazepine?

PST 05104 Pharmacology & Therapeutics 223 NTA Level 5 Semester 1 Facilitator Guide

References

Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education.

Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier.

Tripathi, K. (2018). Essentials of Medical Pharmacology. Place of publication not identified:

Jaypee Brothers Medical P.

Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government printers.

Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael. (2014). Pharmacotherapy: A Pathophysiologic Approach (9th ed.). New York, McGraw-Hill Education.

Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York, Lippincott Williams and Wilkins.

School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).

Dar es Salaam, ARDHI University press.

The Royal Pharmaceutical Society of Great Britain. (2007). Martindale, the Extra Pharmacopoeia (5TH ed). London, pharmaceutical press.

The Royal Pharmaceutical Society of Great Britain. 2009. British National Formulary (59th ed). London, BMJ Group and RPS Publishing.

PST 05104 Pharmacology & Therapeutics 224 NTA Level 5 Semester 1 Facilitator Guide

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