ANTI INLAMMATORY AGENTS(NSAID)

ANTI INFLAMMATORY AGENTS
Inflammation may be defined as the series of changes that occur in living tissues following injury.
The injury which is responsible for inflammation may be variety of conditions such as

1. Physical agents like UV radiation, heat, mechanical trauma.
2. Chemical agents like organic and inorganic compounds.
3. Toxins of various bacteria, intracellular replication of virus.

In old days some steroids like prednisolone, dexamethasone, betamethasone, triamcinalone and hydrocartisone were used as anti inflammatory agents. But these drugs produce some adverse effects. But nowadays much safer and better tolerated Non Steroidal Anti Inflammatory Drugs (NSAID) are used.
The non narcotic analgesics are having the following groups.

1. Analgesics which relieve the pain without interacting the opioid receptors.


2. NSAID which possess anti inflammatory property.


3. Anti pyretic which reduce the elevated body temperature.

CLASSIFICATION
1. Salicylic acid derivatives :
Sodium salicylate, Sodium thio salicylate, Magnesium salicylate, Choline salicylate, Carb ethyl salicylate, Phenyl salicylate, Salicylamide, Aspirin, Aluminium aspirin, Calcium acetyl salicylate, Salsalate.
2. N-Anthranilic acid Derivatives:
Mefenamic acid, Meclofenamate sodium
3. Aryl acetic acid Derivatives:
Indomethacin, Sulindac, Tolmetin sodium, Zomepriac sodium, Ibuprofen, Naproxan, Fenoprofen calcium, Ketoprofen, Flurbiprofen, Diclofenac sodium and potassium, Ketorolac tromethamin, Piroxicam.
4. Aniline and Para Amino Phenol Derivatives:
Acetanilide, Phenacetin, Acetaminophen(Paracetamol).
5. Pyrazolone and Pyrazolidine dione Derivatives:
Anti pyrin, Aminopyrin, Dipyrone, Phenyl Butazone, Oxyphen Butazone.

I. Salicylic acid Derivatives

SAR of Salicylic acid Derivatives

1. Various substitution on the carboxyl or hydroxyl group result in to change in potency as well as toxicity.


2. The hydroxy group in ortho position is very important for activity.


3. Salt of salicylic acid with choline and magnesium possess longer duration of action and lesser gastro intestinal irritation tha aspirin.


4. Salsalate is an ester of two salicylic acid molecules. Since it is insoluble in stomach and is not absorbed until it reaches the small intestine. So it cause less gastric irritation.


5. Introduction of hydrophobic group(F) at 51 positionof flufenasil is more potent, longer acting and with less gastric irritation.

Mechanism of action

The antipyretic and Anti inflammatory actions of salicylates and other acidic drugs are probably due to their inhibitory effect on prostaglandin synthesis by inhibiting prostaglandin synthetase enzyme.
Salicylates exert their antipyretic action by increasing heat elimination of the body through the mobilization of water and consequent dilution of the blood.

II. Aryl acetic acid Derivatives

Synthesis of Indomethacin SAR for Aryl acetic acid Derivatives

I.For Indole acetic acid derivatives

1. N-substitution of indole derivative increase Anti inflammatory activity in the order of benzyl > alkyl > H
2. The methyl group at 2nd position of indole increase the activity.
3. The substitution at 5th position increase the activity in the order of OCH3 > (CH3)2 N >CH3 > H.
4. The carboxyl group is necessory for good Anti inflammatory activity.
5. The N-Benzoyl group of indolehave halogen, CF3 or SCH3 at para position provides the greatest Anti inflammatory activity.

II.For Phenyl propionic acid derivatives

1. The maximum activity is obtained for the substitution at R1 is isobutyl group. The smaller substituents (Methyl, Ethyl) reduces the activity.
2. Maximal activity is found with R2 is methyl group. Smaller and larger groups diminish the activity.
3. Replacement of carboxyl group by an ester, alcoholic, amide, Hydroxamic acid(NHOH) or tetrazole(CHN4) generally produce less active compounds.
4. The anti inflammatory activity resides in the S(+) isomer.

III.For Naphthyl propionic acid derivatives

1. The anti inflammatory activity is reduced when R1 is larger than OCH3 or SCH3 group.
2. The activity may be reduced when the carboxyl group is replaced with alcohol or aldehyde.
3. Dextro rotatory isomer is 11 times more active than phenyl butazone.

IV.For Oxicams

1. The nitrogen of benzothiazine ring have the substituent CH3 and other electron withdrawing groups on the anilide phenyl groups such as Cl, CF3, have good anti inflammatory activity.
2. The introduction of a heterocyclic ring in the amide oxide chain significantly increase the activity. (Sudoxicam is more potent than indomethacin).
3. The benzothiazine have pKa range of 6 to 8 have more activity.

III. Aniline and P-Aminophenol Derivatives

IV. Pyrazolone and Pyrazolidine dione Derivatives:

SAR for Pyrazolidine diones

1. The butyl group of carbon 4 may be replaced by propyl or allyl are less active.
2. The meta substitution of the aryl ring are inactive but para substitution such as CH3, Cl, NO2 or OH retains activity.
3. Replacement of nitrogen in pyrazolidines with oxygen yield isoxazole analog which is as active as pyrazolidine derivatives.
4. Decreasing pKa values of phenyl butazone analogs have shorter half lives.
5. Substitution at C-4 by methyl group destroys anti inflammatory activity.
6. The most active compound have the log P value is 0.7.

Mechanism of actions for NSAIDs

1. The prostaglandins are the mediation of inflammation. The NSAIDs are mainly prevent the formation of unstable proataglandin endoperoxide synthetase enzyme.
2. Most of the drugs are irreversible inhibitors of cyclo oxygenase activity, thus they prevent the formation of prostaglandins and consequently reducing the signs and symptoms of inflammation.
3. Besides inhibiting prostaglandin bio synthesis, the NSAIDs also inhibit the synthesis of leucotrienes, histamine and some biological process such as phagocytosis and platelet aggregation.
4. Other possible mechanisms of NSAIDs are kinin antagonism, prevention of leucocyte accumulation, stabilization of lysosome membranes, uncoupling of oxidative phosphorylation and oxygen radical scavenger action.
5. The inhibition of cyclo oxygenase can occur either by irreversible inactivation of enzyme(Eg-Aspirin) or rapid reversible non competitive inhibition involves anti oxidant or free radical trapping properties.
6. Some NSAIDs (Ibuprofen) reversible competitive inhibit by the propionic acid, which binds reversibly to the enzyme cyclo-oxygenase competing with arachidonic acid.
   
   

NARCOTIC ANALGESICS

ANALGESICS ANTIPYRECTICS AND ANTI INFLAMMATORY DRUGS

NARCOTIC ANALGESIC (MORPHINE AND RELATED DRUGS):


Analgesics are agents which relieve the pain with out disturbing consciousness.
Analgesics are divided in to two main classes
1) Narcotic analgesics (Centrally acting drugs)
2) Non Narcotic analgesics (Peripherally acting drugs)

The narcotic analgesics are also called as opiate analgesics. These are mainly obtained from unripe capsules of papaver somniferum (Opium poppy) plant. The important alkaloid is isolated from opium is morphine. The other alkaloids isolated from opium are codeine, Papaverine and thebain.

The opium group of narcotic drugs is most powerfully acting and clinically useful drugs producing depression of CNS. They depress the CNS and relieve the pain and some drugs like morphine induce sleep in presence of pain, diarrhea and suppress sough.
The term opiod is used generally to designate collectively the drugs (natural or synthetic) which bind specifically to any of sub species of receptor of morphine and produce morphine like actions.

The limitations of opiate analgesics are they have addictive property, respiratory depression, decreased gastro intestinal motility leading to constipation, increases biliary tract pressure and pruritis due to histamine release.

Classification
1. Morphine Analogues :
Morphine SO4, Codiene PO4, Ethyl Morphine, Diacetyl morphine(Heroin), Hydro morphoneHCl, Oxy morphone.HCl, Apo morphine.HCl, Hydrocodone, Oxy codone, Dihydromorphine, Dihydro codeine.
2. Morphinan Analogues:
Levorphanol tartarate, Dextro methorphan, Butarphanol,
3. Morphan Analogues:
Metazocin, Cyclazocin, Pentazocin.
4. 4-Phenyl Piperidine Analogues:
Meperidine.HCl(Pethidine.HCl), Di phenoxylate.HCl, Fentanyl citrate, Anileridine.HCl, Phenoperidine, Alphaprodine.HCl, Loperamide.HCl.
5. Phenyl propylamine Analogues:
Methadone.HCl, Dextro propoxyphene.HCl, Metho Trimeprazine.
6. Miscelleneous:
Tramadol, Tilidate, Nexeridine, Sulfentanil.
7. Narcotic Antagonists:
Nalorphine, Naloxone, Levellorphan, Naltrexene, Cyclazocine, Propiram, Profadol

1. Morphine Analogues:

Morphine



Derivatives of morphine





Apo Morphine II. Morphinan Analogues:




III. Morphan Analogues: IV. 4-Phenyl Piperidine Analogues:



V. Phenyl propylamine Analogues:



VI. Narcotic Antagonist
SAR for Morphine like drugs :


General Structure

The structural activity relationship is studied due to the modifications of the following parts of morphine.
1) Modifications on aromatic ring system
2) Modifications on alicyclic ring system
3) Modifications of Tertiary nitrogen
4) Modifications of Ether Bridge

I. Modifications on aromatic ring system :

1. An aromatic phenyl ring is essential for activity.


2. Modifications of C3 phenolic hydroxyl group decreases analgesic activity.


3. Making the phenolic – OH group by etherification to methyl ether (Codeine) and ethyl ether (ethyl morphine) results in about one tenth of analgesic activity of morphine. Because phenolics – OH group binds with opiate receptor by hydrogen bonding easily. But ethers are not easily hydrolysis.


4. Esterification of 3 – OH group gives compounds more active than morphine.


5. Substances other than 3-position in the aromatic ring results in a reduction of opiod actions. But 1-fluoro codeine possess the some analgesic activity as that codeine.

II. Modifications on alicyclic ring system :

1. The C-6-Alpha- OH group is methylated, esterified, oxidized, removed or replaced by halogen in order to get more potent analgesics. But there is also a parallel increase in toxicity. Example : Codeine, heroin, chloro morphone.


2. The saturation of double bond at C - 8 position gives more potent compounds. Example : Dihydromorphine, Dihydrocodeine.


3. Introduction of 14 – OH in dihydro from gives more potent 14 – hydroxy dihydro codeinone and 14 – hydroxy dihydro morphinone.


4. Bridging of C6 and C14 through ethylene linkage gives etorphine which is 200 times more potent than morphine.


5. Introduction of any new substituents at 5th position does not enhance the activity except 5 – methyl dihydro morphine and azidomorphines.

III Modifications of 30 Nitrogens :

1. Replacement of N-CH3 by N-C2H5 results slight fall in analgesic response. More hydrophobic groups such as propyl, pentyl, hexyl and phenylethyl gave an increase in activity.
2. N-allyl and N-cycloalkyl methyl functions give the narcotic antagonistic properties.
3. N-Phenyl ethyl group enhances the analgesic activity in desmorphine, codeine and heterocodeine.

IV Modifications of ether bridge :

1. Breaking of ether bridge and opening of piperidine ring decreases the activity.

SAR for meperidine analogues

1. Replacement of 4-phenyl group by hydrogen, alkyl, aralkyl or heterocyclic groups reduces the activity.


2. The presence of phenyl and ester group at position 4 of 1-methyl piperidine gives optimum activity.


3. The replacement of N-methyl group by various aryl alkyl groups can increase the analgesic property.


4. Introduction of m –hydroxy group in phenyl ring increases the activity similar to C3 – OH of morphine. Example : Bemidone.


5. Replacement of ester moiety by a ketone in bemidone. Example: ketobemidone is equalent to morphine in activity.


6. The reversed ester of meperidine, propionoxy compounds was more active, being 5 times more active than meperidine. Example: Prodine.


7. When a phenyl and acyl group are separated from piperidine ring by a nitrogen atom, it gives a powerful analgesic. Example: Fertanyl.


8. By enlarging the piperidine ring to seven member hexahydro azepine ring. Example: Proteptazine is more active analgesic agent.


9. Contraction of piperidine ring to five member Pyrrolidine ring was also have good activity. Example: Alpha prodine, Prodilidine

SAR for methadone series:

1. The Levo isomer of methadone and Isomethadone are twice active as its racemates.
2. Removal of any one of phenyl rings decreases the activity.
3. Introduction of m – hydroxy group is phenyl ring decreases the activity.
4. Methadone derivatives are generally more potent analgesic than isomethadone series.
5. The replacement of propionyl group by hydrogen, hydroxy or acetyloxy group leads to decrease the analgesic activity.
6. Replacement of propionyl group by amide group (ex. Racemoramide) is more active than methadone.
7. Replacement of dimethylamino group by heterocyclic ring like morpholine and piperidine are potent as methadone with morphine like activity (Racemoramide).
8. An N-methylated derivative of metabolites of methadone analogues retains the analgesic activity.

Mechanism of Action of Opiods :

1. The Pharmacological actions of opiods are mediated by several types of opiate receptors in the CNS.
2. The structural features which are recognized to be essential for the perfect fit of a narcotic analgesic on receptors are represented below.

3. Opiod receptors compared of three major arts. i) A flat portion with holds aromatic part by Vandar-Waal’s force. ii) A cavity or a hallow portion with entraps ethylene bridge. iii) An an ionic site with holds the 30 nitrogen with get ionized at physiological. pH Beckett and Casy model of the analgesic receptor site is in above figure.

4. The fact that these sites do not bind other substances and are saturated by even very low concentrations of opiods explains the highly stereospecific orientation of these three components of opiod receptors.

5. There are three major types of opiod receptors
   i) Mu (m) – op3 receptors – produce analgesia, respiratory depression, Euphoria
   and addiction.
   ii) kappa (K) – op2 receptors – produce dysphoria, Euphoria and addiction.
   iii) Delta (d) – op1 receptors – G – proteins – linked receptors.

6. Morphine binds to m receptor and induce change in shape and open the ion channel in cell membrane. So K+ ion can flow out of the cell, hyperpolarizes membrane potential. Therefore the frequency of action potential firing is decreased, result in a decrease in ion neuron excitability.

7. The increase in permeability decrease the influx of Ca into nerve retinal and reduces neuro transmitter release. Both the effects shut down the nerve and block pain message.

8. Kappa receptor is directly associated with Ca channel. When an agonist binds to K receptors, the Ca channel is closed. Since Ca is necessary for neurotransmitter it cannot pass on pain message.

9. When agonist binds with d(delta) receptors, the receptor changes its shape and triggers a messenger protein (G protein) to carry a message to a neighboring enzyme with catalyses the formation of cyclic adenosine monophosphate. The G protein inactivates the enzyme by preventing the synthesis of cyclic AMP. This act as a second messenger is the transmission of pain signed and stops the pain.

ANTI TUSSIVES

ANTI TUSSIVES

Anti tussives are agents that are employed in the symptomatic control of cough by depressing cough centre situated in the medulla.
Coughing is a protective mechanism through which foreign materials, irritants and secretions are cleared from the respiratory tract.
Anti tussives can act either by raising threshold of the cough centre or by reducing the no of impulses transmitted to the cough centre from the peripheral receptors.

Classification

1. Centrally acting Anti tussives :-
It affects the cough centre in the medulla.
Example- Dextro methorphan Hydrobromide, Pholcodine, Noscapine, Carbeta pentane

2. Peripherally acting Anti tussives –­­­
It acts at the receptor level in the respiratory tract.
Example- Benzonatate.



Mechanism of action

Dextromethorphan control the cough by depressing the cough centre in the medulla. The potency is almost one-half of the codeine. But this drug does not producing addiction even after the usage of large doses for prolonged duration like codeine.
Benzonatate reducing the cough reflux at its source by anesthetizing the stretch receptors located in the respiratory passages and lungs.

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.