CNS-ANTICONVULSANTS-PART-VI-Contd..

ANTICONVULSANTS-Contd..

4.Primidone (Mysoline)

It is chemically related to barbiturates and also it works very similar to phenobarbital.

Primidone is used in adults as an alternative medicine to treat grand mal and partial seizures.

It can be given orally

Primidone is metabolized in the liver to little phenobarbital with a compound of phenyl ethyl melon amide (PEMA) as a major metabolite.

Primidone is mostly excreted in the urine as unchanged(53%) along with its metabolites PEMA (43%) and a little phenobarbital(4%).

Side Effects

Very similar to phenobarbital

1.Sedation

2.Ataxia

3.Nausea

4.Vomiting 

5.Drowsiness

5.Valproic Acid (Depakene)

It is medically used as a sodium salt.

It is the drug of choice in the treatments of myoclonic and absences seizures.

It is also used to relieve migraine and bipolar psychoses.

Mechanism

Works by prolonging the inactive state of Na+(sodium) channels and increasing the cerebral GABA concentration.

It can be given orally and it is well absorbed thereby.

After absorption 90% of the drug is bound to plasma proteins.

Metabolism

Extensively metabolized in the liver by the CYP-450 system and hence care and dosage adjustment should be considered if taken along with any medicine which affects the CYP-450 system either by induction or suppression.

This drug anyhow is not an inducer of the CYP-450 system.

Excreted in the urine as its metabolites (97%) with a little unchanged.

Side Effects

1.Liver damage

2.Nausea and Vomiting

3.Ataxia

4.Tremor

5.Lethargy

Use in Pregnancy and Lactation

Safety is not well established.

If taken during the first trimester there are high possibilities of neural tube damages.

6.Ethosuximide

It is the drug of choice for absences (Petit mal)

Chemically it is a succinimide derivative.

Mechanism

It is a calcium channel inhibitor and inhibits the influx of Ca++ into T-type channels of thalamic neurons and thereby it regulates abnormal electrical conduction in the brain.

Metabolism and Kinetics

The drug is well absorbed orally.

It is mostly metabolized in the liver by CYP-450 system

It is not inducing the enzyme

Side Effects

1.Dizziness

2.Agitation

3.Nausea

4.Vomiting

5.Diarrhea

6.Mental confusion

7.Liver damage

6.Kidney damage

Blood dyscrasias-Leukopenia, Aplastic anemia, and thrombocytopenia in sensitive patients

7.Allergic skin reactions-Stevens-Jonson syndrome

7.Benzodiazepines

Benzodiazepines are already presented in last posts (Anti-anxiety drugs) well in details however here we see some of them used as anticonvulsants.

1.Diazepam (Valium)

2.Clonazepam

3.Clorazepate

Therapeutics

Diazepam can be given as an intravenous injection in the emergency situation of Status Epilepticus.

Clonazepam can be used in treating myoclonic seizures in children

Clorazepate may be used for partial seizures (simple or complex) in combination with phenytoin or carbamazepine.

Side Effects

Even though the side effects are mild but we should take care of the following effects:-

1.Drowsiness

2.Respiratory depression

3.Cardiac depression.

8.Gabapentin

Gabapentin is chemically a GABA derivative.

It is used to treat partial seizures both simple and complex.

It is acting by increasing GABA secretion in the CNS.

It is excreted unchanged in the urine.

Side Effects

1.Ataxia

2.Somnolence

3.Fatigue

9.Lamotrigene

It is used to treat partial seizures in adults in combination with other drugs.

Mechanism

It is acting by blocking voltage dependant active sodium channels and thereby preventing the sustained firing of action potentials.

The drug is metabolized in the liver

Side Effects

1.Dizziness

2.Blurred vision

3.Rash

4.Urinary retention

5.BPH.

CNS-PAR-VI-ANTICONVULSANTS-Contd..

ANTICONVULSANTS

Seizures can be controlled if not completely treated by various drugs known as Anticonvulsants mentioned below.

1.Phenytoin (Dilantin)

2.Carbamazepine

3.Phenobarbital

4.Pirimidone

5.Valproic Acid

6.Ethosuximide

7.Benzodiazepine

8.Gabapentin

9.Lamotrigine

1.Phenytoin (Dilantin)

Phenytoin is used in treating tonic/clonic seizures and partial seizures. Chemically it is a hydantoin derivative.

Phenytoin is not effective in treating Absences.

Used in treating Status Epilepticus by intravenous route as an adjunct with diazepam.

Phenytoin is acting by blocking voltage-gated sodium channels and thereby prevent the neurons to get depolarized sufficiently to excite an action potential.

Kinetics and Route

Phenytoin can be administered either by intravenous and oral routes.

Since the absorption through the GI system is slow the oral route may have a longer gestation period to reach the required effects pharmacodynamically.

In contrast the intravenous route is rapid and reaches the required effect within minutes and lasts for 24 hours.

Phenytoin is metabolized in the liver by hydroxylation by the endometrial CYP-450 enzymes such as CYP-3A4 and CYP-2-C19. Watch for toxicity if these two enzymes induced by phenytoin get consumed completely.

Side Effects

1.Gingival Hyperplasia-A major toxicity in which there is a painful enlargement of teeth gum. Folic acid supplementation is recommended

2. Megaloblastic Anemia-Because phenytoin interferes with folic acid metabolism. Folic acid supplementation is required.

3.Hirsutism-Unwanted growth of hair.

4.Diminished deep tendon reflexes in the extremities.

5.Stevens-Jonson Syndrome-Severe skin rashes with cell necrosis with fever and usually a life-threatening reaction.

6.CNS depression

7.Endocrine reactions-Diabetes Insipidus(Watery Urine), Hyperglycemia, glycosuria, and osteomalacia(bone weakness)

Drugs Interactions

The following three drugs are competing with phenytoin for the enzyme CYP-450 successfully, by decreasing its metabolism and thereby increasing its plasma concentration.

1.Chloramphenicol-Anti typhoid

2.Isoniazid-Anti T.B.

3.Cimetidine.-Antihistamine to reduce hyperacidity

Dosage adjustment should be necessary when giving Phenytoin concomitantly with the above drugs.

Carbamazepine by inducing rapid metabolism of phenytoin decreases its plasma concentration. Dosage adjustment of phenytoin is important accordingly if given along with carbamazepine.

Use in Pregnancy and Lactation

Phenytoin is a teratogenic drug as it can cross into the placenta and milk and hence it should not be given during pregnancy and lactation as serious reactions such as prenatal growth deficiencies, congenital malfunctions such as the cleft palate and heart malfunctions may occur.

2.Carbamazepine (Tegretol)

Carbamazepine is a neuroleptic drug that can be used as an antipsychotic agent and to relieve neuropathic pain.

Carbamazepine is effective as well as phenytoin and valproic acid in the treatment of grand mal and petit mal as a drug of choice but not in treating absence seizures and myoclonic seizures.

Mechanism of Action

Very similar to phenytoin

Metabolism and Kinetics

Similar to phenytoin but given orally only 

metabolized by the CYP-450 hepatic enzyme system similar to phenytoin but successfully compete with it.

Drug Interactions

The following drugs are competing successfully for CYP-450 enzyme with greater affinity than carbamazepine and hence they increase the carbamazepine plasma level by inhibiting its metabolism.

1.Erythromycin-Antibiotic

2.Isoniazid-Anti-T.B.

3.Propoxyphene-A pain killer

4.Verapamil-Calcium Channel Blocker for B.P

5.Cimetidine-A histamine H-2 receptor blocker used for reducing acid secretion in the stomach.

Hence dosage should be adjusted accordingly.

Side Effects

1. Acutely can cause respiratory depression and coma

2.Liver toxicity-Require frequent liver tests.

3.Aplastic anemia-Lack of blood cells formation due to bone marrow and erythropoietic stem cells damage

4.Agranulocytosis-A deficiency of granulocytes in the blood.

5.Drowsiness

6.Ataxia-Loss of full control of body movements.

7.Nystagmus-Involuntary movements of eyeballs.

3Phenobarbital (Luminol)

Chemically phenobarbital is a barbituric acid derivative.

Mechanism

Phenobarbital enhances the action of GABA at its receptors and thereby inhibiting the neuronal excitation.

Uses

1.Drug of choice for treating febrile seizures.

2.Used to treat grand mal in children

3.Partial seizures

Metabolism and Kinetics

Absorbed well by the oral route. Three fourth of the drug is metabolized in the liver.

It is a potent inducer of the CYP-450 enzyme in the liver.

Care should be taken when given along with any drug metabolized by or inducing this enzyme.

The metabolites are excreted in the urine.

Side Effects

1.Sedation

2.Nystagmus

3.Psychotic reactions

4.Allergic reactions such as serious Stevens-Jonson syndrome

5. Overdosage may result in respiratory depression, coma, and death.

Will be continued.....

CNS-PART-VI-ANTICONVULSANTS

SEIZURES-TREATMENTS-INTRODUCTORY

Seizures are pathological conditions in which the patient frequently suffered by abnormal synchronized electrical depolarization of neurons in the central nervous system.The episodes are commonly called as convulsions and more technically by the name seizures.

Seizures are generally caused by the following factors:-

1.Idiopathic

2.CNS Infecions

3.Fever

4.Metabolic Defects

5.Cerebral Trauma

Types Of Seizures

1.Partial

2.Generalized tonic/clonic

3.Status Epilepticus

4.Absence

5.Febrile

6.Myoclonic

1.Partial Seizures

 

A partial seizure is the one in which abnormal discharges occur from a focal area within the brain.

a)Simple Partial Seizure 

In this type a focal neurological symptom involves that can be sensory like visual or auditory hallucinations,motor or psychomotor.Conciousness always retained.

b)Complex Partial Seizures

In this type the initial focus of abnormal discharge spreads so that patient will loose conciousness and have post seizure confusions.Symptoms can include coordinated motor activity and olfactory hallucinations.

Complex partial seizures most probably originates in the temporal lobes.

2.Generalized Tonic /Clonic(Grand mal)

This type of seizures originates from the entire cerebral cortex(The whole brain)

a)Tonic Phase

The symptoms are loss of conciousness,rigidity,and loss of motion and urine control

b)Clonic Phase

The symptoms are jerking of the entire body.

Grand mal can develop at any time even from a partial seizure if unattended. 

c)Status Epilepticus

 

Grand mal with tonic seizure can develop this state of medical emergency which contains continuous seizures without regaining conciousness.

3.Absences (Petit mal)

These types of seizures usually occur in children of age 2 to 12 years of age.

They are characterized by very brief (10 seconds) loss of conciousness with the episodes of stop doings and stare or facial twisting.

Following the attack the child become immediately alert and is seldom even aware that it has occured.

4.Febrile Seizures

Usually occur in small children

They loss less than 10 minutes.

Sympoms are usually a fever without a cause or infection.

5.Myoclonic Seizures

The usual symptoms are sudden short episodes of either local or generalized muscle contractions.

They can occur at any age.

They are associated with very rare variety of hereditary neurodegenerative disorders.

6.Epilepsy

Epilepsy is a group of chronic recurrent seizures with periods of conciousness.This condition is usually affecting a 1% population.

CNS-PART-V-MANIA-TREATMENTS

MANIA-TREATMENTS

Mania is a kind of mental disorder just opposite to depression in which there are uncontrolled mood elevation,with practically impossible grandiose ideas,expansiveness,pressurised talks,flow of ideas,decreased sleep,restlessness,and over activities.

Schizophrenia and other bipolar affective diseases may induce mania into a person.

Anti-Manic Drugs:-

1.Lithium-Drug of choice

2.Antiepileptics-Valproic acid,and carbamazepine are he best choices.We will discuss about these drugs later on under a separate post wih the heading Antiepileptics.

Lithium:-

Lithium is a metallic basic element with a light alkaline property and mostly available in medicine as slow and controlled release carbonate.

Mechanism

The mechanism of action is still not clear but thought to affect the enzyme inositol-I-phosphate which affects neurotransmitters.

Clinical Use

Mostly to control both positive(schezophrenia and mania) and negative (Depression) bipolar mental disorders.Litghium is a primary choice of manic disorders but can be used as an adjuant in the treatments of schezophrenia and depression.

Kineics

Well absorbed orally and excreted through the kidneys.

Contraindications

Because lithium can cross into the placenta and milk it is highly contraindicated during pregnancy and lactation.

Side Effects

1.In acute intoxication severe tremor,ataxia,seizures,and confusion leads to coma ma may occur.

2.Diabetic insipidus (Lithium is a potential inhibitor of Anti Diuretic Hormone-See he video below)

3.Weight gain

4.Stomach pain and vomiting and diarrhea

5.Thyroidal dysfunction-Hypothyroidsm

6.Depression of T-waves in ECG

7.Leucocytosis (Elevation of WBC count to above normal)

In general lithium has a very narrow therapeutic index and hence all lithium medication should be taken under a doctor's strict supervision.

Drug Interaction

Since lithium competes with sodium in absorption and as well as in tubular elimination effectively  by inhibiting the antidiuretic hormone  and excessive intake of sodium may cause a dip in lithium plasma level.

Thiazide diuretics may enhance sodium excretion and thereby elevate lithium plasma level.

Toxicity Antidotes

1.Diuretics other than thiazides may decrease plasma levels of lithium by increasing its excretion.Sodium bicarbonate can be used effectively.

2.Hemo or peritonial dialysis.

CNS-DEPRESSION TREATMENS -Contd...

ANTI DEPRESSANTS-Contd...

Atypical Antidepressants:

Atypical antidepressants do not have a specific class of action but their antidepressant effects are most probably by an unknown mechanism with minimum side effects.

1.Trazadone:-

An antidepressant is structurally very similar to the benzodiazepine alprazolam but more specific in the inhibition of serotonin reuptake.

It is particularly effective in improving sleep.

It is metabolized in the liver and excreted by the kidneys.

Side Effects

1.Sedation

2.Orthostatic hypotension

3.Nausea

4.Headache and dizziness

5.Agitation

6.Anticholinergic effects(Rare)

2.Bupropion

It is also an atypical antidepressant with an unclear mechanism of action.

Side Effects

1.Headache

2.Nausea

3.Tachycardia

4.Restlessness

Fortunately, with bupropion there is no sexual dysfunction toxicity which is distinctive with SSRIs.

SSRI:-Serotonine Specific Reuptake Inhibitor

x

CNS-DEPRESSION-PART-IV-Contd..

DEPRESSION-TREATMENTS-Contd...

Mono Amine Oxidase Inhibitors (MAOIs):-

Mono Amine Oxidase is a typical enzyme available widely in our body especially in the neuronal mitochondria(a small tissue composed of endothelial cells present within the nerve synapses)in the CNS, liver, and the entire digestive tract. A major portion is present in the liver. Its main duty is to decompose any monoamines(a chemical which contains only one amino -NH2- group in its molecular structure) such as all excess catecholamines neurotransmitters like norepinephrine, epinephrine, dopamine etc.etc. by oxidation. This enzyme is protecting our CNS from overstimulation by the excess monoamine neurotransmitters.

These MAOs are grouped into two as MAO-A; and MAO-B

The former is present mostly in the mitochondrial cells of CNS presynaptic nerves, liver, lungs, placenta, and GI tract. This group is responsible to deaminate(decompose) norepinephrine, epinephrine, serotonin, and melatonin.

The latter group is mainly present in the blood platelets and is responsible to decompose phenylethylamine and benzylamine.

Dopamine and tyramine are affected by both the groups with a little more effect by MAO-B

Mechanisms MAOIs:-

Within the neuronal presynapses, these inhibitors act on MAO-A and block its decomposing effect of the neurotransmitters such as norepinephrine, and serotonin and thereby cause accumulation of the transmitters sufficiently to release from the storage into the synaptic space to act on their respective receptors present at the post synapse. Similarly, blockade of MAO-B will result in the accumulation and release of Dopamine into the synapse to act on its receptor.

All MAOIs are mostly nonspecific except selegiline which specific to block MAO-B and are widely used in Parkinson's Disease in which there is insufficient dopamine present at the synapse and hence it is of little importance here.

Clinical Indications of nonspecific MAOIs:-

Atypical depression, like phobias.

Kinetics:

1. Orally well absorbed

2. Metabolized in the liver by acetylation.

MAOIs are generally having half-life 2 to 3 hours. But they require 3 to 4 weeks of treatment to attain the steady-state plasma concentration.

Side Effects:-

1.Hypertensive crisis such as headache, arrhythmias, and stroke. Hence the patient should be advised not to take tyramine rich foods like seasoned cheese, chicken liver, chocolates, beer, and red wine.

The hypertensive crisis will also occur if taken MAOIs along with any opioids such as meperidine.
2.Orthostatic hypotension
3.Anticholinergic effects such as dry mouth, blurred vision, and weight gain.

CNS-PART-IV-DEPRESSION AND MANIA-Contd...

DEPRESSION-Cond...

 

Tricyclic antidepressants and MAOIs should not be given together as the combination will seriously result in excess accumulation of catecholamines at the receptors that lead to a crisis, convulsions, and coma.

Serotonin Specific Reuptake Inhibitors (SSRIs):-

1.Fluoxetine 

2.Sertraline

3.Paroxetine

4.Fluvoxamine

Mechanism:-

These drugs increase the availability of serotonin (5-Hydroxy Tryptamine) at the synapses by inhibiting its reuptake mechanism. It has no specific effect on norepinephrine and dopamine and hence these drugs are mild and safe.

Therapeutics

1.Depression

2. Fluoxetine is used in Obsessive-Compulsive Disorder (OCD)

Route of Administration:-

By oral route.

Kinetics

They are well absorbed orally and metabolized in the liver by the induction of the enzyme Cytochrome-P-450. Fluvoxamine is exempted as it is metabolized but a powerful C P-450 inhibitor. The metabolites are excreted in the urine.

Side Effects

In general, these drugs are safer than tricyclic and traditional antidepressants as they are specific on serotonin reuptake only. They don't interfere with or inhibit the reuptake of norepinephrine and dopamine. Hence they are milder in producing anticholinergic, antihistaminic, and alpha-adrenergic blockades.

1.Nausea

2.Diarrhea

3.Nervousness

4.Insomnia

5.Dizziness

6.Impotence

7.Decreased libido.

Contraindicated:-

If used with any drug which inhibits the mitochondrial enzyme Mono Amine Oxidase which is responsible for metabolizing norepinephrine dopamine and other catecholamines, and serotonin the excess accumulation of these chemicals will leads to a crisis known as Serotonin Syndrome which leads to hyperthermia, muscle rigidity, myoclonus(spasmodic twitching of group of muscles), and rapid mental disorder.