SYSTEMIC VETERINARY PHARMACOLOGY

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GROUP OF DRUGS- ACTING ON DIFFERENT BODY

SYSTEMS

MAJOR DRUGS ACTING ON SYSTEMS

► DIGESTIVE ►HAEMATOPIETIC SYSTEM ► CARDIOVASCULAR SYSTEM► GENITOURINARY ► RESPIRATORY ► CNS ► MUSCULOSKELETAL

DIGESTIVE SYSTEM

• Emetics• Antiemetics • Appetite stimulants • Antiulcer drugs • Prokinetics /Gastrokinetics • Antidiarrhoeals • Cathartics /Laxatives

• Rumenotorics• Antifoaming agents• Ruminoreticular

antacids and acidifying agents

• Ruminoreticular Motility modifiers

EMETICS

• Apomorphine

• Xylazine

• Syrup of ipecac

• Hydrogen peroxide (3%)

• Salt (1-3 tsp) in warm water or Large crystal of NaCl / Sod. carb. (washing soda)

ANTIEMETICS

Phenothiazine tranquilizers acepromazine, triflupromazine, chlorpromazine, and

prochlorperazine.

Anticholinergic:methscopolamine., glycopyrrolate, propantheline,isopropamide,scopalamine(hyoscine)

dicyclomine Antihistaminics: diphenhydramine, dimenhydrinate,

promethazine, buclizine, cyclizine, and meclizine.

Dopamine antagonists: metoclopramide, clebopride, bromopride ,alizapride, domperidone

Serotonin (5-HT) antagonists: Ondansetron and dolasetron

ANTIEMETICS…contd

Cannabinoids- Cannabis (Marijuana), Dronabinol, Nabilone

Butyrophenone tranquilizers- Butorphanol, Droperidol, Haloperidol

Steroids - Dexamethasone , Betamethasone, methyl prednisolone

Benzodiazepines -Midazolam Lorazepam , Alprazolam

Neurokinin type 1 (NK-1) receptor antagonists- Aprepitant , Maropitant citrate

Others: Trimethobenzamide ,Ginger ,Propofol, Peppermint

Metoclopramide

Antiemetic effects via 3 mechanisms. Anti dopaminergic (D2) transmission in the CNS 5HT4 agonistic on GIT 5HT3 antagonistic in CTZEffects In the upper GI tract, it increases Ach release stimulates and coordinates esophageal, gastric, pyloric, and

duodenal motor activity Increases lower esophageal sphincter (LES) tone and

stimulates gastric contractions Relax the pylorus and duodenum. Inadequate cholinergic activity is incriminated in many GI

motility disorders; hence - most effective in diseases where normal motility is diminished or impaired.

5-HT3 receptor antagonists

Specific inhibitors of 5-HT 3 (Serotonin) receptors in the CTZ

Cytotoxic drugs and radiation -release of serotonin.

Most effective antiemetics in radiation and chemotherapy induced , not effective for emesis caused by motion sickness n

APPETITE STIMULANTS

B vitamin preparations Glucocorticoids -prednisone Anabolic steroids – Stanozolol Benzodiazepines -in cats -Diazepam Cyproheptadine- serotonin antagonist Megestrol acetate -Progestin

ANTIULCER DRUGS Acetylcholine M1 Receptor Antagonists: Pirenzepine,

telenzipine Antacids

Histamine (H2)-receptor Antagonists Proton-pump inhibitors

Cytoprotective drugs

Prostaglandin E1 Analogues

AntacidsSystemic antacid • NaHCO3, Na citrate, Na acetate

• Water soluble, rapid CO2 liberation-• Rebound hyperacidity, lead to perforation, ulcer,

belching • Metabolic alkalosis Non systemic• water insoluble • Al: OH3, PO4, Mg silicate- 30g, • Mg : OH, O, CO3, Mag aldrate, Mag trisilicate, (Milk of

magnesia- MgOH)• Ca : CO3, PO4

Antacids…contd

Alginates

• form a raft that floats on the surface of the stomach contents

• provide a physical barrier to gastro-oesophageal reflux.

Simethicone(activated dimethicone)

• An anti-foaming agent to relieve wind/ flatulence

• Lowers surface tension,allows small bubbles froth to coalese into large bubbles that are more easily passed up from stomach or down from colon.

• Effective in releiving frothy bloat in ruminants

• palliative treatment of hiccups .

Histamine (H2)-receptor Antagonists

Famotidine >Nizatidine >Ranitidine >Cimetidine

Food delays the absorption of cimetidine, minimal effect on ranitidine enhances absorption of famotidine

Cimetidine- hepatic microsomal enzyme inhibitor, reduces the metabolism of other drugs

Proton-pump inhibitors

(H+,K+ATPase Inhibitors)

Omeprazole, Pantoprazole, (caps, injectables)Lansoprazole, Rabeprazole, Esomeprazole( caps)

24 hours single oral dose More effective than H2 blockers Microsomal enzyme inhibitor

Omeprazole mucosal cell hyperplasia, hypertrophy and development

of carcinoids.

Cytoprotective agents Prostaglandin E1 Analogues Promote gastric mucosal defense mechanisms, inhibiting parietal

cell acid secretion , stimulating mucosal blood flow ,bicarbonate secretion, mucus secretion and epithelial cell renewal

Misoprostol –methyl PGE1 ester

• poorer in releiving ulcer pain

• shorter DOA

• Slow healing rate

• employed for GI bleeding and ulceration from NSAID therapy

• less efficacious than H2blockers for treatment of ulcers not associated with NSAIDs

Side effects - diarrhea and flatulence CI: pregnancy

Ulcer protectives/ Ulcerhealing drugsSucralfate • Cytoprotective drug • cross-polymerized to form a viscous gel that binds to the

necrotic tissue proteins in an ulcer to act as a diffusion barrier

• Additional beneficial effects - stimulation of PG production, adsorption of bile salts, and inactivation of gastric pepsins

• Minimal oral absorption• . Combination therapy (sucralfate + histamine H2

antagonist, or sucralfate + H+, K+ - ATPase inhibitor) is frequently employed

• Effective and safest drug in treating gastric erosion/ulcer and patients receiving NSAID therapy

PROKINETICS…contdCisapride

Without antidopaminergic effects (antiemetic action) No extrapyramidal effects ( do not cross BBB) More potent and broader prokinetic activity, 5HT 4 agonistic Increases the motility of the colon, as well as that of the

esophagus, stomach, and small intestine improves coordination of the ileocecal-colonic junction

Withdrawn from market in abroad – potent cardiovascular side effects- heart rhythm disorders in humans.

Indications Gastric stasis,, gastroesophageal reflux, postoperative ileus

(horse) and intestinal pseudo-obstruction (dogs and cats) In idiopathic megaesophagus (dogs) that continue to regurgitate

frequently despite a carefully managed, elevated feeding program Rational agent in the treatment of idiopathic constipation (cats)

PROKINETICS…contd

Domperidone • Regulates the motility of gastric and small intestinal

smooth muscle

• very little physiologic effect in the colon

• superior to metoclopramide in stimulating antral contractions

Macrolide antibiotics

Erythromycin & Clarithromycin - at much lower than antimicrobial dose

PROKINETICS…contd

Histamine H2-receptor antagonists• Ranitidine and nizatidine.• Stimulate GI motility by increasing the amount of AChE available

to bind smooth muscle muscarinic receptors • Stimulate colonic Sm.M contraction in cats by cholinergic

mechanismAChE inhibitors • Neostigmine indicated in paralytic ileus, ruminoreticular atony,

paresis. • Increase secretion into the GI tract, contraindicated in SI disease • Increase frequency, rather than strength, of ruminoreticular

contractions • Stimulatory effect not always reliable, and some inhibition of

motility can be seen as in n horses, it may decrease small-intestinal propulsive contractions and delay gastric emptying

DRUGS USED IN THE TREATMENT OF DIARRHOEA

Mucosal Protectants and Adsorbents a. Kaolin-pectin -reduce bioavailability b. Activated charcoal -common nonspecific treatment c. Bismuth subsalicylate- Salicylate toxicosis in cats Anticholinergic drugs Hyoscine, Aminopentamide, isopropamide, propantheline and dicyclomine side effects- Urine retention,tachycardia, and CNS excitement, intestinal atonyOpiates antisecretory & antimotility effects, not to be used in infection Diphenoxylate and Loperamide Overdose: abnormal pupillary response to light,circling, constant vocalization, head pressing, mydriasis Paralytic ileus, toxic megacolon, pancreatitis, and CNS effects in cats.(collies)

CATHARTICS AND LAXATIVES…contdStimulant Cathartics Emodin Castor oil , Raw linseed oil olive oil glycerine, Phenolphthalein ,bisacodylOsmotic (Saline) Cathartics Mg salts- MgSO4(Epsom salt, not for horse), MgO. MgOH,

Mgcitrate,MgCO3, NaCl, Na2SO4(Glaubers salt), NaPO4, KNa tartrate Sugar alcohols -mannitol and sorbitol, Lactulose

Bulk Laxatives -methylcellulose, psyllium, prunes, wheat bran, and canned pumpkin.

Lubricant Laxatives -Mineral oil( Liquid paraffin)

Fecal Softeners (Surfactants)- Docusate sodium docusate calcium docusate potassium

CATHARTICS AND LAXATIVES…contd

Neuromuscular purgatives• Cholinergic agents with muscarinic action-

Parasympathomimetics- arecholine, carbachol, bethanecol, physostigmine, neostigmine

Prokinetic agents

• 5HT4 agonists & opoid receptor antagonists

RuminotoricsFresh ruminal fluid is considered to be the best available

ruminotoric Magnesium hydroxide

Dioctyl sodium sulfosuccinate ( 90-120 mL in 1-2 L of water)

With ruminal massage helpful in promoting the dissolution , passage of impacted fibrous ruminal contents.

markedly depress rumen protozoa; thus, ruminal fluid transfaunation needed

ANTIFOAMING AGENTS

Poloxalene Polymerized methyl silicone Docusate sodium in emulsified soybean oil Vegetable oils alone, such as peanut oil,

sunflower oil, or soybean oil Ionophores (such as monensin) in the ration

RUMINORETICULAR ANTACIDSMagnesium hydroxide (cattle: 100-300 g;

sheep: 10-30 g) Magnesium carbonate (cattle: 10-80 g; sheep:

1-8 g). Mixed in10 L of warm water to ensure

adequate dispersion through the ruminoreticular contents.

Activated charcoal (2 g/kg) to protect the ruminoreticular mucosa from further injury by inactivating toxins

RUMINORETICULAR ACIDIFYING AGENTS

• Ruminal stasis or simple indigestion• Acute ammonia poisoning. Administration of weak acids in cold water returns the pH of ruminoreticular content toward physiologic levels promotes the uptake of volatile fatty acids. Acetic acid (4-5%) or vinegar (cattle: 4-8 L;

sheep: 250-500 mL)

Drugs acting on respiratory system• Expectorants/mucokinetics

1)Secretory expectorantsA)Reflex acting: ipecacunha,balsam of toluB)Direct acting: guiacol, guiaphenesinC)Mixed acting/saline: potassium iodide,NH3Cl

2) Mucolytic: bromhexine, acetyl cysteine, ambroxol, dembrexine

3) Diluent: steam,propylene glycol and glycerine

4) Miscellaneous: CO2, antimony tartarate28

Antitussives

Peripherally acting:A) Demulscents: honey, glycerineB)Mucosal anaesthetics: benzoateC)Bronchodilators: ephedrine, theophyllineD) Expectorants: bromhexine, steamCentrally acting:A)Opioids: codeine, hydrocodeine, morphineB)Non opioids: dextromethorphan, pholcodeine

and noscapine

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Bronchial asthma

1)Bronchodilators:

a) Beta 2 agonists: salbutomol, terbutaline

b)Methyl xanthines: Theophylline, aminophylline

c)Anticholinergics: glycopyronium, atropine, ipratropium,

2) Leukotriene antagonists: Montelukast, zafirlukast

3) Corticosteroids: hydrocortisone, prednisolone,

beclomethasone

4) Mast cell stabilizers: sodium cromogylate, Ketotifen

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Analeptics

• Doxapram• Nikethamide( coramine)• Bemegride• Methyl xanthines• Pentylene tetrazol • Picrotoxin • Opioid antagonists

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DRUGS ACTING ON HAEMATOPOIETIC SYSTEM

DRUGS

►HAEMATINICS/ ANTIANAEMIC DRUGS ► ANBOLIC STEAROIDS►HAEMOSTATICS/ COAGULANTS►ANTICOAGULANTS ► ANTITHROMBOTICS

HAEMATINICS/ ANTIANAEMIC DRUGS:

►Minerals: Iron, Cobalt and Copper ►Vitamins:VitaminB12,Folicacid,Pyridoxine,

Ascorbic acid

► Anabolic steroids: Nandrolone decanoate, stanozolol etc

IRON

► Oral preparations ► Ferrous ( - sulphate, fumarate, succinate, gluconate) ► Ferric (-ammonium citrate, hydroxide and glycerophosphate).► Ferrous sulphate and ferrous fumarate salts are preferred as

rapidly,better absorbed. ► adverse effects nausea, epigastric discomfort, abdominal

cramps, constipation, and diarrhea. ► These effects are usually dose-related and can often be

overcome by lowering the daily dose of iron or by taking the tablets immediately after or with meals

IRON

Parenteral preparations

► Iron-carbohydrate complexes( Iron dextran and iron sorbitol)► Iron dextran, both IM and IV routes► . Iron sorbitol is used clinically only by IM route, ► Iron-sucrose complex and iron sodium gluconate complex are

newer, alternative preparations, given deep intramuscular

injection or by intravenous infusion.

Adverse effects of parenteral iron therapy

►local pain,tissue staining (brown discoloration of the tissues overlying the injection site)

► fever, arthralgias► flushing, urticaria, bronchospasm► anaphylaxis and death.

ANABOLIC STEROIDS

► synthetically produced variants of the naturally occurring male hormone testosterone

►promote the growth of skeletal muscle, and the androgenic effects promote the development of male sexual characteristics

► Nandrolone decanoate and Stanozolol.

HAEMOSTATICS

Topical hemostatics

► Feracrylum : is another topical haemostatic solution applied as spray/ gel for capillary bleeding, surface bleeding.

► Adrenaline and Noradrenaline induce localized haemostasis by virtue of their vasocconstrictive effects. They are applied intranasally(1%) to decrease capillary bleeding, epistaxis.

► Styptics (Astringents) that arrest bleeding by precipitation of proteins of blood and soft tissues; should not be used in high concentration as they irrite and can damage the surrounding tissue.

Examples include: ferric sulphate,ferric chloride, silver nitrate, tannic acid, alum, zinc chloride, zinc oxide

HAEMOSTATICS:

Topical haemostatics► Thromboplastin, Thrombin, Fibrin foam and Fibrinogen ► in capillary bleeding , dental sockets, epistaxis, surgery of nose ,

throat and glandular tissues. ► Gelatine sponge ( Absorbable) moistened with saline or

thrombin is left in bleeding area, which is completely absorbed within 4 weeks.

► Calcium alginate dressing may also be left at bleeding site in the same manner

Systemic Haemostatics

Adrenochrome monosemicarbazone (carbazochrome salicylate):

► is an oxidation product of adrenaline

►used for systemic control of capillary bleeding associated with increased capillary permeability.

►both orally and parenterally , often given in combination with vitamin K for variety of bleeding disorders like: epistaxis, haematuria, secondary haemorrhage from wounds etc.

Rutin: ►is a a plant glycoside that improves capillary

fragility► used orally in combination with vitamin C and

vitamin K. Protamine sulphate ► clinically (slow IV) as an antagonist for

heparin overdosage associated bleeding only.

Ethamsylate► reduces capillary bleeding by correcting

abnormal platelet adhesion leading to the repair of capillary wall.

► capillary haemorrhage► haematemesis► epistaxis► post partum haemorrhage etc. ► 250-500mg. IM, PO► CI: pregnancy

Bothrops venom ►coagulant compound derived from the venom

of SouthAmerican pit vipers. ► Excellent haemostatic-coagulant► It should not be used as a coagulant in viper

bites as it simply prolongs the coagulation abnormality.

►10.0 ml in 500 ml of DNS/NSS, I.V. daily for two days. (94.40% accuracy)

N-Butanol

► with Citric acid ( vit c)-REVICI- 5ml Amp ► Ext , int haemorraghes- surg procedures►capillary haemorrhage► haematemesis► epistaxis► post partum haemorrhage etc. ►

Fibrinolytic inhibitors

►Epsilon Aminocaproic Acid: (EACA), Tranexamic acid and Aprotinin

► primarily used as therapy for bleeding from fibrinolytic therapy

►as prophylaxis for rebleeding postsurgical gastrointestinal bleeding and

►postprostatectomy bleeding and bladder hemorrhage secondary to radiation

Vitamin K

► is used therapeutically in the prophylaxis and treatment of bleeding disorders due to deficiency of vitamin K dependent clotting factors as in warfarin rodenticide poisoning.

► Used as haemostatic agent in the oral anticoagulant rodenticide (Coumarin derivatives- warfarin, dicoumarol, acenocoumarol)

► poisoning,indanedione derivatives rodenticide(phenindione, diphenadione, anisindione)

►Available as: ►the natural plant form-Phytomenadione

(vitamin K1)

►Synthetic vitamin K compounds; Menaquinones (vitamin K2 )

►and Menadione (vitamin K3).

Antihemostatic drugs

A) Anticoagulants:1)Invitro: a) Lab use: oxalates, NaF, EDTAb)Blood transfusion: heparin, Na citrate and acid

citrate dextrose2)Invivo/systemic:a) parenteral: heparin and heparinoidsb)Oral anticoagulants: coumarin derivatives ie.,

warfarin, dicoumarol

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B) Antithrombotics: aspirin, sulphinpyrazone, ticlopidine, timolol

C) Thrombolytic drugs: streptokinse, urokinase, anistreplace

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Antithrombotics/Antiplatelet drugs

► aspirin, dipyridamole, ticlopidine ►e useful in the prevention of arterial

thrombosis, thus inhibiting the growth/ reoccurrence of thrombus formation

►as in conditions of feline cardiomyopathy, canine heart worm infection etc.

DRUGS ACTING ON CVS

• Antihypertensives• Antiarrythmics• Ionotropics• Cardiotonics and Cardiac glycosides (in CHF) • Vasodilators• Antihyperlipedmics • Pressors

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Antihypertensive Agents( Antianginals)• Adrenergic agents

• Alpha1 blockers- doxazosin prazosin, terazosin

• Beta blockers (cardioselective and nonselective) – metorprolol, propranolol, acebutalol, pindolol,

• Centrally acting alpha blockers – clonidine, methyl dopa

• Combined alpha-beta blockers - labetalol• Peripheral-acting adrenergic agents

– ADNB- reserpine, guanethedine

• Angiotensin-converting enzyme (ACE) inhibitors– captopril, enalapril, lisinopril

• Angiotensin II receptor blockers– losartan, irbesartan,candesartan, telmisartan

• Calcium channel blockers – ampldipine,diltiazem, nifedipine, verapamil

• Diuretics – thiazide, frusemide

• Vasodilators – sodium nitroprusside, diazoxide, glyceryl trinitrate, isosorbide, minoxidil

Cardiac glycosides• Digitalis purpurea or Purple foxglve (leaf) -

Digitoxin, Gitoxin, Gitalin • Digitalis lanata or White foxglove (leaf) -

Digitoxin, Gitoxin, Digoxin• Strophanthus kombe (seed) - Strophanthin K• Strophanthus gratus (seed) - Strophanthin G

(Ouabain)• Thevetia neriifolia (nut) - Thevetin• Convallaria majalis - Convallotoxin• Bufo vulgaris (Toad skin) - Bufotoxin

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Antiarrythmics

– Class I drugs act by blocking the sodium channel. • Subclass IA drugs Eg. quinidne, procainamide, disopyramide• Subclass IB drugs Eg. lidocaine, phenytoin • Subclass IC Eg. flecainide, encainide

– Class II drugs -by blocking beta-adrenergic receptors (increasing PR).

– eg. propranolol – Class III drugs -interference with potassium

conductance is one possible mechanism), – eg. sotalol, amiodarone

– Class IV drugs act by blocking the voltage-sensitive calcium channels.

– eg. verapamil, nifedipine

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PRESSORS (VASOCONSTRICTORS)

• α1 adrenergic agonists – epinephrine, norepinephrine, dopamine, PPA,

oxymetazoline, phenyl ephrine, • Drugs that release noradrenaline from the

sympathetic nerve terminals or inhibit its reuptake – ephedrine, amphetamine,

• Eicosanoids like thromboxane A and several peptides like endothelin, angiotensin and vasopressin

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Drugs acting on Uterus and cervix

• Myometrial stimulants• Uterine relaxants • cervical dilators • Hormones

Drugs acting on Urinary system

• Diuretics • Drugs for urinary retention and incontinence• Urinal acidifiers• Urinary alkalisers• Drugs for urolithiasis

Myometrial Stimulants (ECBOLICS)

• stimulate contraction of the oestrogen-sensitised uterine myometrium and mammary myoepithelial cells.

Indications: • In dystocia due to secondary uterine inertia. However, should not be

used when dystocia is due to malpresentation or obstruction. • Control of postpartum hemorrhage to hasten uterine involution

immediately• after parturition in all species, to aid clearance of uterine discharge• they have no effect on separation of the placenta in ruminant species• To reduce the size of a uterine prolapse after replacement in cattle.• agalactia due to failure of milk let down Examples- Oxytocin, PGF2alpha, ergot alkaloids

Prostaglandin F2alpha and derivatives

• Alfaprostol, cloprostenol, dinoprost, etiproston, luprostiol and tiaprost are synthetic

• As ecbolics: in obstetrics are dinoprostone (PGE2), carboprost (15-methyl PGF2α) cloprostenol, and gemeprost or misoprostol (PGE1 analogues)

PGF2alpha

• causes myometrial contraction• cervical relaxation• luteolysis. • regression of the corpus luteum • to treat ‘open’ pyometra in bitches• to terminate pregnancy in bitches in combination with

cabergoline.

ERGOT ALKALOIDS

• stimulate uterine smooth muscle directly, thereby increasing muscular tone

• enhancing the rate and force of rhythmical contractions.

• Ergometrine (ergonovine) maleate and Methylergometrine (methyl ergonovine) maleate

• the routine expulsion of the placenta after delivery • postpartum and postabortal atony and hemorrhage. • Ergonovine also stimulates cervical contractions. • These drugs are capable of inducing a sustained

tetanic contraction, which can shorten the final stage of labor and aid in the reduction of postpartum blood loss

Ergot alkaloids

• excreted in milk• should not be administered longer than

necessary,since prolonged use can lead to ergot poisoning (ergotism)

• should not be used in cases of threatened spontaneous abortion .

MYOMETRIAL RELAXANTS( Tocolytics)

• inhibit uterine contraction or result in relaxation of uterus to aid obstetrical manoeuvres during dystocia • to facilitate handling of the uterus during caesarean

operation. • to facilitate the recovery of embryos from donors for embryo

transfer• to facilitate replacement of a prolapsed uterus.• to delay parturition so that it may occur when greater

observation and care are available• In addition, when used in heifers, calving can be delayed

sufficiently to allow better relaxation of the birth canal and perineum.

• incomplete cervical dilation (ringwomb) in sheep, although their effect is questionable

TOCOLYTICSβ2-adrenoceptor agonists

• clenbuterol( Cattle: 300 micrograms as a single dose, IM,IV) terbutaline, isoxsuprine, ritodrine or salbutamol

• isoxsuprine, terbutaline

Magnesium sulfate• prevents convulsions in preeclampsia and directly

uncouples excitation–contraction in myometrial cells.• Mg toxicity can be life threatening.

Tocolytics…contd

Indomethacin • given orally or rectally for 24 or 48 hours to

delay premature labor. • . Long-term use of maternal indomethacin is

associated with primary pulmonary hypertension, of intraventricular hemorrhage in the newborn.

Tocolytics…contd

Nifedipine• calcium channel blocking agentHydroxyprogesterone. A concern relating to teratogenic potential has

limited its use.

DIURETICS

• increase urine flow by increasing renal plasma flow or by altering nephron function

• indicated to reduce oedema in cases of heart failure, hepatic disease, cerebral oedema, hypoproteinaemia, inflammation, and trauma.

Diuretics

• Loop diuretics: furosemide, bumetanide, ethacrynic acid- Most potent ones

• Thiazide diuretics: hydrochlorothiazide, chlorothiazide

• Potassium-sparing diuretics: spironolactone, triamterene,amiloride

• Osmotic diuretics: Mannitol, urea, glycerol • CAse inhibitors: Acetazolamide • Methyl xanthines: theophylline

Drug interactions

• Acetazolamide• aminoglycoside• antidiabetic drugs• beta-blockers, captopril• cardiacglycosides• cephalothin and other cephalosporins• corticosteroids• lignocaine, quinidine

Osmotic Diuretics

• Hypertonic solutions of mannitol, urea, glycerol

• mannitol causes water retention with in the nephron,which dilutes urinary sodium and opposes its reabsorption especially in the proximal tubule and loop of Henle.

Mannitol

• used to promote urine output, as in acute renal failure, or to reduce cerebral oedema.

• s not suitable for the mobilization of general or local oedema because it may lead to cardiac overload.

• Excessive administration- severe hypovolaemia and maintenance of extarcellular fulid volume may require administration of an electrolyte solution such as compound of sodium lactate intravenous infusion.

Indications.:Cerebral oedema, forced osmotic dieresis.• Extravasation causes inflammation and

thrombophlebitis.

Potassium sparing diuretics

• Act by inhibiting the action of aldosterone on distal tubular cells or blocking sodium reabsorption in the latter regions of the distal tubule and collecting tubules.

• Weak diuretics when used alone as diuretics and thus should never be used as sole agents

• In a patient, refractory to other diuretics. administered with other diuretics, potassium loss is decreased

• Spironolactone: used in combination with other diuretics, primarily furosemide, to produce additional diuresis/ to decrease potassium excretion.

• used in the management of fluid retention associated with non cardiac disease-hepatic disease and nephrotic syndrome.

Diuretics Interactions

• ACE inhibitors, potassium supplements increased risk of hyperkalaemia with potassium sparing diuretics

• Acetazolamide increased risk of hypokalaemia with loop and thiazide diuretics

• Aspirin antagonism of diuretic effect of spironolactone

• Beta-adrenoceptor blocking drugs increased risk of ventricular arrhythmias in the presence of hypokalaemia

URINARY ACIDIFIERS

• Ascorbic acid (Horses: 2 g/kg daily,PO; Dogs: 100–500 mg 3 times daily,PO; Cats: 100 mg 3 times daily)

• Ammonium chloride (Dogs: 100 mg/kg 1–2 times daily,PO; Cats: 400 mg/4.5 kg body-weight twice daily with food. Adjust dose until desired urinary pH change achieved) ;

• Ammonium sulfate (Horses: 175 mg/kg daily,PO); ethylenediamine, arginine HC1,

• Calcium chloride , methionine and sodium acid phosphate

URINARY ALKALINISERS

• Sodium bicarbonate, sodium citrate, and potassium citrate

• some antibacterial effects, as well as decreasing irritation or inflammation in the urinary tract.

• Potassium citrate: Dose: . Dogs, cats: 75 mg/kg , PO, twice daily or 2mmol/kg twice daily

• Sodium bicarbonate: Dose. Dogs, cats: 10–50 mg/kg 2–3 times daily,PO

DRUGS FOR UROLITHIASIS

• Urate uroliths are more soluble in alkaline urine. • Dietary control to reduce protein intake and urine alkalinisers • Allopurinol (Dogs: urate calculi, 10 mg/kg,PO, 3 times daily for 4 weeks

then 10 mg/kg once daily) reduces the formation of uric acid from purines by inhibiting xanthine oxidase.

• Penicillamine (Dose. Dogs: cystine calculi, 15 mg/kg,PO, twice daily preferably on an empty stomach.

• Thiazide diuretics may be used to reduce the recurrence of calcium-containing uroliths (for example, calcium oxalate calculi) in dogs.

• Dietary management and potassium citrate have also been used in the control of calcium oxalate urolithiasis.

•

DRUGS ACTING ON CNS

Nervous system

• Central nervous system(CNS): Brain and spinal cord

• Peripheral nervous system• 1. Sensory (affarent) system: somatic sensory

nerves, autonomic/visceral sensory nerves• 2. Motor(efferent ): somatic motor nerves,

autonomic motor nerves

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CNS Depressants • Injectable anesthetics and sedatives

– Barbiturates, benzodiazepines, alpha 2 agonists(xylazine, romifidine), chloral hydrate, propofol, dissoaciative anaesthetic (ketamine) steroidal(altheisn), chloralose, urethane, propanidid, metomidine

• Inhalational anesthetics– Volatile-

• Chlorofor, ether, halotahne, methoxy flurane, enflurane, isoflurane, sevoflurane, desflurane

– Gaseous:• Nitrous oxide, cyclopropane, xenon

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Barbiturates

• Thiopentone – Ultra short acting • Phenobarbitone- Long acting anticonvulsant• Pentobarbitone

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Benzodiazepines ( BZDs)

► Anxiolytics work by enhancing the action of GABA (gamma-aminobutyric acid), an inhibitory neurotransmitter.

► oxazepam, clorazepate, lorazepam, temazepam, clonazepam, diazepam and alprazolam

► The last two being most commonly indicated for treatment of anxiety related behaviour problems like urine spraying and short treatment for sound phobias (eg: fireworks, thunderstorms) because of their episodic nature and the rapid onset of action in dogs and cats.

► At therapeutic levels there is calming effect but little or no effect on motor or mental functions.

► Cats may stagger for the first 3 - 4 days but this resolve spontaneously.

► Oxazepam has non active metabolites and is biotransformed by conjugation not oxidation, it is preferred in patients with liver disease.

Tricyclic antidepressants (TCAs)

►Closely related to phenothiazines and block amine (serotonin,norepinephrine, dopamine) re-uptake

►Antianxiety effects .

►Take about two wks to produce any beneficial effects .

►Indicated for anxiety related behavioural disorders in dogs and cats such as separation anxiety, obsessive-compulsive behaviors, stereotypies, aggression, and inappropriate elimination, urine spraying in cats, feline hyperaesthesia, compulsive disorders and behavioural problems secondary to idiopathic cystitis.

►Clomipramine and amitryptilline are the TCAs licensed for use in veterinary medicine

Selective Serotonin ReUptake Inhibitors (SSRIs)

► Selectively block the reuptake of serotonin► Indicated for the treatment of behavioural conditions which involve

a component of impulsivity ► Fluoxetine, sertraline and fluvoxamine ► For treating psychogenic alopecia, allergy-related pruritus, anxiety

related condition, s dominance-related aggression, fearful behaviors, obsessive-compulsive behaviors, and urine marking

► Fluoxetine is approved drug in dogs, useful in the treatment of some but not all forms of aggression.

► It is used for inter-dog aggression in conjunction with behavioral training and neutering of the less dominant dog.

► Fluoxetine is also used for the treatment of obsessive-compulsive disorders in dogs.

Monoamine oxidase inhibitors(MAOIs)

Selegiline► For treatment of behavioural disorders with an emotional origin,

which includes fears and phobias.

► Used to increase the confidence of a dog that has become afraid of going outside after dark due to a number of fearful experiences

► Approved drug for Canine cognitive dysfunction syndrome

Antiepileptics► Mood-stabilizing drugs, primarily indicated in those cases where

epileptic activity is in the etiology of the condition ► Agents: phenobarbitone, carbamazepine, and valproic acid are

unrelated chemical compounds that are used in human medicine to treat bipolar disorder, impulsivity, emotional reactivity, and aggression.

► Carbamazepine in cats decrease fear-related aggression against people, but it may

paradoxically increase aggression against same species. ► Lithium (75 mg total dose, bid) has been used to treat dominance-

related aggression and psychotic behavior (random air-snapping, pawing) in a Cocker Spaniel; has narrow therapeutic index exhibiting side effects like polyuria, polydipsia, memory problems, weight gain, and diarrhea.

Muscle relaxants

• Directly acting– Dantrolene sodium- in malignant hyperthermia

(halothane)• Centrally acting

– Baclofen, mephenesin • Peripherally acting

– Depolarizing( Noncompetitive) • succinyl choline(suxamethonium), hexamethonium,

decamethonium– Nondepolarizing (Competitive)

• Curare, Atracurium, pancuronium, vancuranium, gallamine(FLAXEDIL)

89

Autonomic nervous system(ANS)

• Visceral, vegetative, involuntary N.S• Regulates vital body functions viz., BP, body

temperature. Heart beat, urination etc• Differences between somatic and autonomic

nervous system• ANS: sympathetic and parasympathetic• Differences, preganglionic, postganglionic nerve

fiber, location of ganglia• Type of neurotransmitter involved

90

• Neurotransmission, neurohumaoral transmission

• Neurotransmitter• Neuromodulator• Neuromediator• Criteria for neurotransmitter• Steps involved in neurotransmission

91

Adrenergic receprors

• Two families alpha (α) and Beta (β)• Adrenergic agonists: adrenaline,

noradrenaline and isoprenaline• Α α 1 and α 2 • β β 1, β 2 and β 3

• All are G-protein coupled receptors(GPCR)• α - excitatory response, except in GIT• β- inhibitory response, except on heart

92

Adrenergic receptors

• β receptors: • β 1 receptors: mainly heart, JG cell sof kidney• β 2 receptors ;blood vessels of skeletal

muscles, liver and smooth muscles of intestine, bronchi and uterus

• β 3 receptors: adipose tisue, cause lypolysis.

93

Cholinergic transmission• Acetyl choline(ACh)• Biosynhesis, storage and release of NT• Acetyl co A+ Choline Ach

• Cholinergic receptors: Nicotinic and Muscarinic• Nicotinic:( Nicotine) ligand gated cation channels• Muscarinic:(Muscarine) G-protein coupled

receptors94

Choline acetyl transferase (choline acetylase

Nicotinic

• :occour peripherally at neurotransmitter junction, autonomic ganglia, adrenal medulla and also part of CNS

• Mediate fast excitatory synaptic transmission• Two types : Nn and Nm • Ligand gated ion channel receptor• Response is always excitatory

95

• Muscarinic:occour on autonomic effector cells in heart, smooth muscles, exocrine glands and parts of CNS

• Belongs to GPCRs• Response may be excitatory or inhibitory• Receptor: 5, M1,M2, M3, M4 and M5• M1: ganglion cells of stomach and oesophagus• M2: hear and smooth muscles• M3: smooth muscles and secretory glands• M4 and M5: CNS

96

• Other neurotransmitters: Non Adrenergic Non Cholinergic(NANC):adenosine, ATP, VIP(vaso active intestinal polypeptide), Neuropeptide y etc

• Neuromodulation: presynaptic and postsynaptic

97

Adrenergic agonistsI. Nonselective adrenergic receptor agonists:• A. Catecholamines: adrenaline, noradrenaline,

isoprenaline and dopamine• B. Non catecholamines: amphetamine, ephedrine,

pseudo ephedrine, phenylpropanolamineII. Selective adrenrgic agonists:• A. Alpha 1 agonists: phenylephrine, methoxamine• B. Alpha2 agonists:clonidine, xylazine,detomidine,

medetomidine• C: Beta 1 agonist: dobutamine• D. Beta 2 agonists: clenbuterol, terbutaline,

salbutamol, orciprenaline98

• Mechanism: • 1. Direct acting agonists: directly on alpha and

beta receptors: adrebnaline, noradrenaline, methoxamine, salbutamol

• 2. Indirect acting agonists: amphetamine, tyramine

• 3. Mixed acting agonists: ephedrine, dopamine, metarminol etc

99

Adrenergic antagonists

• I. Nonselective alpha receptor antagonists:• A. Haloalkylamines/alkylating agents:

phenoxybenzamine, dibenamine• B. Imidazoline derivatives: tolazoline, phentolamine• C. ergot alkaloids: ergotamine, dihydroergotamine• D. Miscellaneous: 1. Neuroleptics: chlorpromazine,

haloperidol• 2. benzodioxan derivatives: piperoxane and dibozane• 3. dibenzepine derivatives: azapetine

100

• II. Selective alpha adrenergic receptor antagonists:

• A. Selective alpha 1 antagonists:• 1. Quinazoline derivatives: prazosin, terazosin,

doxazocin• 2. Indole derivatives:indoramine• 3. Miscellaneous drugs:ketansarin, urapidil• B.Selective alpha2 adrenergic antagonists:

yohimbine, atipamezole

101

• Beta adrenergic receptor antagonists:• I.Nonselective: propranolol. Nadolol, timolol,

sotalol• II. Selective:• A.Selective B1 blockers: metaprolol, atenolol,

esmolol• B.Selective B2 blockers: butoxamineMixed antagonists:Labetolol,dilevalol, carvedilol

102

• Cholinergic agonists(cholinomimetics):• I. Direct acting• A.Choline esters: acetylcholine, bethanechol,

carbachol,,methacholine• B.Cholinomimetic alkaloids: pilocarpine (Pilocarpus

jaborandi ), arecoline (Areca catechu), muscarine, (from the mushroom Amanita muscaria) nicotine (Nicotiana tabacum)

• II.Indirect acting(Ch Esterase inhibitors)• A.Reversible: neostigmine. Pyridostigmine,

physostignine• B.Irreversible: malathion, parathion, dichlorovos,

sarin ,tabun etc103

Anticholinergic drugs

• Nonselectve:• A. natural alkaloids: atropine, hyoscine• B.Semisynthetic and synthetic: a. a.Mydriatics:

homatropine, tropicamide, cyclopentonate b. antisecretory drugs: propantheline,

glycopyrronium, dicyclomine, c. Antiparkinsons:nbenzhexol, procyclidine

104

• II. Selective:• A. M1 antagonists: pirenzepine, telenzipine• B. M2: tripitramine, methoctromine• C. M3: darifenacin, hexahydrosildifenidol

105

ANALGESICS: OPIODS AND NONSTEROIDAL ANTINFLAMMATORY AGENTS

Analgesics: Pharmacological agents

• OPIOIDS

• NON STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)

• CORTICOSTEROIDS

• LOCAL ANAESTHETICS

• Αlpha 2-AGONISTS

• KETAMINE, GABAPENTIN ETC.

OPIOID ANALGESICS

History of Opioids

• Opium is extracted from poppy seeds (Papaveer somniforum)

• Used for thousands of years to produce:– Euphoria– Analgesia– Sedation– Relief from diarrhea– Cough suppression

Terminology

• “opium” is a Greek word meaning “juice,” or the exudate from the poppy

• “opiate” is a drug extracted from the exudate of the poppy

• “opioid” is a natural or synthetic drug that binds to opioid receptors producing agonist effects

• Morphine analogues. These are compounds closely related in structure to morphine and often synthesised from it. They may be

• Agonists (e.g. morphine, diamorphine [heroin] and codeine),• Partial agonists (e.g. nalorphine and levallorphan) • Mixed agonist-antagonisor weak partial agonist (buprenorphine)

• Antagonists (e.g. naloxone, naltrexone). • Synthetic derivatives with structures unrelated to morphine:

– phenylpiperidine series (e.g. pethidine and fentanyl) – methadone series (e.g. methadone and dextropropoxyphene) – benzomorphan series (e.g. pentazocine and cyclazocine) – semisynthetic thebaine derivatives (e.g. etorphine and

buprenorphine

111

Pharmacological Effects• Sedation and anxiolysis

– Drowsiness and lethargy– Apathy– Cognitive impairment– Sense of tranquility

• Depression of respiration– Main cause of death from opioid overdose– Combination of opioids and alcohol is especially dangerous

• Cough suppression– Opioids suppress the “cough center” in the brain

• Pupillary constriction– pupillary constriction in the presence of analgesics is characteristic of

opioid use

Pharmacological effects cont’d.• Nausea and vomiting

– Stimulation of receptors in an area of the medulla called the chemoreceptor trigger zone causes nausea and vomiting

– Unpleasant side effect, but not life threatening• Gastrointestinal symptoms

– Opioids relieve diarrhea as a result of their direct actions on the intestines

• Other effects– Opioids can release histamines causing itching or more severe allergic

reactions including bronchoconstriction– Opioids can affect white blood cell function and immune function

Mechanism of action• Activation of peripheral nociceptive fibers causes

release of substance P and other pain-signaling neurotransmitters from nerve terminals in the dorsal horn of the spinal cord

• Release of pain-signaling neurotransmitters is regulated by endogenous endorphins or by exogenous opioid agonists by acting presynaptically to inhibit substance P release, causing analgesia

Primary Effect of Opioid Receptor Activation

• Reduction or inhibition of neurotransmission, due largely to opioid-induced presynaptic inhibition of neurotransmitter release

• Involves changes in transmembrane ion conductance– Increase potassium conductance (hyperpolarization)– Inactivation of calcium channels

Three Opioid Receptors

• Mu

• Kappa

• Delta • epsilon • Theta

Mu-Receptor: Two Types

• Mu-1– Located outside spinal

cord– Responsible for central

interpretation of pain

• Mu-2– Located throughout CNS– Responsible for

respiratory depression, spinal analgesia, physical dependence, and euphoria

Mu and Kappa Receptor Activation

Response Mu-1 Mu-2 Kappa

Analgesia

Respiratory Depression

Euphoria

Dysphoria

Decrease GI motility

Physical Dependence

Mu and Kappa Receptors

DRUGS MU KAPPA

Pure Agonists Agonist Agonist

Agonist-Antagonist

Antagonist Agonist

Pure Antagonists

Antagonist Antagonist

120

AGONISTS

*Morphine*Heroin

*Hydromorphone*Fentanyl*Codeine

*

122

OPIOIDS

• Morphine • Oxymorphone • Diamorphine[heroin] • Codeine • Nalorphine • Levallorphan • Pethidine (meperidine)• Fentanyl • Methadone • Nalbuphine• hydromorphone

• Dextropropoxyphene • Pentazocine• Cyclazocine• Etorphine• Buprenorphine • Sufentanil, • Methadone • Butorphanol• Alfentanil• Carfentanil• Remifenatnil • Tramadol hydrochloride

Indications• Acute/chronic moderate to severe visceral pain • In horses for various ailments, particularly to relieve acute

pain of spasmodic colic. • Combined with suitable tranquilliser as part of of neurolept

analgesia for the restraint of animals(wild) • To provide analgesia as part of a balanced anaesthetic

technique • Pentazocine as preanaesthetic in SA and horses • Some opiates are also used for the antitussive (eg: codeine,

hydrocodeine, hydrocodone, morphine) property and antidiarrhoeal (eg: loperamide, diphenoxylate, difenoxin) action.

Side effects

• Severe respiratory depression • Excitement (Transient, overstimulation of the CNS)

In animals such as. cats, horses, cattle, sheep, goats, pigs

• Irregular effects in horses and ox, requiring higher analgesic dosage

• Nausea and vomition, constipation, sedation, allergy , respiratory depression

• Reversed by specific opioid antagonists such as Naloxone or Naltrexone together with the suitable symptomatic therapeutic agents like antiemetics, respiratory stimulants etc.

Tramadol hydrochloride

• Centrally acting analgesic with opioid, monoaminergic, (monoamine reuptake inhibitor) and local anesthetic effects.

• Approved for acute or chronic mild to moderate pain relief in dogs and cats.

• Can be combined with other classes of analgesics including steroids, NSAIDs, NMDA antagonists, and gabapentin to allow a lower dose of both drugs

• Should not be combined with tricyclic antidepressants (TCA; eg: clomipramine), selective serotonin reuptake inhibitors ( SSRIs; eg: fluoxetine) or monoamine oxidase inhibitors (MAOI; eg: selegiline ) due to the risk of serotonin syndrome.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs)

• Most widely prescribed drugs in the treatment of pain and inflammation in many conditions.

The advantages over opioids No immunosuppressive and metabolic side effects

associated with corticosteroids. Devoid of sedation, hypotension, bradycardia and

respiratory depression Long acting analgesia for mild to moderately

painful conditions,   Analgesic, antipyretic and antiinflammatory

actions Not controlled substances

NSAIDS.. contd

Drawbacks Potencywise : lesser than opioids .with

their effect on visceral pain considered to be poor.

Other potential adverse effcets: gastric, hepatic and renal

Mechanism of action • Inhibition of cyclo-oxygenase (COX) enzyme(s) which leads

to a decrease in the synthesis of various prostaglandins and thromboxanes

• May also inhibit phospholipase A enzyme; major mechanism for effects of glucocorticoids on prostaglandin production.

• Few agents like ketoprofen and tepoxalin inhibit lipooxygenase enzyme involved in leukotrienes synthesis, in addition to cyclooxygenase inhibition

NSAIDS.. contdNSAIDS.. contd

COX-1 Virtually all tissues of the body Catalyzes the formation of constitutive PG, which mediate a

variety of normal physiologic effects including hemostasis, GI mucosal protection, and protection of the kidney from hypotensive insult.

COX-2 Activated in damaged and inflamed tissues and catalyzes

the formation of inducible PG, including PGE2, associated with intensifying the inflammatory response

Involved in thermoregulation and the pain response to injury.

COX-3 In brain, involved with central pain relief

NSAIDS.. contdNSAIDS.. contd

• Most are nonselective COX inhibitors, with COX 1 inhibition ratio being highest

• Meloxicam, nimesulide, etodolac and aceclofenac are considered as preferential COX-2 inhibitors.

• The newer ‘Coxib’ class of selective COX-2 inhibitors includes rofecoxib, celecoxib, valdecoxib, parecoxib, deracoxicb, etoricoxib, firocoxib, lumiracoxib

• Paracetamol (acetaminophen) is a selective COX-3 inhibitor with only analgesic and antipyretic actions, devoid of anti-inflammatory action

NSAIDS.. contdNSAIDS.. contd

Pharmacological Effects – Antipyretic, analgesic, and anti-inflammatory properties.

( acetaminophen: no antiinflammatory)– Less potent analgesics than opioids – Potent antithrombotic and antiendotoxic poroprties (few)

– Reduce the effect of endotoxaemia by inhibiting the production of eicosanoids and thromboxanes, which are responsible for many of the clinical manifestations of endotoxaemia such as changes in cardiovascular output (vasoconstriction, followed by vasodilation), and renal bl;ood flow, fever, ileus, leucopenia and a tendency to develop coagulaopathies. It is most common secondary to ischemic gastrointestinal injury or metritis.

Flunixin, phenyl butazone, ketoprofen and meloxicam are the most effective

–

NSAIDS.. contdNSAIDS.. contd

Indications • Pain resulting from musculoskeletal injury

either due to trauma or surgery

• As adjunctive therapy to antimicrobial treatment in acute respiratory diseases in cattle.

• Antiendotoxic to reduce endotoxaemia( eg: flunixin, phenyl butazone)

• Antithrombotic (eg: aspirin) to prevent thrombosis.

NSAIDS.. contdNSAIDS.. contd

Side /Adverse effects• Cellulitis, thrombophlebitis and tissue necrosis• Gastric ulceration • Renal toxicity • Haematological effects : Bleeding, thrombocytopenia,

haemolytic anaemia and agranulocytosis • Hepatotoxicity • CNS (behavioural disturbances, seizure precipitaion) • Skin (rashes, pruritus) manifestations

NSAIDS.. contdNSAIDS.. contd

Acetaminophen

• Little ulcerogenic potential • No effect on platelets or bleeding time. • More effective in inhibiting COX-3, in the

brain rather than in the periphery. • Dose-dependent adverse effects include

depression, vomiting, and methemoglobinemia

• Use in cats is contraindicated due to a lack of glucuronosyl transferase and the potential for hemolytic anemia and centrilobular hepatic necrosis.

Gabapentin– A newer anticonvulsant – Used in dogs and cats for the treatment of chronic pain,

particularly of neuropathic origin and also used in chronic arthritic pain and pain associated with malignancy.

– Most effective when combined with other types of analgesic agents, NSAIDs, permitting the use of lower doses.

– Side effects are mild sedation and ataxia. – Care to be taken in animals with decreased liver or renal

function. – It should not be discontinued abruptly because withdrawal may

precipitate seizures or rebound pain. – The dosage should be decreased over the course of two to three

weeks. – The commercially available human liquid-product contains

xylitol, which can be hepatotoxic in dogs.

Adjuvant analgesic drugs…contd

Other Antiinflammatories

CHRONDROPROTECTIVE COMPOUNDS• Heparinoids: Polysulfated glycosaminoglycan and Pentosan

polysulfate sodium • Sodium hyaluronate: • Chondroitin and glucosamine • Dimethyl sulfoxide (dimethyl sulphoxide, DMSO):

Antiseborrheic agents

Sulfur • Seborrheic dermatitis and primary seborrhea

sicca and oleosa.• keratolytic. antibacterialpossible antifungal

action of sulfur• nota good degreasing agent and is therefore

not as drying as other antiseborrheic agents.

Antimicrobial agents

Benzoyl peroxide• superficial and deeppyodermas• follicular flushing activity, in demodicosis• prominent degreasing activity• choice for patients with greasy or• oily skin. • at concentrations of 2–3%

Chlorhexidine

• greater efficacy for bacterial infections, particularly Staphylococcus spp, than for yeast or dermatophyte

• concentrations between 0.5% and 3%. • Shampoos containing combinations of• chlorhexidine and miconazoleOthers• fusidic acid • polymixin • Neomycin

Topical corticosteroids:• Mild: e.g. hydrocortisone prednisolone,

dexamethasone• Moderate: e.g. betamethasone valerate

triamcinolone acetonide fluocinolone acetonoide.

• potent: e.g. betamethasone dipropionate betamethasone valerate, diflorasone diacetate;

• Very potent: e.g. clobetasol propionate, halobetasol propionate,, betamethasone

PHARMACOLOGY OF GLUCOCORTICOIDS

ANATOMY

Adrenal Anatomy:• small, triangular glands loosely attached to the kidneys • divided into two morphologically and distinct regions :

adrenal cortex (outer) , adrenal medulla (inner)

Hormones of the Adrenal Medulla : Adrenaline (epinephrine ) , noradrenaline (norepinephrine)

Hormones produced by the adrenal cortex corticosteroids.-glucocorticoids an dmineral corticoids

Steroid Preparations

• Short-acting – (duration of action < 12 hours)

• Cortisone and hydrocortisone Intermediate-acting

– duration of action 12–36 hours);

– Prednisone, prednisolone, prednisolone sodium succinate, methylprednisolone, methylprednisolone acetate, and triamcinolone

Long-acting

– (duration of action > 36 hours)

– Dexamethasone, betamethasone, and fluocinolone

Pulse therapy: parenteral administration of supra pharma. doses of short acting

steroids for shorter periods of time

Short term therapy: ( <2weeks) • Use short acting steroids • Administer in divide doses ,BID• Used till the condition is controlled (4-7days)• Discontinue therwapy once the condition is controlled

Long term therapy • Starting as above for 2 weeks, then bring the dosage to the

lowest possible single dose per day. • Giving other adj. therapy: antihistaminics, NSAIDS to keep

steroid dose as low as possible. • Gradual withdrawl by tapering the dose, in order to avoid

iatrogenic hypoadrenocortisism.

Principles of GC therapy..contd

• Tapering the dose and gradually withdrawing before stopping therapy

to avoid iatrogenic hypoadrenocortisism.

• The antiinflammtory effect is palliative and routine use in inflammatory conditions should be avoided

• Short/Intermediate acting GC : more flexible dosing schedules, potent GC effects, lesser

suppression of HPAA and less GIT irritation.

Clinical Indications of GCs

Adrenocortical insufficiency (acute,chronic)Addison’s disease• In acute adrenocortical insufficiency, a rapidly acting

parenteral corticosteroid with the most mineralocorticoid effect available

• RelativeMC: most to the least potency is hydrocortisone > prednisolone/prednisone > methylprednisolone > dexamethasone

Clinical Ind. of GCs…contd

Allergic disorders • Dexamethasone injection, methylprednisolone

acetate inj. Susp.,methylprednisolone tablets prednisolone sodium succinate, triamcinolone acetonide inj. table suspension and triamcinolone tablets

• Allergic : such as bee stings, drug allergy, pruritic dermatoses

and allergic lung (rhinitis, astma) and GI diseases.

Clinical Ind. of GCs…contd

Ocular and Aural Inflammtion(otitis externa) • Important drug therapy for suppressing inflammation

in eye and ears• Topical steroids are used for conditions of the anterior

chamber• systemic steroids for posterior chamber• Contraindicated in viral infections, fulminant bacterial

infections, fungal infections, injuries (ulcers) and glaucoma

Clinical Ind. of GCs…contd

Musculoskeletal Inflammation• indicated for reduction of pain, inflammation, and

swelling in cond. of musculoskeletal disorders • osteoarthritis, bursitis, tendonitis, immune mediated

rheumatoid arthritis, myositis;• should be used in conjunction with therapies that

target the underlying cause

Clinical Ind. of GCs…contd

Adjunct therapy of cardiogenic ,hemorrhagic shock

• The primary treatment-adm. of large volumes of crystalloid solutions.• High doses of GC may aid in reversing some of the effects when

administered in conjunction with IV fluids• The rapidly acting ones dexamethasone sodium phosphate and

prednisolone sodium succinate • Short-acting soluble steroids such as the succinate esters • Routinely used in the treatment of circulatory shock. When given IV in

the early stages of shock, GC and aggressive fluid therapy may improve hemodynamics and survival rates

Clinical Ind. of GCs…contd

Adjunct therapy of septic shock (endotoxemia)• Use of GC is controversial • primary treatment- antimicrobial therapy and supportive parenteral fluid

therapy • High doses of a rapidly acting GC, preferably of short

duration, should be given in conjunction with fluid and electrolyte therapy within a short period of time, possibly less than 1 hour, after the onset of sepsis

Clinical Ind. of GCs…contdAs immunosuppressive in immune mediated haematopoietic and skin diseases

• immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, immune-mediated neutropenia

• Dexamethasone, prednisolone, and prednisone • immune mediated skin diseases like Systemic lupus erythematus,

pemphigus complexus. • Primary underlying causes should be ruled out to be certain therapy

is appropriate. • Myasthenia gravis. • Dogs and cats that do not respond well to anticholinesterase

treatment maybe considered candidates for corticosteroid therapy.• initially given GC at anti-inflammatory doses, which may be

increased to immunosuppressive levels over a 1-2 week period

Clinical Ind. of GCs…contd

Termination of pregnancy/ Induction of abortion

• Dexamethasone injection is used in the induction of abortion

• Generally administered after the 100th to 150th day of gestation, when prostaglandins administered alone are no longer effective

• usually administered in conjunction with a prostaglandin

• Risk of fetal mummification, retained placentas, metritis, or dystocia

Clinical Ind. of GCs…contd

Induction of Parturition• Dexamethasone,betamethasone and flumethasone• In conj. with a prostaglandin in order to produce a predictable

response time.• In cattle, retained placentas are a common sequale even when GC

are administered with prostaglandin • Parturition may be induced in the last few weeks of gestation to

speed the onset of lactation or to control timing of parturition • Involves much less risk to the fetus than earlier termination of

pregnancy.• Administration of GC more than 1 month before expected gestation

leads to poor neonatal survival

Clinical Ind. of GCs…contd

Intervertebral disc disease• Dexamethasone, flumethasone injection• supportive therapy in intervertebral disk disease (Hansen

type:1;disk syndrome).• Methylprednisolone, prednisolone, or prednisone,

administered at an anti-inflammatory dosage, may be a more appropriate choice of therapy in many cases

• However, acute paralysis due to intervertebral disk disease is an emergency usually requiring surgery and/or higher anti-inflammatory dosages of GCs

Clinical Ind. of GCs…contd

Ketosis in Cattle• Dexamethasone,flumethasone,isoflupredone

acetate,prednisolone acetate

• administered with IV glucose solutions

• For secondary bovine ketosis, GC should be used concurrently with other therapies for underlying disease, including local and systemic antibacterials to treat primary bacterial infections

• A significant decrease in milk production

DRUGS ACTING ON SKIN

Ethyl lactate

• mild superficial bacterial infections• in normal to dry skin.• Conflicting results arereported from various

studies: some show it to be as• effective as benzoyl peroxide, others that it is

no more• effective than water.

Triclosan

• antibacterial ingredient in some shampoos• used for seborrheic disorders and may be

helpful• in preventing infections of seborrheic skin.

Emollients

• fats such as lanolin, hydrocarbonssuch as paraffi n, petrolatum and

• mineral oil, humectants such as carboxylic acid and lactic acid

• oilssuch as olive, cottonseed, corn, almond, peanut and coconut oil.

• added to shampoos as vehicles and for their local effects in softening and protecting the skin.

Moisturizing agents

• Urea, glycerin and propylene glycol • protection and moisturizing of the• skin. • Essential fatty acids and colloidal oatmeal.

Mupirocin

• is an antibacterial agent G+ve• localized bacterial infections \effi cacious in

the treatment of felin acne, even when Malassezia spp rather than bacteria

Tacrolimus

• immunomodulator synthesized• for canine atopic dermatitis, perianal fi stula

and discoid lupus erythematosus.• It is also used for other immune-mediated

Antipruritic agents

• Hydrocortisone• antihistamines • aloe vera extracts