ANTI HISTAMINIC DRUGS

ANTI HISTAMINIC AGENTS

Histaminie is a beta imidazole ethylamine derivative which is present in essentially all mammalian tissues. In the living organism histamine is synthesized from the naturally occurring a - amino acid, histidine by the loss of a carboxyl group through bacterial or enzymatic decarboxylation.

Histamine is produced naturally by human system and released in response to tissue damage. In human beings, histamine cause immediate allergic and inflammatory response cause gastric acid release and function as a CNS neuro transmitter.

Systemically, histamine contracts smooth muscle of lungs and gastro intestinal system and cause vasodilatation, low B.P and increase heart rate. It causes symptoms such as itching, sneezing, watery eye and running nose.

Histamine receptors
The physiological effects of histamine are mediated by specific cell-surface receptors. These receptors are divided into three types.
1) H1- receptors
It is found in smooth muscles of intestine, bronchi, blood vessels, adrenal medulla, endothelial cell and lymphocytes. Histamine H1 receptors are G-protein linked receptors. It is sequence of 491 amino acids residue. The third and fifth membrane domain is responsible for binding histamine.
H1 - receptors mediate smooth muscle contraction, increased vascular permeability, pruritus, prostaglandin, decreased artrio ventricular conduction time accompanied by tachycardia and activation of vagal reflexes.

2) H2 - receptors:
They are located on the cell membrane of acid secreting cells of gastric mucosa and mediate the gastric acid secretary actions of histamine. The physiological effects of H2 - receptor ligands are mediated by a stimulatory G- protein coupled receptor which activates adenylate cyclase / cyclic AMP intra cellular second messenger. The TM3 aspartate and aspartate and threonine residue in TM5 is responsible for binding histamine.

3) H3 - receptors :
It is presynoptic receptor that influences the release of histamine and other neuro transmitters from neurons.
Anti Histamines
Anti histamines are drugs which inhibit the action of histamine by competitively blocking the histamine receptors.

A) HISTAMINE H1 RECEPTOR ANTAGONIST:

Classification :
I. First generation anti histamines :
1) Amino alkyl ethers: Diphen hydramine HCl, Dimenhydrinate, Bromodiphenhydramine HCl, Doxylamine succinate, Carbinoxamine maleate, Clemastine fumerate, Diphenyl pyraline HCl.
2) Ethylene diamines: Tripelennamine HCl, Pyrilamine maleate, Metha pyrilene HCl, Thonzylamine HCl, Antazoline PO4.
3) Piperazine derivatives : Cyclizine HCl, Chlorcyclizine HCl, Meclizine HCl, Buclizine HCl.
4) Propylamine derivatives (Mono amino propyl derivatives): Pheniramine maleate,
Chlor Pheniramine maleate, Triprolidine HCl, Phenindamine tartarate, Pyrrobutamine PO4, Dimethindene maleate, Dexchlorpheniramine maleate, Brompheniramine maleate, Dex brompheniramine maleate.
5) Phenothiazine derivatives : Promethazine HCl, Trimeprazine tartarate, Methdilazine.
6) Dibenzocyloheptene derivatives : Cyproheptadine HCl, Azatadine maleate.

II. Second generation H1 antagonist: Terfenadine, Astemizole, Loratadine, Cetirizine, Acrivastine.

III. Inhibition of Histamine release (Mast cell stabilizers) : Cromolyn sodium,
Nedocromil sodium.

B) HISTAMINE H2 RECEPTOR ANTAGONIST :
Cimetidine, Famotidine, Ranitidine, Nizatidine.

C) OTHER ANTI ULCER AGENTS:
Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole.

1) Amino alkyl ethers
The General formula is
(Ar)2 – CH – O – CH2CH2 N (R)2

Carbinoxamine
Doxylamine
Doxylamine Synthesis
Clemastine
Clemastine Synthesis
Diphenyl pyraline

SAR for amino alkyl ethers :

1. The aromatic group may be phenyl or substituted phenyl or heterocyclic for good antihistaminic activity.
2. P – substituted aromatic groups have good activity but O – substitution in aryl groups loss the activity.
3. Removal of a1 – methyl group and insertion of chlorine in to Para position of the phenyl ring in Doxylamine enhanced activity.
4. Substitution of 2 – thionyl for 2 – pyridyl group decreased the activities.
5. Compounds with an asymmetric carbon atom, the Dextro isomer is more active.
6. If double bond is introduced between a , b carbon atoms of the propyl chain drowsiness will be developed.

Ethylene Diamines

The General formula is

(Ar)2 N - CH2CH2 -N (CH3)2




SAR for ethylene diamines :

(Ar)2 N - CH2CH2 -N (CH3)2


1. One of the aryl group is 2 – pyridinyl system is more significant anti histaminic activity.


2. Substitution of P – methoxy (Pyrilamine), chloro (Chlor pyramine) or bromo (Brom tripelenamine) group enhances the activity.


3. The two Tertiary nitrogens are separated by two carbon chain for good activity. Extension or branching of this chain decrease activity.


4. The Tertiary nitrogen may be a part of heterocyclic ring (antazoline) also has good activity.
   
   3) Piperazine derivatives




Buclizine.HCl SAR for Piperazine Derivatives :


1. P-Substitution of any one aryl group by chlorine enhances the anti histaminic activity.


2. The both nitrogen atoms of Piperazine are aliphatic and have basicities for good activities.


3. The R- group may be methyl or aralkyl for good activity.

Propylamine derivatives

The General formula is

(Ar)2 CH CH2CH2 -N (R)2

Phenindamine

SAR for Propylamines :


1. One of the aryl group may be 2 – Pyridinyl group is more significant antihistaminic activity.


2. Introduction of chlorine in P- position of benzyl group has 20 times more potent than un substituted compounds.


3. These drugs have an asymmetric carbon atom, the Dextro isomers exhibiting the greater potency.


4. In the unsaturated derivatives, the trans isomers are more active.


5. The tertiary nitrogen may be a part of heterocyclic ring (Triprolidine) has greatest activity.

V. Phenothiazine derivatives :


Trimeprazine

SAR for Phenothiazines


1. The side chain of phenothiazines contain two or three carbon atoms, branched alkyl chain between ring system and terminal nitrogen atom gives good anti histaminic activity.


2. The phenothiazines with a 3 carbon bridge between nitrogen atoms are more potent in vitro.


3. The 30 nitrogen of side chain may be a part of heterocyclic ring also shows good activity.

6.Di benzo cycloheptanes

II. Second generation H1 antagonist:

III. Inhibition of Histamine release (Mast cell stabilizers) MECHANISM OF ACTIONFor histamine H1 antagonist :

1. H1 antagonist mainly competitively inhibit the action of histamine on tissues containing H1 receptors.
   
2. The drugs have the pharmacological actions, opposite to that of histamines and also prevent the access of histamine to its receptors by competitive antagonism.


3. Some antihistamines also antagonize serotonin and bradykinin which are released along with histamine during anaphylaxis reaction.


4. Stimulation of H1 receptors leads to an increase of the intracellular calcium concentration and hydrolysis of phosphatidylino – sitol -4,5-bis phosphate to inositol triphosphate (IP3) and 1,2 diacyl glycerol (DAG). So these histamine induced production of IP3 and DAG is antagonized by H1 receptor antagonist.


5. The increased intra cellular level of IP3 and DAG by histamine is the mobilization of intra cellular calcium.


6. Elevation of intracellular calcium level is associated with various biochemical consequences including the activation of PLC and phospholipase A2, which liberates arachidonic acid from cell membrane, leading to production of powerful mediator like prostacyline and thromboxene A2.


7. In intestine smooth muscles histamine activate the ion channels permeable to Na+ and K+ leading to depolarization and muscle contraction.


8. So the H1 antagonist competitively inhibits the histamine H1 receptor and prevent the above actions.

B) HISTAMINE H2 RECEPTOR ANTAGONIST :

SAR for H2 Antagonist :

1. Imidazole ring exist in two tautomeric forms. In these form – I to be necessary for maximal H2 antagonist activity.


2. When R is substituted with methyl group, the activity is potentiated.


3. The other heterocyclics like furan, thiazole are enhance the potency and selectivity of H2 receptor antagonism.


4. The ring and terminal nitrogen should be separated by four carbon atom for optimum activity. The shorter chain decrease the activity.


5. The side chain should contain an electron with drawing substituents and an Isosteric thioether (- S-) link in place of methylene group (- CH2) leads to more active compound.


6. The terminal nitrogen should be polar, non basic substituents for maximal activity.


7. Though a positively charged group binds more tightly to the receptor, it leads to an agonist activity rather than an antagonist activity.
   
   C) OTHER ANTI ULCER AGENTS:
   
   Mechanism of action For Histamine H2 antagonists :

1. H2 antagonists mainly antagonize the action of histamine at its H2 receptors which is responsible for acid secretion and peptic ulcer disease.


2. Mucus secreted by the gastric mucous cells combined with surface epithelial bicarbonate secretion contributes to a barrier that prevents gastric acid and pepsin from damaging the gastric mucosa.


3. The acid secretary unit of gastric mucosa is the parietal cell which contain a hydrogen ion pump, H3O+ - K+ - ATP ase system that secretes H3O+ is exchange for the uptake of K+ ion.


4. Secretion of acid by gastric parietal cells is regulated by the actions of various mediators at receptors including histamine agonism of H2 receptors.


5. Since H2 – receptor antagonists are potent inhibitors of all stimulants of gastric acid secretion, histamine may be considered as a single common final mediator of acid secretion on the parietal cells.


6. The H2 antagonists simple inhibit the direct actions of histamine on acid secretion.
   H2 antagonists also protect mucosal barriers, proton pump inhibitors, prostaglandins.

DIURETICS

DIURETICS

Diuretics are drugs that promote the output of urine excreted by kidney.

Diuretics mainly promotes the excretion of the sodium ions(Na+),chloride ions(Cl-) or bicarbonate ions(HCO3-) and water from the body, the net result being increase the urine flow. The excretion by kidney is dependent on glamerular filtration, tubular reabsorption and tubular secretion.

These drugs also act by decreasing tubular reabsorption, a process that involves the active transport of electrolytes and other solutes from tubular urine to the tubular cells and then to the extra cellular fluid and increase glamerular filtration. But the diuretics do not affect the glamerular filtration rate or the action of anti diuretic hormone (ADH) on the distal portion of the nephron.

Diuretics are very effective on the treatment of cardiac edema (extra vascular accumulation of fluid in tissues), specifically with congestive heart failure and also employed for various disorders such as nephrotic syndrome, diabetes insipidus, hyper tension, nutritional edema, edema of pregnancy, cirrhosis of liver and also lower the intracellular and cerebrospinal fluid pressure.

CLASSIFICATION

I. Carbonic anhydrase inhibitors (Site-I Diuretics)
Acetazolamide, Methazolamide, Dichlorphenamide, Disulfamide, Ethoxzolamide.

II. Thiazide and Thiazide like Diuretics (Site-III Diuretics)

Chlorthiazide, Benzthiazide, Hydrochlorothiazide, Hydroflumethiazide, Bendroflumethiazide, Trichlormethiazide, Methyclothiazide, Polythiazide, Cyclothiazide, Mefruside, Clopamide, Xipamide, Indapamide, Quinethazone, Metolazone, Clorexolone, Chlortalidone.

III. High ceiling or Loop Diuretics (Site-II Diuretics)
1. Organo mercurials – Chlormerodine mercury, Meralluride, Mercaptomerin, Merethoxylline

procaine, Mersalyl.
2. 5-Sulpamoyl & 3-Amino Benzoic acid derivatives- Bumetanide, Furosemide,
3. 4-Amino-3-pyridine sulphonyl ureas- Torsemide, Triflocin.
4. Phenoxy acetic acids- Ethacrynicacid.

IV. Potassium sparing Diuretics (Site-IV Diuretics)
1. Aldosteron inhibitors – Spiranolactone, Metyrapone
2. 2,4,7-Triamino-6-aryl pteridines – Triamterene
3. Pyrazinoyl Guanidines – Amiloride. HCl.

V. Xanthine Derivatives -

Caffeine, Theophylline. Theobromine.

VI. Miscelleneous -
Mannitol, Potassium acetate, Sodium acid phosphate, Urea.

I. Carbonic anhydrase inhibitors (Site-I Diuretics)

Structure Activity Relationship for CAI

1. The free sulfamoyl nitrogen is important for diuretic activity. The mono and Di substituents at SO2NH2 abolish the activity.


2. Substitution of the methyl group on one of the ring nitrogen (Methazolamide) retains the activity.


3. The heterocyclic sulphonamides have highest lipid/water partition coefficient and lowest pKa values have greatest CA inhibitory and diuretic activity.


4. The benzene meta sulphonamide derivatives have activity only when substituted with chlorine or methyl groups.

Mechanism of action of CAI

Carbonic anhydrase found in many sites such as renal cortex, eye, CNS, gastric mucosa, and pancreas. This enzyme catalyses the reversible hydration of CO2 to carbonic acid.
CO2 + H2O --------H+ + HCO3-

The diuretics inhibit the Carbonic anhydrase enzyme at the proximal convoluted tubules cause reduction in H+ ions for Na+-H+ exchange CO2 reabsorption from glamerular filtrate is suppressed and HCO3- excretion is increased and facilitates K+ secretion.

Due to decreased Na+ reabsorption, the Na+-H+ exchange in distal convoluted tubule increases cause loss of K+ in urine. To maintain ionic balance Cl- is retained by kidney and decreased diuresis. So they are weak diuretics.

II. Thiazide and Thiazide like Diuretics (Site-III Diuretics)

Synthesis of Hydrochlorthiazide

Structure Activity Relationship for Thiazides

1. Thiazides having benzothiadiazine 1,1-dioxide with weakly acidic character is important for good activity.


2. Presence of electron withdrawing group at C-6 is necessity for good diuretic activity. Substitution of chlorine at C-6 has good activity.


3. Substitution of CF3 group has more lipid soluble and larger diuretic action than Chloro compound.
4. Presence of electron releasing groups like methyl or methoxy at C-6 reduces the diuretic activity.


5. Removal or replacement of sulphonamide at C-7 reduces the diuretic activity.


6. Saturation of double bond between 3&4 having 10 times more diuretic activity than unsaturated analogue.


7. Introduction of lipophilic groups such as aralkyl, halo alkyl, thioether enhances the diuretic activity and increase the duration of action.


8. Alkyl substitution at N2 lowers the polarity and enhances the duration of action.

Mechanism of action of Thiazides.
These drugs blocks the reabsorption of Na+, Cl- exchange in the distal convoluted tubule by inhibiting the luminal membrane-bound Na+/ Cl- co transport system.

As a result of these drugs act on site-III, alter the renal excretion rate of important ions other than sodium. Inhibition of sodium reabsorption at site-III ultimately results in the delivery of more of the filtered load of sodium at a faster rate to site-IV.

So there is an enhanced exchange of luminal fluid sodium for the principal cell potassium and an increase in the urinary excretion rate of potassium follows.
Long term use of these agents leads to reduction in calcium excretion.

III. High ceiling or Loop Diuretics (Site-II Diuretics)

Structure Activity Relationship for Loop diuretics

1. 5-sulfomoyl and 2-aminobenzoicacid group is required for good diuretic activity.



2. Substitution at 1st position must be acidic for good diuretic activity.


3. The activating group at 4th position can be Cl or CF3 group increases the activity.


4. Phenoxy, alkoxy, anilino, benzyl or benzoyl groups substituted at 4th position decreases diuretic activity.



5. Furfuryl,benzyl and thienyl methyl group at 2-position increases the activity.

Mechanism of action of Loop Diuretics

1. The diuretics inhibit the Na+/K+/ Cl- cotransport system located in the luminal membrane of cells in the limb of Henle’s loop.
2. The carboxylate moity is responsible for their competing with Cl- for the Cl- binding site on Na+/K+/ Cl- cotransport system.
3. These drugs inhibits the reabsorption of 20-25% of the filtered load sodium at site-II with in minutes and the net result is that when Na+&Cl- are not reabsorbed at site –II. So large amount of water, sodium and chloride are excreted.
4. These diuretics increase the flow rate of luminal fluid past the macula densa cells, the expected reduction in GFR does not occur.
5. These drugs blocks the reabsorption of K+at site-II by inhibiting the Na+/K+/ Cl- cotransport complex.
6. These may induce the renal excretion up to 20-30% of the filtered load calcium.

IV. Potassium sparing Diuretics (Site-IV Diuretics)

Mechanism of action of Spiranolactone

It inhibits the reabsorption of 2-3% of the filtered load sodium at site-IV by competitively inhibiting the action of aldosterones.

So the passage of luminal fluid sodium in to and potassium, Hydrogen ions out of the late distal convoluted tubule and the early collecting tubule cell is enhanced. So they enhance the water, sodium and chloride excretion.

Mechanism of action of Triamterene& Amiloride
These drugs plugs the sodium channels in the luminal membrane of the principal cell at site-IV and there by inhibits the electrogenic entry of 2-3% of the filtered load sodium in these cells.

It decrease the antiluminal membrane bound Na+/K+-ATP ase activity, leads to decrease in cellular extusion of sodium and in the cellular uptake of potassium at site-IV.

LOCAL ANESTHETICS

LOCAL ANESTHETICS

Local anesthetics are mainly used to produce loss of sense of pain in particular area of the body. They act by blocking both sensory and motor nerve conduction to produce a temporary loss of sensation with out a loss of consciousness.

Local anesthetics are drugs with reversibly prevent the generation and propagation of active potentials in all excitable membranes including nerve fibres by stabilizing the membrane.
They are administered locally in correct concentration; block the nerves that carry the pain sensation and automatic impulses in local areas of the body.

Local anesthetics are used in dentistry, ophthalmology and minor surgical operations including endoscopy. They are also used topically for temporary relief of pain insect bites, burns wounds.

On the basis of method of administration and sites of action of the anesthetics agent, they are in different types.

Surface or Topical Anaesthesia : - The local anaesthic is applied directly to the mucosal surface damaged skin surface, wounds or burns to relief pain or itching. It must be able to penetrate tissues readily. Example – Lignocaine.

Infiltration Anaesthesia:- The drug is injected subcutaneously to paralyse the sensory nerve endings around the area with is to be anaesthetized.

Example – An area to be incised or for tooth extraction –(Prilocaine).

Nerve block Anaesthesia:- The local anesthetic is injected as close as possible to the nerve trunk supplying the specific area to be anaesthetized. This block conduction is both sensory and motor fibres.

Spinal Anaesthesia:- The drug is injected subarachnoid space and is to cerebrospinal fluid to paralyse the roots of spinal nerves. It is used to induce anesthesia for abdominal or pelvic surgical operations.

Epidural Anaesthesia:- The drug is injected in to epidural space and the root of spinal nerves are anaesthetized. It is mainly used for painless childbirth.

Caudal Anaesthesia:- It is similar to epidural anesthesia where the injection is made through sacral hiatus in to the vertebral canal which contains cauda equina. It is used for operation on the pelvic viscera.

Classification

1. Naturally occurring local anaesthetic:- Ex- Cocaine (ester).


2. Esters: -
   a) P-aminobenzoic acid derivative (PABA)- Benzocaine, Procaine, Tetracaine, Butacaine, orthocaine, Benoxinate.
   b) Esters of benzoic acid- Meprylcaine, Cyclomethycaine,(propoxycaine), Hexylcaine, Piperocaine.


3. Amides or Anilides :- Lignocaine, Prilocaine, Mepivacaine, Bipivacaine, Pyrrocaine, Etidocaine, Diperodone.


4. Piperidine or Tropane derivatives :-Alpha- Eucaine, Benzamine, Euphthalmin.


5. Quinoline derivatives :- Dibucaine (Chincocaine)


6. Isoquinoline derivative:- Dimethisoquine.


7. Miscelleneous :- Phenacaine (Amidine), Pramoxine, Euginol, benzyl alcohol, Phenol, Dyclomine, Saligenin.

Esters of P-Amino Benzoic acid

Benzocaine
Butacaine
Benoxinate
Propoxycaine

Esters of Benzoic acid Derivative

Meprylcaine

Amide and Anilides


Etidocaine

Quinoline Derivatives

Miscelleneous

SAR for local anaesthetic containing ester linkage

General Structure :

Aryl – CO – X - Amino alkyl Chain

1. The aryl radical attached directly to the carbonyl group enhances local anaesthetic activity. It is lipophilic centre of compound.
2. Alicyclic and aryl aliphatic carboxylic acid esters are also active local anaesthetics.


3. The compounds containing aryl-vinyl group (Ar-CH = CH -) does not having local anaesthetic activity, because of the mesomeric effect of aryl radical does not extend to carbonyl group.
4. The aryl substituents such as alkoxy, amino and alkyl amino groups at ortho or para position increases electron density of carbonyl oxygen enhances the activity.


5. The number of methylene groups is substituted to aryl moiety; the maximum activity is achieved for the C4 to C6 homologues.


6. The bridge X may be carbon, oxygen, nitrogen or sulphur. The nature of X affects duration of action and relative toxicity. The conduction anaesthetic potency decreases in the order of S, O, C and N.


7. The amino alkyl group is the hydrophilic part of molecule. The local anaesthetic activity decreases and irritation property increases in the following order. 10 <>


8. In general amino alkyl group is not necessary for activity, but it is used to from water soluble salts. Example : Benzocaine.


9. Local anaesthetic activity improves if the aryl lipophilic center has electron donor substitution but decreases with electron acceptor substituents

SAR for local anaesthetic containing an amide linkage

1. The alkyl substitution (-CH3) in aryl group at ortho or Para position enhances the activity by providing steric hindrance to the hydrolysis of amide linkage and contributes lipid solubility.


2. In general X may be carbon (Isogramine), oxygen (lidocaine) (or) nitrogen (Phenacaine) for good activity.


3. The relative activity of amino alkyl group is similar to the ester linkage containing compounds.

Mechanism of action

1. It sufficient number of sodium channels are blocked, there would be no significant charges in membrane potential and so the conduction of an action potential along the neuron would be prevented.
2. Blocking of conduction would automatically prevent the release of neuro transmitter at the presynaptic site.
3. Increasing the concentration of calcium ions of the extra cellular fluid may enhance or reduce the activity by affecting the opening of sodium channels.
4. Local anesthetic containing both lipophilic and hydrophilic groups may penetrate the excitable cells and decrease the excitability which associated with membrane of sodium ions across the membrane. Therefore local anesthetic interfere with sodium movements and interferes with excitability of cells.
5. The local anesthetic activity is dependant on its entering the channel from inside the neuron.

DRUGS ACTING ON CNS- CNS STIMULANTS AND PSYCHEDELICS

CNS STIMULANTS AND PSYCHEDELICS

The drugs that produce stimulation of central nervous system and enhancement in excitability of different portions of the brains or the spinal cord.

The CNS stimulants include analeptics, antidepressants, central sympathomimetic agents (Psychomotor stimulants). Some times CNS stimulants lead to convulsions so they are limited therapeutic value because of their convulsant activities and side effects.

Classification :

1. Analeptics – Picrotoxin, Nikethamide, Etamivan, Pemoline Pentylene t e t r azole( Pen tetrazole), Doxopram, Bemegride, Strychnine.


2. Methyl xanthines – Caffeine, Theophylline, Theobromine, Aminophylline, Etophylline, Proxyphylline.


3. Central sympathomimetic agents ( Psychomotor stimulants) –
   Amphetamine, Methamphetamine, Phentermine, Benz phentamine, Chlorpentermine, Ferfluramine, Chlortermine, Phenmetrazine, Phendimetrazine, Mazindol, Methyl phenidate.


4. Mono amino oxidase Inhibitors (MAO – inhibitors) – Phenelzine, Isocarboxazid, Tranyl cypromine, pargyline, clorgyline.


5. Tricyclic Antidepressants – Imipramine, Desipramine, Amitryptyline, Nortriptyline, Protriptyline, Trimipramine, Doxepin, Maprotiline.


6. Psychedelics –
   1. Indole ethyl amines – Bufotenine, Psilocybin, Psilocyn
   2. 2 – Phenyl ethylamines – Mescaline
   3. Agents have both indolethylamine and phenyl ethylamine – (+) Lysergic acid, Diethylamide (LSD).
   4. Dissociative agents – Phencyclidine (PCP)
   5. Depressant - Intoxicant – Tetra hydro cannabinol (THC)

I.Analeptics:

Analeptics are agents which stimulate various areas of the central nervous system. These are mainly used for the treatment of respiratory depression resulting from overdose of depressant drugs. So these are used as respiratory stimulants.

An excessive dose of analeptics may result a wide – spread stimulation of the brain that may ultimately cause convulsions.

Mechanism of action for analeptics

1. Some drugs block post synaptic inhibition (Strychmine) or pre synaptic inhibition (Picrotoxin).


2. Some drugs acts as GABA ontagonist (Picrotoxins bemegride) or release prostoglandin and also decrease energy levels (rentetrazole)
   

Nikethamide Synthesis

Doxapram Synthesis

II.Methyl Xanthines

III. Psychomotor Stimulant

Dextro amphetamine Synthesis


SAR for central sympathomimetic agents :

1. Any decrease in distance between aromatic ring and heterocyclic nitrogen decrease the activity.
2. The branched CH3 group or similar substitution is important for activity, since it provides resistance to enzymatic is activation by steric protection of the amino group.
3. In phenidate series, activity is maximal at the methyl ester.
4. In morpholine series aromatic substitutions and replacement of ring by heterocyclic groups decrease the activities.

Mechanism of action

1. They inhibit reuptake mechanisms for several biogenic amines.


2. They enhance neuronal release of catecholamines.


3. They stimulate a - adrenergic receptor and inhibit mono amino oxidase is higher concentration.

IV.Mono amino oxidase Inhibitors

Tranyl Cypromine

SAR for mono amino oxidase inhibitors

1. Cyclo alkyl substituents has equal potency with corresponding N- alkyl group Di alkyl substituted hydrazine (R2NNH2) devoid of significant activity.
   
2. Hydroxyl alkyl hydrazines are usually less effective MAO inhibitors than the corresponding alkyl hydrazines.
   
3. Aromatic ring substituents with polar groups decrease the activity Un substituted hydrazides (RCONHNH2) do not inhibit MAO.
   
4. Mono substituted hydrazides may enhance MAO inhibitory activity.

V. Tricyclic Anti depressant

Imipramine

Desipramine

Amitriptyline

Doxepin


SAR for Tricyclic Antidepressants

1. The maximum antidepressant activity results on separation of the basic amino group from tricyclic nucleus by propylene bridge. The chain exceeding propyl group decrease activity.
   
2. 3 – chloro derivative has less active than imipramine.
   
3. O-(CH3)2 derivative has equal potency.
   
4. Nuclear di substitution decreases the activity.
   
5. Piperazine propyl derivative are found to be ineffective
   
   For Dibenzo Cyclopentane derivatives

1. 3 – Cl substitution enhance potency while a 3-CH3 group diminish CNS depressantDouble bond between 10 &11 positions increases activity
   
2. The higher central ring homologue (octane) is more effective.
   
3. At position 11 the carbon is substituted by O,S,SO are clinically effective anti depressant
   The bridged central ring also possess power full anti depressant activity.
   
   VI. Psychedelics

Psychedelics are agents which producing an increased awareness and enhanced perception of sensory stimuli. These are mind expanding drugs.

These drugs can produce anxiety, fear, panic, hallucinations resembling to a psychosis. Hence they are called as hallucinogens and psychoto mimetics.

Indole ethyl amines
2 – Phenyl ethylamines
Agents have both indolethylamine and phenyl ethylamine



Dissociative agents – Phencyclidine (PCP)

Depressant - Intoxicant – Tetra hydro cannabinol (THC)

Mechanism of action of Psychedelics

1. They induce or accelerate the production of hallucinogenic metabolites for noradrenaline.
   
2. They may cause charges in cerebral blood flow and permeability of cerebral capillaries.
   
3. They alters the levels of adrenal corticoidal and thyroid hormones or changes in synthesis or metabolism of serotonin, nor epinephrine, acetyl choline or other potential transmitter.
   
4. Since serotonin is an inhibitors neurotransmitter, the removal of its inhibition could lead to behavioral changes.
   
5. These drugs may disrupt cerebral energy production or utilization in such a fashion that it alters the behaviours.

DRUGS ACTING ON CNS-ANTI CONVULSANT DRUGS

ANTI CONVULSANT DRUGS (OR) ANTI EPILEPTIC DRUGS

Epilepsy is a collective term for a group of chronic CNS disorders having in common, sudden and transitory seizers of loss or disturbance of consciousness with characteristic body movements (convulsions) and some times with autonomic hyperactivity.
The principal types of epilepsy are
1. Grandmal epilepsy:
It is normally characterized by complete loss of consciousness followed by transient muscular rigidity and clonic convulsions in all voluntary muscles.
2.Petitmal epilepsy :
It is usually momentary loss of consciousness. There is free of convulsions and occasionally blinking movements of eyelids and jerking movements of the head and arms.
3.Psychomotor epilepsy :
It is characterized by attacks with out convulsions lasting from 2-3 mts. It display mental apathy and sudden irrational and destructive attitude.
4.Myoclonic seizers :
It is characterized by jerky muscular movements of head, limbs or body as such. The duration of attack remains near about one second and reappears at about 5 secs intervals for 1 min. It is rapid rhythmic movement.
Anti Convulsants:
Anti Convulsant drugs are also termed as antiepileptic drugs are drugs which selectively depress the CNS and prevent or control the epileptic seizers.
The drugs are adequate and impressive control and management of CNS disorders essentially characterized by recurrent transient attacks of disturbed brain function which ultimately give rise to motor(convulsive), sensory(seizures) and psychic sequence of events.

CLASSIFICATION

1. Barbiturates – Phenobarbital, Mepho barbital, Metharbital


2. Hydantoins – Phenytoin, Mephenytoin, Ethotoin


3. Oxazolidine dione - Trimethadione, Paramethadione


4. Succinimides – Phen suximide, Methsuximide, Ethosuximide


5. Urea derivatives – Phenacemide, Carbamezepine


6. Benzodiazepines – Clonazepam, Diazepam, Chlorazepate


7. Miscellaneous – Primidone, Valproic acid, Gabapectin, Felbamate.
   

1. BARBITURATES

2. HYDANTOINS

Synthesis of phenytoin

3.OXAZOLIDINEDIONES

Synthesis of Trimethadione

4. SUCCINIMIDES

Synthesis of Ethosuximide

5.UREA DERIVATIVES

i. Phenacemide

2.Carbamazepine

6. BENZODIAZEPINES

Clonazepam

7. MISCELLANEOUS

i.Pyrimidone

ii. Valproic acid

Structure Activity Relationship

For Barbiturates

1. Phenyl or other aromatic substituents at 5th position is essential for good activity.


2. 5,5 diphenyl derivative has less active than phanobarbitone.


3. N-substitutions also increases the antiepileptic activity.


4. 5,5-dibenzyl barbiturates causes convulsions.

For Hydantoins

1. Phenyl or other aromatic substituents at 5th position is essential for good activity.


2. Alkyl substitution at 5th position may contribute to sedation.


3. Some Thio hydantoins, Dithio hydantoins and 1,3-disubstituted hydantoins exhibit activity against chemically induced convulsions and ineffective against electroshock induced convulsions.

For Oxazolidine diones

1. The nature of substituents at 5th position is essential for good activity.


2. The lower substituents tend towards anti-petitmal epileptic activity and aryl towards anti-grandmal epileptic activity.


3. N-alkyl substituents does not affect the activity, because the N-dealkylated metabolites are active anticonvulsant agents.


4. Alkylation of imido nitrogen is more active, because it increase partition coefficient and prevent the dissociation of imido nitrogen and more distribution to CNS.

For Succinimides

1. Meth suximide and phen suximide have phenyl substituents at 3rd position are active ineffective against electroshock induced convulsions.


2. N-methylation decreases the activity against electroshock induced convulsions and more activity against chemically induced convulsions.


3. Alpha-methyl alkoxy phenyl succinimides and alkoxy benzyl succinimides were active anti convulsants.

For Benzodiazepines

1. The electron withdrawing groups at 7th position increases antiepileptic activity and electron donating groups at 7th position increases antiepileptic activity.


2. A phenyl group at 5th position is necessary for good activity. But the halogen substituents in phenyl group in ortho position increase the activity.


3. The electron withdrawing groups at ortho or diortho positions at 5-Phenyl group increases antiepileptic activity while any substituent on meta or para position of 5-Phenyl group decreases antiepileptic activity.


4. Methyl substitution at 1st position increases the activity.

Mechanism of action

1. The generation of seizures is due to excessive discharge of neurotransmitter in CNS.The anti convulsant drugs increase the level of serotonin in brain which causes non specific depression of CNS functions and controls the release of neurotransmitters.


2. Gama Amino Butyric Acid(GABA) levels in brain is also important to prevent the speed of seizures. So anti convulsant drugs increase the level of GABA in brain.


3. Anti convulsant activity of barbiturates is attributed to their ability to exert conformational rearrangement of oxidative enzymes essential for brain respiration.


4. Many carbonic an hydrase inhibitors have Anti convulsant activity by decreasing the cerebral respiration due to excess Co2 depress the nerve function.


5. Anti convulsant drugs usually display various combined activities on the neuronal function such as act on ion channels and maintain the neuronal membrane, the resting potential having range of -50 mv to -80 mv between inside (K+) and outside (Na+ & Cl-) of the cell.


6. GABA binds to GABA A and GABA B receptors. The oscillation rhythms in epilepsy caused by GABA A receptors. Therefore the drugs potenciate GABA mediated inhibitors or to affect the GABA concentration in brain.
   
   
   

DRUGS ACTING ON CNS- ANTI PSYCHOTICS

ANTIPSYCHOTICS [TRANQUILIZERS (OR) NEUROLEPTICS]

Antipsychotic drugs are also CNS depressants. Anti psychotic drugs are drugs which are used in the treatment of mental disease that are characteristic of the psychoses which is a behavioral disorder.
These agents have the capacity to sedate or tranquilize the emotional expressions , aggressive and impulsive behavior and influence being free to mind from disturbance and thus calms the mind with out inducing sleep.
Psychosis: The psychoses are inhibition of sharpens or alter the behavioral, mood and emotional responses.
Psychiatric illness can be divided in to neuroses and psychoses.
A neurotic patient usually retains sufficient insight to realize that he is ill. But the psychotic patient have difficulty understanding reality and their own conditions, they lives in a world of his own. They are often hallucinations and delusions (paranoid in nature), thought disorders and with drawel from social contacts and flattering of emotional responses.

The most important types of psychosis are
i) Schizophrenic :
It is neurological as well as psychological disorder. So fundamental and characteristic distortions of thinking and perception.
ii) Affective (mood) disorders :
Disorders in fundamental disturbance is a change in mood to depression associated by a change is the overall activity
iii) Organic psychosis :
Mental disturbances caused by head injuries, alcoholism, or other kind of organic diseases.

Classification :

1. Rauwolfia alkaloids : Reserpine, deserpidine
2. Phenothiazine derivatives : Chlorpromazine hydrochloride, Triflupromazine, Thioridazine hydrochloride, Mesoridazine hydrochloride, Piperacetazine hydrochloride,Prochlorperazine maleate, Trifluoperazine hydrochloride.
3. Ring analogues of phenothiazines :
   i) Thioxanthines – Chlorprothixene, thiothixene
   ii) Dibenzoxazepines – Loxapine succinate
   iii) Dibenzodiazepines – Clozapine
4. Butyrophenones : Haloperidol, Droperidol, Resoperidone
5. Diphenyl methane derivatives : Pipradrol, captodiame, Hydroxyzine, benactyzine
6. beta - Aminoketones : Molindone, Ondansetron
7. Benzamides : Sulperide, Remoxipride.
8. Miscellaneous : Buspirone, Meprobamate, Tybamate

Phenothiazine derivatives :

Synthesis of chlorpromazine:

Synthesis of prochlorperazine:

Ring analogues of phenothiazines :

1. Chlorprothxene

2. Thio thixene

3. Loxapine succinate SAR for Phenothiazine derivatives :

I. Modification in tricyclic systems :

1. Most of the compounds have either a six membered central ring (6-6-6)
   (Example : phenothiazine) classes for good antipsychotic activity.
   
2. Compounds having larger central ring Example : Imipramine (7 membered) and smaller central ring Example : carbazole (5 membered ring) are lack in antipsychotic activities and produce only antidepressant activity.
   
3. Analogues of tricyclic compounds that lock a central ring (Example :Rimozide) generally devoid of antipsychotic activity.

II. Modifications of alkyl side chain at R10 :

1. The maximum potency is obtained when the nitrogen of phenothiazine and basic amino group is connected by a three carbon side chain, because it permits maximum resemblance with that of most preferred conformational form of dopamine.
   
2. Introduction of methyl group at position 1, 2 or 3 of 3 – amines propyl side chain decrease the antipsychotic activity and may result Imipramine like activity.
   
3. If the side chain may be cyclopropane ring decrease neuroleptic activities and produce potent imipramine like activity.
   
4. If oxygen is introduced in to the 1st position of 3 – amino propyl chain results potent anti depressant activities (example : Chlorthiazine).
   
5. Bridging of position 3 of side chain to position 1 of phenothiazine nucleus reduces neuroleptic activity.

III. Modifications of basic amino group :

1. Maximum neuroleptic potency is obtained in amino alkyl substituents having 30 amines group than 20 and 10 amines group containing compounds.
   
2. Alkylation of basic amino group with groups larger than methyl group decreases neuroleptic potency. Example : Diethylamine analogues.
   
3. Replacement of dimethylamine group with Pyrrolidine, morpholine groups decreases the neuroleptic potency.
   
4. The activity is retained or increased if the amino group is replaced with piperidyl or Piperazine groups. Example : Mesoridazine, carphenazine.
   
5. Bridged piperidine derivatives retains the neuroleptic activities.
   
6. Introduction of hydroxyl , methyl, hydroxy ethyl groups of piperidine and Piperazine moieties increase the potency.
   
7. N4-Piperazine substituents with phenyl ethyl, p – amino phenyl ethyl or estirified long chain fatty acids increases the activity.

IV. Phenothiazine ring substituents at R2 :

1. Substituents at position 2 is optimal for neuroleptic potency, In general, potency increases in the following order of position of ring substitution 1<>
   
2. 2 – substitution is an electron withdrawing group increases the neuroleptic activity, the potency increases in the following order OH <>
   
3. Oxidation of sulfur at 5 – position decrease the neuroleptic activity.


4. 1,2,3,4 – Azo phenothiazines are more effective. 1-Azo phenothiazine is more potent than parent compound. Example: Prothioperdyl.

Butyrophenones :

1. Haloperidol

2. Droperidol 3. Risoperidone

SAR for Butyro phenone derivatives :

1. The 4- fluro phenyl group is necessary for optimal anti psychotic activity.


2. Reduction of carbonyl group and replacement of oxygen, sulphur or sulphone decreases the neuroleptic potency.


3. The bridge between benzoyl and amino group is propyl for good activity. If lengthening, shortening or branching the propylene chain of 4-amino Butyrophenones decreases neuroleptic potency.


4. The amino group is in tertiary form or part of six membered ring like piperidine, Piperazine for good neuroleptic activity.


5. Replacement of six membered ring by larger, smaller or uncyclized diminishes neuroleptic potency.


6. Neuroleptic potency is generally associated with 4,4- disubstituted piperidine. Substitution of 2 or 3 position of piperidine decreases potency

Mechanism of action

1. The neuronal activity in brain is mediated by neuro transmitter. Dopamine is a precursor of adrenaline and nor adrenaline and also function independently as a neurotransmitter. The dopamine have been found in thalamus, hypothalamus and basal ganglia and has depressant action.


2. The control of emotional responses, the hypothalamus is closely associated with reticular and limbic system which incorporates a balanced complex of excitatory(acetyl choline) and inhibitory (dopamine) components.


3. The psychoses associated with the presence of dopamine is greater than the normal level at central synopses in striatum and other brain regions.


4. The anti psychotic drugs act by increasing metabolic rate of dopamine or blocking dopamine (D2) receptors. This results an increasing concentration of excitatory (acetyl choline) and decreasing concentration of inhibitory (dopamine) components.


5. Since anti psychotic drugs shift the balance in favour of acetyl choline. Hence all the anti psychotic drugs are always associated with extra pyramidal effect.


6. The superimposibility of the conformations of dopamine ad phenothiazine derivatives blocks the dopamine receptors, because it possess 3 carbons in side chain separating two nitrogens.

DRUS ACTING ON CNS - Sedatives and Hypnotics

ANXIOLYTICS, SEDATIVES AND HYPNOTICS

These drugs are under the category of CNS depressants.
Sedatives are drugs which decreases activity and excitement of the patients and calm the anxiety by producing mild depression of CNS with out causing drowsiness or sleep.

Hypnotics are drugs which produce drowsiness and induce sleep resembling to natural sleep by depressing CNS.

Anxiolytics are also called as minor tranquillizers which are used in treatment of psychotic disorder by depressing CNS. They are used to treat abnormalities of mental functions.

The various sedatives and hypnotic agents are also employed as :
i) Antianxiety agents in emotional strain and chronic tension ii) Anticonvulsant
iii) Muscle relaxants iv) General anaesthetic v) Potentiation of analgesic drugs
vi) Adjuvants to anesthesia vii) In hyper tension

Classification :

I. Barbiturates:-

1. Long acting barbiturates (More than 8hours) – Barbitone, Barbital sodium,
Phorobarbital, Mephobarbital
2. Intermediate acting barbiturates (4 - 8hours) – Allo barbital, hexobarbitone,
pento hexital sodium
3. Short acting barbiturates (less than 4 hours) – Seco barbitone, hexobarbitone,
Pento barbitone, cyclo barbitone
4. Ultra short acting barbiturates ( I-V anaesthetics) – Thiopental sodium.

Metho hexital sodium

II. Benzodiazepines -

Diazepam, Chlordiazepoxide, oxazepam, chlorazepate dipotassium, prazepam,

Lorazepam, Halazepam, Flurazepam, Alprazolam, Triazolam

III. Amides and Imides –

Glutethimide, methyprylon, methaqualone

IV. Aldehydes and their derivatives –

Chloral hydrate, Paraldehyde, Triclofos sodium

V. Alcohol and their carbamate derivatives –

Ethinamate, Meprobamate

VI. Miscellaneous –

Antihistamines, KBr, Morphine, Pethidine

I.Barbiturates

Barbiturates are cyclic diurides which are the derivative of barbituric acid( 2,4,6 tri oxo hexahydro pyrimidine). As such barbituric acid has no CNS depressant activities. But substitution at 5th position by alkyl or aryl groups confers sedative and Hypnotic activity.
barbituric acid or barbiturates are prepared from malonic acid or its esters.

1.Barbital (Barbitone sodium)

2.Pheno barbitone

Structure-activity relationship of barbiturates (SAR):

1. Barbituric acid itself does not possess any sedative and hypnotic activity. The sedative
   or hypnotic activity is produced when the two active hydrogen atoms at position 5,5
   have appropriate substituents by alkyl or aryl groups.
2. The total number of carbon atoms present in two groups at 5th position must not be less
   than 4 and more than 10 for their optiomal activity.
3. Only one of the substituents may be a closed chain for good activity
   (Example : Hexobarbital, Cyclobarbital, Phenobarbital)
4. The branched chain isomer exhibits greater activity and shorter duration. The drug
   having greater branching is more potent (Example : Pento barbital, amobarbital).
5. Double bonds are present in alkyl substituents groups produce compounds more
   readily to tissue oxidation. Hence they are short acting (Example : Seco barbital) .
6. Stereo isomers have appropriately same potencies.
7. Aromatic or alicyclic substituted analogues are more potent than the corresponding
   aliphatic analogues having same number of carbon atoms.
8. Short chain at carbon 5 resists oxidation and hence long acting .Long chains are readily
   oxidized and thus produce short acting (Example : Barbital, Pentobarbital, Seco barbital)
9. Introduction of halogen atom is to 5 – alkyl substituents increases potency
10. Introduction of polar groups (OH, NH2, COOH, SO3H, CO, RNH) is to 5 – alkyl or
    aryl substituents decrease lipid solubility and Potency.
11. Alkylation at 1 or 3 position enhances onset and reduce duration of action
    (Example : Hexobarbital).
12. Replacement of oxygen by sulphur at 2 – carbon (thio barbiturates) shortens on set and duration of action due to increased lipid solubility. But more sulphur at C4SC6 decrease the activity (Example: Thio pental)

Mechanism of action

1. Barbiturates either have a Gam amino butyric acid (GABA) like action or enhance the effect of GABA, an inhibitory transmitter.
2. The effects of barbiturates on synaptic transmission are caused by an alteration of post synaptic sensitivity of the neurons to excitatory and inhibitory transmitters.
3. When GABA receptors are activated, chloride channels are open and chloride enters the cell, hyper polarizes it and produces decreased excitation.
4. Barbiturates bind to picrotoxin site of GABA receptor and decrease chloride ion flux and produce an increased chloride ion concentration.
   They may interfere with the passage of impulses from centers in hypothalamus to the cortex.

Benzo diazepines:

Bendiazepines and their derivatives are mainly used for sedative, hypnotic, tranquillizer, muscle relaxant and anti convulsant.
1. Diazepam

Synthesis of Diazepam

2.Chlor Diazepoxide

Synthesis of Chlor Diazepoxide

3. Oxazepam

4. Chlorazepate Dipotassium 5. Lorazepam

6.Halazepam

7.Flurazepam
8. Alprazolam

Structure-Activity Relationship Of Benzo Diazepines

1. All Benzodiazepines are used as CNS depressant are usually substituted with a 5-aryl or 5- cyclo hexenyl groups .
2. The substituents present in position 1 to 3 does not affect the activity.
3. The N(4) usually substituted with a low electron density group.
4. The electron with drawing group present in the position 7 is required for hypnotic activity. Position 6,8 & 9 should not be substituted.
5. A phenyl group at 5th position promotes the activity. An electron withdrawing group in ortho or di ortho position increase the activity. (Eg. Lorazepam, Flurazepam)
6. If 4,5 double bond is saturated or shift to 3,4th position decrease the activity.
7. Alkyl substitution at 3rd position decrease the activity.

Mechanism of action

1. The mid brain reticular activating system which is responsible for the maintenance of a wakefulness is depressed by benzodiazepines.
2. The anti anxiety activity of benzodiazepines may be attributed to the depressant action of these drugs on the mechanism which evoke anxiety and aggression.
3. Like GABA, the benzodiazepines cause either pre synoptic or post synoptic inhibition in poly synaptic neuronal pathways in CNS, affecting the various turnover of various neurotransmitters in the brain, therefore interfere the transmission process.
   

Trichlofos sodium