ANTIEPILEPTIC

EPILEPSY

Epilepsy is a very common disorder. affecting approximately 0.5% of the population.

Cause: Usually there is no recognizable cause, although it may develop as a consequence of various kinds of brain damage, such as trauma, infection or tumor growth.

The characteristics event in epilepsy is the seizure, which is associated with the episodic high frequency discharge of impulses by a group of neurons in the brain; spread to other areas of the brain.

Classification of Epilepsy

The site of the primary discharge and the extent of its spread determines the symptoms that are produced. Depending on the symptoms epilepsy is classified into two broad groups: namely, partial seizures and  generalized seizures.

A. Generalized seizures:

Site: Generalized seizures involve the whole brain , including the reticular system (center of consciousness), thus producing abnormal electrical activity throughout both hemispheres (of cortex). Immediate loss of consciousness is characteristic of generalized seizure.

(i)Grand mal (major epilepsy or tonic-clonic seizures)

Symptoms:

Tonic phase

·         A Tonic-clonic seizure consist of an initial, strong contraction of the whole musculature, causing a rigid-extensor spasm.

·         Respiration stops and defecation, micturation and salivation often occur.

·         This toxic phase lasts for about 1 minute.

Clonic phase:

Tonic phase is followed by a series of violent, synchronous jerks gradually dies out in 2-4 minutes.

The patient stays unconscious for a few minutes and then gradually recovers, feeling ill and confused.

Electro-encephalogram of brain:

                                                normal

                                                tonic

                                                clonic

(ii) Petit mal (minor epilepsy / absence seizures)

Absence seizures occur in children. They are much less dramatic, but may occur more frequently (many seizures a day).

Symptoms:

The patients abruptly ceases whatever he was doing, sometimes stopping speaking in mid-sentence, and stares vacantly for a few seconds, with little or no motor disturbances (i.e. no convulsion).

The patient is unaware of his surrounding ( a kind of unconsciousness) and recovers abruptly with no after effects.

EEG (Electro Encephalogram) pattern:

                                                normal

                                                petitmal

(iii) Akinetic (atonic seizures)

Unconscious with relaxation of all muscles due to excessive inhibitory discharges. Patient may fall.

B. Partial Seizures:

Partial seizures are those in which the discharge begins locally, and often remain localized. These may produce  relatively simple symptoms without loss of consciousness.

(i) Cortical focal epilepsy: (Jacksonial epilepsy)

Symptoms:

Repetitive jerking of a particulate muscle groups which spreads and may involve much of the body within 2 minutes. No voluntary control over the body.

No loss of consciousness.

(ii) Psychomotor epilepsy

Site: the focus is in the temporal lobe.

Symptoms: The attack may consist of stereotyped purposive movements such  as rubbing or patting movements, or much more complex behavior such as dressing or walking or hair-combing.

the seizure usually lasts for a few minutes, after which the patient recovers with no recollection of the events.

Mode of action of antiepileptic drugs:

Two main mechanisms appear to be important:

(i) enhancement of GABA action (e.g. barbiturates, benzodiazepines)

(ii) inhibition of sodium channel function.

A. Enhancement of GABA action:

(i) Many of the clinically effective anticonvulsants (e.g. phenobarbitone and benzodiazepine) when binds with the GABA-benzodiazeoine-chloride-channel receptor complex

®        enhance the affinity for GABA to its receptor site

®        opens chloride channel

®        inhibitory impulse is prolonged

(ii) A recently introduced drug, Vigabatrin acts by inhibiting GABA-transaminase which is responsible for inactivating GABA - thereby  increasing the GABA content of the brain.

Valproate also has GABA-transaminase-inhibiting effects.

B. Inhibition of sodium channel function

(e.g. phenytoin and carbamazepine)

They affect membrane excitability by an action on voltage-dependent sodium channel which carry the inward membrane current necessary for the generation of action potential.

Their blocking action shows the property of use-dependent i.e. they block preferentially the excitation of cells that are firing respectively, and the higher the frequency of firing, the greater the block produced.

Hence, these drugs block the high frequency discharge that occurs in an epileptic fit without unduly interfering with the low frequency firing of neurons in the normal state.

There are three state of sodium channels - resting, open and inactivated states. Phenytoin and carbamazepine bind preferentially to the channels inactivate state, thus preventing them from returning to the resting state, and thus reducing the number of functional channels available to generate action potentials.

They limits spread of seizure activity.

CLASSIFICATION OF ANTIEPILEPTIC DRUGS

Classification is base on chemical structure:

1.      Barbiturates:                      Phenobarbitone, Mephobarbitone, Primidone

2.      Hydantoin:                         Phenytoin, Mephenytoin

3.      Iminostilbine:                     Carbamazepine

4.      Oxazoladinedione:             Trimethodione (Troxidone)

5.      Succinimide:                      Ethosuximide

6.      Aliphatic carboxylic acid:  Valproic acid

7.      Benzodiazepines:               Clonazepam, diazepam

8.      Newer drugs:                     Progabide, Vigabatrin, Gabapentin, Lomotrigine.

PHENYTOIN

Pharmacology:

On CNS

Phenytoin is not a CNS depressant; some sedation occurs at therapeutic doses, but this does not increase further with dose; rather toxic doses produce excitement.

It abolishes tonic phase generated by electric shock but have no effect on clonic phase. It limits the spread of seizure activity.

On CVS

It is found to produce bradycardia (heart going slow), prolong PR interval, and produce T-wave abnormalities on electrocardiogram (ECG). Phenytoin is used in digitalis-induced arrhythmias. It causes depression of ventricular automaticity produced by digitalis, without adverse intraventricular conduction. Because it also reverses the prolongation of AV conduction by digitalis, phenytoin is useful in supraventricular tachycardias caused by digitalis intoxication.

Adverse effects:

These are numerous.

At therapeutic levels:

(a)    Hyperplasia of gums which is disfiguring rather than harmful, often develops gradually - occurs more in young patients, can be minimized by maintain oral hygiene.

(b)   Hirsutism (abnormal hair growth) coarsening of face (troublesome in young girls), acne - etc. which probably results from increased androgen activity.

(c)    Hypersensitivity reactions are - rashes, neutropenia is rare but requires discontinuous of therapy.

(d)   Megaloblastic anaemia - phenytoin decreases folate absorption and increases its excretion. This can be connected by giving folic acid.

(e)    Osteomalacia desensitizes target tissues to Vit D and interferes with calcium metabolism.

(f)    It may inhibit insulin release and cause hyperglycemia.

(g)    Used during pregnancy- may produce foetal malformations in children born to epileptic mother.

At high plasma levels (dose related toxicity):

(a)    Cerebellar and vestibular manifestations:- e.g. ataxia, vertigo etc.

(b)   Drowsiness, behavioral alterations, rental confusions and hallucination.

(c)    nausea, vomiting - it can be minimized by taking with meal.

(d)   Intravenous injection can cause local vascular injury edema and discoloration of injected limb. Rate o injection should not exceed 25 mg/min.

(e)    Fall in blood pressure and cardiac arrhythmias occur only on i.v. injection.

Uses

1.      Grand mal, cortical focal and psychomotor epilepsy. It is ineffective in petit mal.

2.      Status epilepticus: Occasionally used by slow i.v injection.

3.      Trigeminal neuralgia - second by a carbamazepine.

4.      Cardia arrhythmias - specially digitalis induces.

N.B. Status epilepticus

It is the continuous clinical manifestation of an epileptic discharge without intermission. Recurrent tonic-clonic convulsions without recovery of consciousness is an emergency; fits have to be controlled as quickly as possible.

Treatment:

(a)    Diazepam 10 mg i.v. bolus injection (2 mg/min) followed by slow infusion titrated to control the fits is the therapy of choice. Clonazepam (1-2 mg i.v.) is an alternative.

(b)   Phenobarbitone (100-200 mg i.m.) or phenytoin (25 mg/min i.v., maximum 1 g) act more slowly; may be substituted after the convulsions have been controlled.

(c)    Paraldehyde (5-10 m deep i.m. or 16 ml per rectum) may be used if i.v. injection is difficult.

(d)   a general anaesthetic and curarization with positive pressure respiration may be required in cases not responding to the above drugs.

(e)    General measures including maintenance of air way, oxygenation, fluid and electrolyte balance, BP, normal cardiac rhythm and care of the unconscious must be taken.

TREATMENT OF EPILEPSIES

The choice of anti-convulsant drug and dose is given according to the seizure type(s) and need of the individual patient.

Type of seizures	First choice	Second choice	Alternatives
1.       Generalized tonic-clonic (grand mal) & simple partial (cortical focal) 2.       Absence (petit mal) 3.       Complex partial (Psychomotor) 4.       Akinetic 5.       Febrile seizures 6.       Status epilepticus	Phenytoin, Carbamazepine Valproate Carbamazepine Valproate Diazepam(rectal) Diazepam(i.v.)	Phenobarbitone, Valproate Ethosuximide Valproate, Phenytoin Primidone - Phenytoin(i.v.) Phenobarbitone(i.m.)	Primidone, Vigabatrin Clonazepam, Troxidone Primidone, Vigabatrin Clonazepam Phenobarbitone Clonazepam, Paraldehyde

GENERAL ANAESTHETIC

General anaesthetics are drugs that produce reversible loss of all sensation and consciousness. The main features of general anaesthesia are:

(i)     Loss of all sensation

(ii)   Sleep (unconsciousness)

(iii) Muscle relaxation and

(iv) Abolition of reflexes

THEORIES OF ANAESTHESIA

The mechanism of action of the general anaesthetics is not precisely known. A wide variety of drugs or chemicals produce general anaesthesia. Therefore, general anaesthesia is probably not exerted through specific receptors but by a more generalized membrane action. The different theories of anaesthesia are:

1. Lipid/water partition theory

If an anaesthetic agent is more lipid soluble then it will produce more intense anaesthesia. It has been found that minimal alveolar concentration (MAC) (i.e the lowest amount of anaesthetic in pulmonary alveoli needed to produce immobility) decreases with inhalational anaesthetics having higher o/w partition coefficient.

But this is not the perfect mechanism of action.

2. Surface tension theory

General anaesthetics reduce surface tension at cell membrane and thus affect its permeability, electrical and/or enzymatic properties. However, this is not generally accepted.

3. Inhibition of energy production/utilization

Higher concentrations of general anaesthetics in the brain directly inhibit metabolic processes and oxygen consumption in neurons. But it is an effect rather than the cause.

4. Clathrates formation theory

Water is normally partially structured, i.e. has crystal like molecular arrangement. General anaesthetics are believed to fill up the spaces between the microcrystals (clathrates) and make water more structured; thus they plug the pores and impede ionic fluxes. However, there is no evidence of clathrate formation at body-temperature.

5. Membrane expansion theory

The anaesthetics occupy space in the membrane and expand it disproportionately (about 10 times their molecular volumes). This causes increased surface pressure in the membrane, thereby closing ion channels. This has been prompted by the fact that application of external pressure reverses anaesthesia.

6. Membrane fluidization / perturbation theory

Anaesthetic, by dissolving in the membrane lipids, increases the degree of disorder in their structure, favoring a gel-liquid transition (fluidization). Normally, fluidization occurs at high temperatures; anaesthetic may make it possible to occur at lower temperature. This affects the state of membrane bound proteins that regulate ionic fluxes.

STAGES OF ANAESTHESIA

When a general anaesthetic is administered first the higher functions of brain are lost then progressively lower segments of the brain are involved. In case of spinal cord lower segments are affected somewhat earlier than the higher segments.

The vital centers located in the medulla are paralyzed the last as the depth of anaesthesia increases.

When ether is administered as inhalation the following four stages are seen. The IIIrd stage is again divided into 4 planes.

1. Stage of Analgesia

Starts from beginning of anaesthetic inhalation and lasts upto the loss of consciousness.

Pain is progressively abolished.

Patient remains conscious, can hear, and feels a dream like state.

Reflexes remain normal.

·         Though some minor and even major operations can be carried out during this state, it is rather difficult to maintain - Use is limited to operations taking short time.

II. Stage of Delirium

From loss of consciousness to the beginning of regular respiration.

Apparent excitement is seen, patient may shout, struggle and hold his breath; muscle tone increases, jaws are tightly closed, breathing is jerky; vomiting, involuntary micturation or defecation may occur.

Heart rate and blood pressure may rise.

Pupils dilate due to sympathetic stimulation.

No stimulus should be applied or operative procedure carried out during this stage.

This phase is cut short by rapid induction, premedication, etc.

III. Surgical anaesthesia

Extends from onset of regular respiration to cessation of spontaneous breathing. This has been divided into 4 planes that may be distinguished as:

Plane 1                        Roving eye balls. T

This plane ends when eyes become fixed.

Plane 2                        Loss of corneal and laryngeal reflexes.

Plane 3                        Pupil starts dilating and light reflex is lost.

Plane 4                        Intercostal paralysis, shallow abdominal respiration, dilated pupil.

Most surgical operations are done in Plane 2 and Plane 3.  Plane 4 is never attempted.

IV. Medullary paralysis

Cessation of breathing to failure of circulation and death. Pupil is widely dilated, muscles are totally flabby, pulse is thready or imperceptible and blood pressure is very low.

PROPERTIES OF AN IDEAL ANAESTHESIA

A. For the patients:

It should be pleasant, non-irritating, should not cause nausea or vomiting.

Induction and recovery should be fast with no after effects.

B. For the surgeon

It should provide adequate analgesia, immobility and muscle relaxation.

It should not be inflammable and nonexplosive (so that hot cautery may be used).

C. For the anaesthetist

Its administration should be easy, controllable and versatile.

Margin of safety should be wide - no fall in blood pressure.

Heart, liver and other organs should not be affected.

It should be potent so that low concentrations are needed and oxygenation of the patient does not suffer.

Rapid adjustments in depth of anaesthesia should be possible.

It should be cheap, stable and easily stored.

It should not react wit rubber tubing or sodalime glass.

Dose:-

Most inhalational anaesthetics have a steep concentration - response curve. Increasing the concentration only by 1/3 over MAC makes almost all individuals immobile (at MAC only 50% of the patients are immobilized), and 2-4 MAC is often lethal.

Complications of general anaesthesia:

A. During anaesthesia

(i)     Respiratory depression.

(ii)   Salivation, respiratory secretions - less now as non-irritant anaesthetics, are mostly used.

(iii) Cardiac arrhythmias.

(iv) Fall of blood pressure.

(v)   Aspiration of gastric contents.

(vi) Laryngospasm and asphyxia.

(vii)Delirium, convulsions.

(viii)Fire and explosion.

B. After anaesthesia

(i)     Nausea and vomiting.

(ii)   Persisting sedation: impairs psychomotor function.

(iii) Pneumonia

(iv) Organ toxicities: liver and kidney damage.

CLASSIFICATION OF GENERAL ANAESTHETICS

1. Inhalation anaeshetics:

            (a) Gases:                     Nitrous oxide (N₂O)

                                                Cyclopropane

            (b) Volatile liquids       Ether

                                                Chloroform

                                                Halothane

                                                Enflurane

                                                Trichloroethylene

                                                Isoflurane

2. Intravenous anaesthetics:

(i) Inducing agents:      Thiopentane sodium

                                    Methohexitone sodium

(ii) Slower acting drugs:

                                    (a) Benzodiazepines e.g.                      Diazepam

                                                                                    Lorazepam

                                                                                    Midazolam

                                    (b) Dissociative anaesthesia e.g.          Ketamine

                                    (c) Neutoleptic analgesia i.e. Fentanyl + droperidol.

GASEOUS  ANAESTHETICS

Nitrous oxide (N₂O)

It is also called laughing gas. It is an inorganic gas, colorless and sweet in taste.

It is heavier than air. It is insoluble in blood and it does not combine with haemoglobin. It is carried in blood in the form of physical solution.

It does not decompose in the body. So the oxygen of nitrous oxide is not available for tissue respiration. It is excreted unchanged through the lungs. A small quantity may be eliminated through skin.

Advantages:

1.      Induction and recovery are quick.

2.      No irritation to mucous membranes.

3.      It can produce analgesia which can be used for minor surgery or tooth extraction.

4.      It is non-toxic to liver and kidney.

Disadvantages:

1.      It is not a potent anaesthetic.

2.      Muscle relaxation is not adequate.

3.      Special apparatus is required for its use.

4.      It produces euphoria and excitation during induction.

Cyclopropane

It is the simplest cyclic hydrocarbon. it is colorless gas with a sweet odour and taste.  

It is heavier than air.

It is rapidly absorbed and completely eliminated through lung.

A small amount is metabolized in the body and eliminated as CO₂ and water.

Advantages:

1.      Induction is quick and pleasant and recovery is smooth and rapid.

2.      Useful for major surgery like thoracic and abdominal surgery.

3.      Less-irritant to mucous membranes. So coughing and respiratory secretions are less.

4.      Does not affect blood pressure and cardiac rate.

5.      It does not produce any visceral damage.

Disadvantages:

1.      Explosive when combined with oxygen.

2.      It causes increased capillary bleeding.

3.      Produces cardiac arrhythmia and reflux bradycardia.

4.      Nausea and vomiting are produced during bradycardia.

5.      It requires complicated instruments for use.

VOLATILE LIQUIDS

Ether (C₂H₅ - O - C₂H₅) [Diethyl ether]

It is a colorless and volatile liquid with a pungent odour. It is highly inflammable and explosive. It is quickly absorbed and eliminated through lungs.

Advantages;

1.      It produces satisfactory muscle relaxation.

2.      It does not produce liver or kidney damage.

3.      It can be given by open drop (through congestion of eye, soreness of trachea and ether burns on face can occur) without the need for any equipment, and is relatively safe in inexperienced hands.

4.      It is cheap hence still popular in developing countries.

Disadvantages:

1.      It is highly soluble in blood - induction is prolonged.

2.      Unpleasant with struggling, breath holding, salivation and marked respiratory secretions (atropine must be given as premedication to prevent the patient from drowning in his own secretions).

3.      Recovery is slow.

4.      Produces nausea and vomiting during  recovery.

5.      Inflammable and explosive.

Chloroform:

It is a clear liquid with a sweet odour.

Advantages:

1.      Non-inflammable and non-explosive.

2.      Induction is rapid and pleasant.

3.      It is less irritant to mucous membranes.

4.      Does not produce capillary bleeding.

Disadvantages:

1.      It decomposes into phosgene, a poisonous gas and this can be prevented by the addition of 1% alcohol.

2.      Produces cardiac arrhythmias due to sensitization of myocardium to adrenaline.

3.      Fall in blood pressure and decrease in cardiac output are produced.

4.      It is toxic liver.

5.      Produces nausea and vomiting during recovery.

Halothane:

It is volatile liquid wit sweet odour, non-irritant and non-inflammable.

Advantages:

1.      Non-inflammable and non-explosive.

2.      It has intermediate solubility in blood - induction is reasonably quick and pleasant.

3.      It is a potent anaesthetic.

4.      Non-irritant to mucous membranes.

5.      It produces relaxation of bronchial smooth muscles and hence is helpful in asthmatic patients.

Disadvantages:

1.      Halothane causes direct  depression of myocardial contractility by reducing inter-cellular Ca++ concentration. Cardiac output is reduced with falling of blood pressure. Myocardium  is sensitized to adrenaline and may produce cardiac arrhythmia.

2.      Muscle relaxation is not adequate and analgesia is poor. (This poor analgesia and muscle relaxation and neuromuscular blockers.)

3.      It is toxic to liver.

4.      It is expensive.

Trichloroethylene

It is clear, colorless liquid with a characteristic odour.

Advantages:

1.      Induction is rapid.

2.      It does not irritate mucous membranes.

3.      It is useful for short operations and in dentistry.

Disadvantages:

1.      Muscle relaxation is not adequate.

2.      Produces cardiac arrhythmias due to sensitization of myocardium to adrenaline.

3.      Produces nausea and vomiting during recovery.

4.      It is not useful for long operations.

INTRAVENOUS ANAESTHETICS

INDUCING AGENTS

These are drugs which on intra-venous injection produce loss of consciousness in one arm-brain circulation time (approximately 11 seconds); are generally used for induction because of rapidity of onset of action. Anaesthesia is then usually maintained by an inhalation agent. They also serve to reduce the amount of maintenance anaesthetic. Supplemented with analgesics and muscle relaxants, they can also be used as the sole anaesthetic.

1. Ultrashort acting barbiturates:

E.g. Thiopentone sodium, methohexitone sodium.

These ultra short-acting barbiturates produce hypnosis, deep sleep and unconsciousness in that order. These drugs have short duration of action due to high lipid solubility rapid destruction in the liver.

Advantages:

1.      Injection produces unconsciousness in 15 to 20 secs. Its undissociated form has high lipid solubility -enters brain almost instantaneously. Other less vascular tissues (like muscles, fats, etc.); gradually takes up the drug - blood concentration falls and drug comes out from the brain. Consciousness is regained in 10 to 20 mins.

2.      Respiration is quiet and salivation is absent.

3.      Less post-anaesthetic complications.

Disadvantages:

1.      Extravenous injection or inadvertent intra-arterial injection produces intense pain - necrosis and gangrene may occur. Poor analgesic. Painful procedures should not be carried out under its influence unless an opioid or N₂O has been given, otherwise the patient may struggle, shout and show reflex changes in blood pressure and respiration.

2.      It is weak muscle relaxant.

3.      Respiratory depression with large doses is severe.

2. SLOWER ACTING DRUGS

1. Benzodiazepines

e.g. Diazepam, Lorazepam, Midazolam

Advantages:

(i)     Benzodiazepine in large dose injected i.v. produce sedation, amnesia and then unconsciousness in 5-10 minutes.

(ii)   Does not markedly depress respiration, cardiac contractility or blood pressure.

Disadvantages:

(i)     Benzodiazepines decrease muscle tone by central action but require neuromuscular blocking drugs for muscle relaxation of surgical grade.

(ii)   Relatively large dose is required.

2. Ketamine

It is a non-barbiturate general anaesthetic. It produces “dissociative anaesthesia” characterized by superficial sleep and complete analgesia. [Light sleep and feeling of dissociation from ones own body and the surroundings].

Advantages:

(i)     It is useful only for short procedures like dressing of burns and bronchoscopy.

(ii)   It does not affect respiration.

Disadvantages:

(i)     Delirium and hallucinations are produced during induction and recovery.

(ii)   Blood pressure and heart rate are increased.

(iii) Muscle relaxation is poor.

(iv) It produces laryngospasm and salivation.

3. Fentanyl-Droperidol combination

Fentanyl is a short acting (30 to 50 minutes), potent opioid analgesic related to pethidine, while droperidol is a rapidly acting potent neuroleptic related to haloperidol. When a combination of these i injected i.v a state of “neurolept analgesia” is produced, i.e., intense analgesia without unconsciousness.

This state lasts for 30-40 mins.

Patients remain drowsy but conscious and his cooperation can be commanded.

Neurolept analgesia is quite suitable for endoscopies, angiographies, burn dressing, etc. and has been used for a variety of minor surgical procedures in severely ill or otherwise poor risk patients.

PREANAESTHETIC MEDICATION

The term ‘preanaesthetic medication’ refers to the use of drugs prior to the administration of anaesthetics, so as to make anaesthesia safe and agreeable to the patient. Pre-medication aims at providing the following effects:

1.      Sedation  : To reduce anxiety of the patient before surgery. This can be achieved by sedative, hypnotics and tranquilizers. Usually morphine and its derivatives and barbiturates are given.

2.      Analgesia: achieved by morphine and pethidine. They reduce pain-sensation and also reduce the amount of general anaesthesia required.

3.      Inhibition of parasympathetic activity: so as to decrease bronchial and salivary secretion induced by drugs like ether.

SEDATIVES AND HYPNOTICS

Sedatives:- A drug that subdues excitement and calms the subject without inducing sleep, though drowsiness may be produced.

Hypnotics:- A drug that induces and/or maintains sleep, similar to normal arousalable sleep.

These are more or less general CNS depressant with differing time-action and dose -action relationships.

·         Those with quicker onset, shorter duration and steeper dose response curve are preferred as hypnotics.

·         more slowly acting drugs with flatter dose response curves are preferably used as sedatives.

·         However, a hypnosis at lower dose may act as sedative. Thus, sedation - hypnosis - general anaesthesia may be regarded as increasing grades of CNS depression. All hypnotics given in higher dose can produce general anaesthesia.

USE:    Sedatives and hypnotics are mostly used in insomnia (loss of sleep).

CLASSIFICATION OF SEDATIVES AND HYPNOTICS

1. Barbiturates: According to duration of action divided into :

Long acting	Short acting	Ultra short acting
Phenobarbitone Mephobarbitone	Butobarbitone Secobarbitone Pentobarbitone	Thiopentone Hexobarbitone Methohexitone

2. Benzodiazepines: May be divided according to their primary use:

Hypnotics	Antianxiety	Anticonvulsant
Diazepam Flurazepam Nitrazepam Flunitrazepam Temazepam Triazolam Midazolam	Diazepam Chlordiazepoxide Oxazepam Lorazepam Alprazolam	Diazepam Clonazepam

3. Miscellaneous:

            Chloralhydrate, Glutethimide, Methyprylon, Paraldehyde, Methaqualone, Meprobamate.

4. Others:

            Some antihystaminics:             Promethazine, Diphenhydramine

            Some neuroleptics:                  Chlorpromazine, Triflupromazine

            Opioids;                                   Morphine, Pethidine

            Some anticholinergics:             Hyoscine

MODE OF ACTION of Barbiturates:

N.B.

            GABA = Gama Amino Butyric Acid

            GABA_A receptors in CNS ®   produce an increased chloride conductance.

            GABA_B receptors in CNS ®   reduce the calcium currents and increase K⁺ - permeability.

The GABA-benzodiazepine-chloride channel receptor complex:

·         This is receptor complex consisting of receptor sites for GABA and BZDs. The complex contains a chloride channel. when GABA binds with its site the chloride channel opens and an inhibitory signal is propagated through the neuron.

·         When BZD binds with its site the affinity of the GABA molecules for its own site is increased and vice versa; i.e. they are allosteric sites to each other.

·         BZD binds to its own site ® Affinity of GABA to its site is increased ® Chloride channel opens ® Inhibitory signals are propagated.

·         b-carboline 3-carboxylate (b-CCE) inhibits binding of BZD ® inhibits chloride channel opening by GABA ® so convulsant action is produced and anxiety precipitates.

Two state model

Benzodiazepine exists in two distinct conformations:

(i)     Conformation A can bind GABA molecule and open chloride channel.

(ii)   Conformation B cannot remain in equilibrium.

·         When BZD-agonist (e.g. diazepam) is not present, between these two conformations, sensitivity to GABA is present, but sub-maximal.

·         BZD-agonist (e.g. diazepam) binds to conformation A

            ® shifting the equilibrium in favour of A

            ® enhances GABA sensitivity

            ® more amount of GABA binds ® chloride channel open ® inhibitory impulse.

·         BZD-inverse agonist binds selectivity with conformation B

            ® shifting the equilibrium in favor of B and

            ® reduces GABA sensitivity

            ® less GABA binds (practically do not binds) ® Cl^- channels do not open

            ® anxiety and convulsion occurs.

MOA of Barbiturates

·         Barbiturates share the same BZD-GABA-Chloride channel ion receptor complex but they bind to a different site.

·         Barbiturate potentiate GABA-ergic inhibition by increasing the life-time of Cl^-channel opening induced by GABA

            (i) Barbiturates enhance BZD binding to its receptor.

            (ii) At high concentration barbiturates directly increases Cl^-  conductance i.e. GABA-mimetic           action.

            (iii) a very high concentration depress Na⁺ and K⁺ channels also.

Pharmacology of barbiturates

Barbiturates are general, non-specific depressants of all excitable cells. CNS is most sensitive.

1  CNS

Barbiturates produce dose dependent effects:

                        sedation ® sleep ® anaesthesia ® coma

(i)      Sedative dose: (i.e. smaller dose of a long acting barbiturate) given at day time produces drowsiness, reduction in anxiety and excitability.

(ii)   Hypnotic dose (100 - 200 mg of a short-acting barbiturate) shortens the time taken to fall asleep and increases the sleep duration. The sleep is arousable, but the subject may feel confused and unsteady if waken earl. REM and Stage 3 and 4 of NREM sleep decreases.

(iii) REM ad NREM sleep cycle is disrupted. S nightmare is reduced.

(iv) Longer acting (phenobarbitone) barbiturates have high anti-convulsant action which is independent of general CNS depression.

(v)   Barbiturate depresses all areas of the CNS, but the reticular activating  system is most sensitive, its depression is primarily responsible for inability to maintain normal wakefulness.

2 Respiration

At relatively higher dose they depresses the respiration-centre in the brain.

3. CVS

hypnotic dose produce slight decrease of blood pressure(BP) and heart rate.

toxic dose produce marked fall in BP due to

            ganglionic blockade

            vasomotor center depression and

            direct decrease in cardiac contractility.

Dose required to produce cardiac arrest is 3 times larger than that required for causing respiratory failure.

4. Smooth muscles

Hypnotic dose reduces the tone and motility of muscles of intestine. Action on other smooth muscles are not significant.

5. Kidney

Barbiturates tend to reduce urine flow by

                        decrease in BP

                        increase in ADH release (Anti-Diuretic Hormone).

Dose:

Drug	Dose	(mg)	Trade Names
	Hypnotic	Sedative
Phenobarbitone Butobarbitone Pentobarbitone Secobarbitone	60 to 100 100 to 200 100 100	15 to 30 15 to 60 30 30	GARDENAL/ LUMINAL SONERYL NEMBUTAL LIPATON

Uses:

1.      As hypnotic and to control mania and delirium (N.B.) now superseded by BZDs and phenothiazines).

2.      Sedatives: as adjuncts in chronic asthma, peptic ulcer, hyper tension, thyrotoxicosis etc.

3.      Anticonvulsant: used in epilepsy. It is also used intravenously for emergency control of continuous, but has slow action. Thiopentone may be used for quick action.

4.      Anaesthetic Thiopentone given intravenously.

5.      Preanaesthetics Pentobarbitone, secobarbitone or butabarbitone - long acting barbiturates are given before the anaesthesia to calm down the patient.

6.      Congenital non-haemolytic jaundice: Phenobarbitone induces conjugation of bilirubin and hastens the clearance of jaundice.

Mainly they are used in anaesthesia and in the treatment of epilepsy.

ADVERSE EFFECTS

1. Side effects:

hangover is common after the use of barbiturates as hypnotics, because they have long plasma half-life. On repeated use  they accumulate in the body - produce tolerance and dependence. Mental confusion, impaired performance and traffic accident may occur.

2 Idiosyncrasy

In some patients barbiturates produce excitement. This is more common in the elderly patients.

3 Hypersensitivity

Rashes, swelling of eye-lids, lips etc.

4. Tolerance and dependence

Barbiturates produce a high degree of tolerance and dependence.

On repeated use both cellular and pharmacokinetic tolerance occurs.

Cellular / Tissue tolerance       Higher dose is required at the site of action to produce the same effect                                                          that was produced initially.

Pharmacokinetic tolerance      production of lower blood concentration with prolonged usage.

MOA: Barbiturates strongly induce the synthesis of hepatic cytochrome P-450 and conjugating enzymes and this increases the rate of metabolic degradation of many other drugs, giving rise to a number of potentially troublesome drug interactions.

5. Dependence

After a prolonged treatment, if the treatment is stopped then anxiety, tremor, dizziness occurs. The withdrawal syndrome is intense in human - excitement, hallucinations, delirium, convulsive disorders.