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.