Seminar 13. Antiepileptics & Parkinsonism. PDF

Preview

Summary

Seminar 13.Antiepileptic drugs andanticonvulsants.Pharmacologic management ofParkinsonism.I. Antiepileptic drugs andanticonvulsants.EpilepsyEpilepsy: definitionA neurological disorder, characterised by seizuresNeurological disease, characterised by a group of abnormally active (hyperactive) neurons,...

Description

Seminar 13. Antiepileptic drugs and anticonvulsants. Pharmacologic management of Parkinsonism. I. Antiepileptic drugs and anticonvulsants. Epilepsy

Epilepsy: definition A neurological disorder, characterised by seizures " Neurological disease, characterised by a group of abnormally active (hyperactive) neurons, firing signals in random directions at random speed. "

Epilepsy: causes • Genetics"

- Several genes are associated with epilepsy" - If one of the parents suffers from epilepsy, there is a higher chance the children develop epilepsy " • Trauma of the head, neurosurgery" • Drugs, environmental factors" !

1 

Types of seizures 2 groups of seizures: partial & generalized Seizures

Partial

Generalized

Tonic Simple

Complex Atonic

Myoclonic Clonic

Tonic-clonic

Absence

1. Partial seizures: patient does not lose consciousness • The patient can afterwards describe what happened, the patient knows something abnormal is happening " • Hyperactivity of the neurons is limited" • We can recognise where the group of hyperactive neurons are • 2 types of partial seizures: simple & complex: " Simple partial seizure: "

- No muscle twitches, no shaking "

- Strange sensation for the patient: tickling of the skin, feeling of sudden cold/hot in limited area of the skin, strange smell, strange taste in the mouth (eg: patient will smell smoke, but there is no smoke)

Complex partial seizure: "

- Patients are either totally awake (are aware of whats happening) or they are in a changed mental state"

- Changed mental state ➝ patient wont experience strange sensations, muscle twitches are possible, stares at one point, might be talking nonsense "

- Short duration ➝ patient will be

- Patient is less aware of what’s

wondering where the strange feeling/sensation came from

happening, but does not lose consciousness "

- The patient can afterwards describe what he experienced

!

2 

2. Generalized seizures: • Shaking of the whole body • The onset of a generalized seizure can be in the form of a partial seizure ➝ patient has a bad feeling, feels the seizure coming (the so-called prodromal period) • We don't know which neurons were the initial hyperactive neurons • 6 types of generalized seizures:" Tonic generalized seizure: "

- Muscles suddenly become stiff and flexed"

Atonic generalized seizures: "

- Opposite of the tonic seizure" - Sudden relaxation of the

- If patient is walking, he will most likely fall backwards ➝ patient won't move (muscles are stiff), will remain in 1 position

skeletal muscles"

- If patient is walking, he will most likely fall forward

- Short duration (several seconds up to 1 or 2 minutes) Clonic generalized seizures (convulsions): "

- Typical shaking of the body " - Frequent contractions and relaxations in very short period of time

Myoclonic generalized seizures: "

- Like the clonic type, but it affects only 1 group of skeletal muscle"

- Affects only 1 part of the whole body "

- Usually affects the arm! Tonic-clonic generalized seizures (grand mal): "

- Most common type of seizure " - Most dramatic type of seizure ➝ the type of seizure shown on TV

- If this seizure continues for more than 5 minutes: status epilepticus

- 1.Tonic phase / 2. Relaxation phase / 3. Clonic phase !

Absence generalized seizures (petit mal): "

-

Usually occurs in children" Most difficult seizure to treat " No muscles twitches " Child loses consciousness Short duration (up to 30 seconds)"

- Children can grow out of it with puberty& 3 

Postictal period After the seizures have passed, there is the so-called postictal period (post seizure period)"

- Extreme fatigue" - Paralysis: not of the whole body, but 1 muscle group (can last several hours after seizure)"

- Headache, nausea, vomiting" - Patient is unaware of what has happened"

Epilepsy: pathogenesis 3 factors involved in seizure formation: 1. Decreased inhibitory neurotransmission (GABA) 2. Increased excitatory neurotransmission (glutamate)" 3. Increased excitatory ions activity (calcium and sodium)

!

4 

Antiepileptic drugs 1st generation antiepileptic drugs / Major antiepileptic drugs: Phenytoin, Carbamazepine, Valproic acid, Ethosuximide, Phenobarbital ↳ 1st gen. drugs are highly lipid-soluble, they have very long plasma half lives (up to 40 hours), they tend to accumulate in the tissues (intoxications are possible), most of them interact with the cytochromes (induce or inhibit), most of them are contraindicated in pregnancy

- The only major drug that is not an inducer of the cytochromes: Valproic acid - The only major drug that has no effect on the cytochromes: Ethosuximide - Cytochrome inducing drugs should not be used in combination with contraceptives! → contraceptives are metabolised in the liver → faster inactivation of the contraceptive when combined with a cytochrome inducer

2nd generation antiepileptic drugs: Lamotrigine, Gabapentin ↳ 2nd gen. drugs do not interact with the cytochromes, they have short plasma half lives, they do not accumulate in the tissues, usually safe to use during pregnancy, they have less adverse drug reaction

Type of seizure

Antiepileptic drug

Partial seizures

Phenytoin" Lamotrigine" Gabapectin

Tonic seizures

Carbamazepine

Myoclonic seizures

Valproic acid

Tonic-clonic seizures

Phenytoin" Carbamazepine" Valproic acid

Absence seizures

Valproic acid" Ethosuximide" Lamotrigine

!

5 

1.

Phenytoin

• The oldest drug to treat epilepsy" • Phenytoin is contraindicated in pregnancy • Phenytoin is a cytochrome inducer (induces liver enzymes) • Mechanism of action:" • Blocks voltage-gated sodium channels • Blocks calcium channels • Phenytoin slows down the generation & propagation of the chaotic and fast signals" • Clinical usage:" • All forms of partial seizures • Tonic-clonic seizures • Tachyarrhythmias • Used like Lidocaine ➝ phenytoin can be used intravenously to treat tachyarrhythmias (but not used as a local anesthetic like Lidocaine) • Adverse reactions:" • Teratogenic effect (disturb the development of the embryo or fetus) → should not be given during pregnancy!" • GI irritation" • Eye problems: diplopia (double vision) & nystagmus (involuntary movements of the eyes) • Gingival hyperplasia / hypertrophy1 (can be so dramatic that the gingiva covers the teeth) → patients on phenytoin require good dental care! • Phenytoin blocks the activation of folic acid → can lead to some neuropathies and myoblastic anemia"

1

Gingival hypertrophy is very specific for Phenytoin! " Only seen in Phenytoin, not in Carbamazepine & Valproic acid

!

6 

2.

Carbamazepine

• Carbamazepine is contraindicated in pregnancy • Carbamazepine is a cytochrome inducer (induces liver enzymes)" • Mechanism of action (similar to phenytoin):" • Blocks voltage-gated sodium channels • Clinical usage:" • Not used for the treatment of partial seizures • Tonic seizures • Tonic-clonic seizures • Can also be used in the treatment of neuropathic pain • Can also be used in the treatment of bipolar disorder (especially the mania phase) • Adverse reactions:" • Teratogenic effect" • Eye problems: diplopia (double vision) & nystagmus (involuntary movements of the eyes) • Hair loss" • Hirsutism → Male-type of hairiness on female patients"

3.

Phenobarbital

• Potentiates GABA activity • Drug like diazepam" • Diazepam & Phenobarbital are not used like the classic antiepileptic drugs ➝ they are predominantly used in the treatment of status epilepticus (in the form of an intramuscular or intravenous injection) • Phenobarbital is not used for the chronic treatment of epilepsy

!

7 

4.

Valproic acid

• Drug of choice in the treatment of absence seizures ↳ remember: absence seizures are the most difficult to treat, there aren't many drugs affective in this type of seizure (but Valproic acid is one of them)" • Valproic acid is contraindicated in pregnancy" • Unlike Phenytoin & Carbamazepine, Valproic acid isn’t an enzyme inducer ➞ Valproic acid is a cytochrome inhibitor • Mechanism of action:" • Blocks voltage-gate sodium channels • Blocks the receptors for glutamate • Clinical usage:" • Absence seizures • Myoclonic seizures • Tonic-clonic seizures • Can also be used in the treatment of neuropathic pain • Can also be used in the prophylaxis of migraine • Can also be used as a mood stabiliser in the treatment of mania • Adverse reactions: (simular to Carbamazepine & Phenytoin)" • Teratogenic effect (disturb the development of the embryo or fetus) → should not be given during pregnancy!" • GI irritation" • Eye problems: diplopia (double vision) & nystagmus (involuntary movements of the eyes)

!

8 

5.

Ethosuximide

• Only used in the treatment of absence seizures 2 • The only major antiepileptic drug that does not affect the cytochromes (no inhibition, no induction) • Ethosuximide is contraindicated in pregnancy • Different from the other antiepileptic drugs → different mechanism of action • Mechanism of action: ! !

!

(unique mechanism of action)

• Blocks T-type calcium-channels T → located in the Thalamus" ! !

T-type calcium channels act as a pacemaker regulator / they initiate ! the pacemaker activity of the thalamic neurons"

!

Hyperactivity of T-type calcium channels are the reason for absence !

! #

seizures → this is the reason why Ethosuximide is only used in the # # treatment of absence seizure

• Clinical usage:" • Absence seizures • Adverse reactions (pretty mild adverse reactions):" • GI irritation → not only nausea and vomiting, but also anorexia • Hair loss" • CNS hyperactivity → hallucinations, seizures"

2

2 drugs used in the treatment of absence seizures: Valproic acid & Ethosuximide

Treatment of absence seizures: the treatment will usually start with Ethosuximide ➝ if Ethosuximide isn’t efficient, then we can switch to Valproic acid

!

9 

6.

Lamotrigine

• 2nd generation antiepileptic drug" • Mechanism of action:" • Blocks voltage-gate sodium channels • Blocks the calcium channels • Clinical usage: • Both forms of partial seizures • Absence seizures • Adverse reactions:" • GI irritation" • Hypersensitivity "

7.

Gabapentin

• 2nd generation antiepileptic drug" • Mechanism of action:" • Blocks the calcium channels • Clinical usage: • Both forms of partial seizures • Additional therapy in the treatment of generalized seizures (Gabapentin is a weak drug) • Main use nowadays: treatment of neuropathic pain • Adverse reactions:" • Hypersensitivity ➝ rash, leukopenia"

!

 10

II. Pharmacologic management of Parkinsonism. Parkinson's disease

Parkinson: definition A neurodegenerative disease, that mainly affects the movements " Occurs mainly in elderly patients

Parkinson: symptoms 1. Bradykinesia / akinesia (Suppression of the voluntary movements) • Bradykinesia: Difficulty starting and stopping a motor activity" • Akinesia: patient is unable to initiate a motor movement" 2. Muscle rigidity (muscle stiffness) ➝ resistance in passive limb movements • Affects the extremities and fine movements" 3. Tremor at rest • Usually seen in the hands (shaking of the hands) " 4. Cognitive impairment • Dementia, depression, autonomic disfunction • Occur because the neurodegenerative process is not limited to the basal ganglia

!

 11

Parkinson: causes No obvious cause, but usually associated with cerebral ischemia, viral infections, …

- Parkinson affects the basal ganglia - Decrease in dopamine activity in substantia nigra - Degeneration of dopaminergic neurons in corpus striatum - Elevated levels of acetylcholine "

Acetylcholine ➝ associated with the tremor" Dopamine ➝ associated with the bradykinesia"

!

 12

Drugs used to treat Parkinson's disease "

Classification Levodopa

Precursor of dopamine Careldopa (Levodopa + Carbidopa)

Bromocriptine

Dopamine receptor agonists

Drugs stimulating dopaminergic transmission

Muscarinic receptor antagonists

!

Pramipexole

Monoamide oxidase-B (MOA-B) inhibitors

Selegiline

Drugs enhancing dopamine release

Amantadine

Biperiden

 13

Mechanism of action It’s not possible to inject dopamine into the brain (would need to be injected very precise) & can’t be taken in the form of a tablet (dopamine is water-soluble)"

• Levodopa can be metabolised into dopamine in the periphery by the enzyme dopa decarboxylase " • Keep in mind: dopamine production in the periphery is associated with adverse drug reactions!! ! ! ! ! ! ! ! ! ! ! ➝ So the transformation of Levodopa into dopamine is unwanted!" • The majority of Levodopa can’t penetrate the blood-brain barrier (only 1-3 % of levodopa is capable of reaching the brain)" • ➡ we need drugs that block dopa decarboxylase in the periphery ➝ will increase the amount of drug available and the the amount of drug penetrating the bloodbrain barrier • Carbidopa will inhibit the dopa decarboxylase • Carbidopa is always given in combination with Levodopa" • Once Levodopa has crossed the blood-brain barrier, it is transformed into dopamine by dopa decarboxylase "

!

 14

There are other options available as well since Levodopa has a lot of adverse reactions:"

• It’s also possible to use drugs that directly activate the dopamine receptors ➝ Bromocriptine" • It’s also possible to block the inactivation of dopamine ➝ Selegiline" • Dopamine can be inactivated by MAO (Mono Amino Oxidase)➝ Selegiline inhibits MAO" • Main problem: MAO is also responsible for the inactivation of norepinephrine and serotonin " • It’s also possible to increase the release of dopamine ➝ Amantadine" • Amantadine not only increases the release of dopamine, it also stimulates the dopamine receptor "

• Biperiden (muscarinic receptor antagonist) can be used to treat the tremor and muscle rigidity → it does not affect the movement (bradykinesia)" • Biperiden has atropine-like adverse reactions"

!

 15

Adverse reactions in drugs used to treat Parkinson's disease Elevated levels op dopamine lead to adverse reactions"

Elevated dopamine levels in the periphery: " • GI discomfort 3 → nausea, vomiting, diarrhoea " • Dopaminergic receptors in blood vessels → vasodilation & stimulation of the heart (tachycardia) Elevated dopamine levels in the CNS:" • Nausea, vomiting (there are dopaminergic receptors in the vomiting center)" • Psychosis, hallucinations, impaired impuls-control • Inappropriate behaviour, risky type of behaviour (eg. excessive gambling, excessive shopping) "

Levodopa: adverse reactions • Very specific effect: on-off phenomenon" • On-phase → when patient takes the drug → patient is capable of walking, less tremor,… • Off-phase → when there's a lack of effect → suddenly patient stops walking, freezes, and can’t move • There is recovery of the off-phase and return to the on-phase" • Explanation: plasma-concentration fluctuations" • Happens at standard dosses of Levodopa" • Tends to happen after some time into the therapy, it's not an initial reaction"

3

Initiation of the therapy is associated with GI problems, GI problems tend to diminish as therapy goes on

!

 16

Biperiden: adverse reactions Atropine-like adverse reactions

• Xerostomia (dry mouth)" • Constipation" • Sedation" • Urinary retention" • Biperiden is contraindicated in prostate hyperplasia " • Biperiden is contraindicated in glaucoma"

!

 17...