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DRUGS ACTING ON DIGESTIVE SYSTEM OF ANIMALS

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I. APPETITE STIMULANTS (OREXIGENS) IN MONOGASTRICS

B vitamin preparations : particularly used in horses as appetite stimulants

Glucocorticoids – increase gluconeogenesis and also have catabolic effects: -prednisone , PO is commonly used

Anabolic steroids: Anabolic effects with reduced androgenic effects. antagonize the catabolic effect of glucocorticoids, negative nitrogen balance associated with surgery, illness, trauma, and aging..Anabolic steroids stimulate hematopoiesis, appetite, and weight gain. adverse effects -hepatotoxicity, masculinization, and early closure of bony epiphyses in young animals. They are contraindicated in -congestive heart failure because of sodium and water retention. Stanozolol and boldenone undecylenate, used orally, IM in horses.

Benzodiazepines: act by GABA stimulation at appetite center and by central inhibition of the satiety center in the hypothalamus. Diazepam,. Elfazepam, Oxazepam, a metabolite of diazepam, , Used in cats ,less effective in dogs; po, IV -in cats

Cyproheptadine: An antihistamine with antiserotonin action. It promotes appetite by inhibition at

the serotoninergic receptors, which control sati antihistaminic and antiserotonergic agent. It acts as a 5-HT2 receptor antagonist and also blocks calcium channels.

• used in the treatment of allergies (specifically hay fever) and to stimulate appetite • used in serotonin syndrome, a complex of symptoms associated with SelectiveSerotonin

Reuptake Inhibitors (SSRI), especially when taken in excess dose, and in the disease carcinoid in which serotonin is overproduced by tumor cells.

• an useful alternative to benzodiazepine hypnotics in the treatment of insomnia, as it enhances sleep quality and quantity whereas benzodiazepines tend to decrease sleep quality

Side effects- sedation, likely due to its anti-histamine effects. Digestive system: epigastric distress (dysphagia), loss of appetite, nausea, vomiting, In cats as an appetite stimulant. CNS excitement and aggressive behavior may be seen.ety.

Megestrol acetate: a synthetic progestin with significant antiestrogen and glucocorticoid activity, resulting adrenal suppression-stimulate appetite and promote weight gain in people with cancer and cachexia in anorectic cats and dogs. It is contraindicated in pregnant animals and in animals with uterine disease, diabetes mellitus, or mammary neoplasia..

Anti psychotic ,antidepressant drugs , Bitters and Zinc – do have some appetite stimulating property

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II. EMETICS

The vomiting reflex is initiated by conditions that stimulate the Emetic/ Vomiting center(E/VC) of the medulla oblongata protected by Blood brain barrier(BBB).

Neurotransmitters involved in emesis

1. Acetyl choline - Primarily- Muscarinic receptor(M1); 2. Histamine- primarily H1 receptor (H2)

3. 5-HT- primarily 5HT 3 receptor; 4. Dopamine- primarily D2receptor; 5. Endorphins- Opoid (µ and δ) receptor

Receptors involved in sources of afferent input / stimulus to vomiting centre

Vomiting centre ----- M1 , H1 , (H2) 5HT 3 receptors;

CTZ ------- H1, D 2 , M1 , 5HT 1A , 5HT 3 5HT 4 and Opoid : endorphin (µ δ, ) receptor

Vestibular system ----- M1 M2 and H1 receptor;

Irritatin of pharynx, GIT, innervated by vagus afferent nerve( heart, liver gallbladder, kidney, ureter, uterus, bladder) and enteric afferent nerves

--- 5HT 3receptor, (α2 receptor)

CNS ---------- 5HT 1A , M1 , H1, 5HT 4 NK1 receptor

True emesis occurs in - cornivores, primates, swine felines some birds, reptiles; Emesis is Absent in – horse, ruminants, rodents, guinea pigs, rabbits

Potentail Causes: Adverse effect from drugs, medications ; Systemic disorders, infection, helminthiasis ; Vestibular dysfunction ; CNS infection ; Gastrointestinal disorders/ obstruction/ dysmotility/ infecion ; Hepatobiliary disorders and Radiation/ Chemotherapy (anticancerous therapy)

Emetics are the drugs/ agents used to evoke/ stimulate nausea and vomiting

Indication: to induce vomiting as a means of removing ingested poison/ toxic material; generally within 4 hours of ingestion; to remove ingested foreign body and Prior to induction of general anaesthesia

Contraindications: in corrosives- acid, alkali poisoning,- risk of perforation ; Petroleum products poisoning- aspiration due to low viscosity ; CNS stimulation state- precipitate convulsions ; Severe CNS depression, coma, unconsciousness- may aspirate vomitus ; Hernia, prolapse, oesophageal obstruction and recent abdominal surgery in which emesis may aggravate the condition

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Emetics stimulate either peripheral receptors or directly stimulate central vomiting centers.

Classification

1. Centrally acting emetics- stimulation of CTZ

Eg: Apomorphine, Xylazine HCl other drugs- Digitalis glycosides, NSAIDS

2. Peripherally acting/ reflex acting/ irritant emetics- distension of hollow organs- pharynx, oesophagus, stomach, duodenum reflexly induce emesis by irritation

Examples: Warm water, 1% CuSO4 ZnSO4 , Syrup of ipecac(Ipecacuanha), Hydrogen peroxide (3%), NaCl, Na2CO3 , Liquid dish washing detergents containing phosphates

1. Peripheral acting emetics

The mechanism is by - irritation of pharynx, esophagus, stomach, duodenum; or stretch of the muscular layer of the stomach or duodenum. Either mechanism evokes normal reflex arc to produce vomiting. These vary in reliability, safety, availability. The peripheral-acting emetics directly stimulate the pharynx, which triggers the E/VC via IXth cranial nerve, or the visceral afferent nerves of the stomach and intestines by causing irritation, inflammation, or distention.

1% copper sulfate: 25-30ml, efficacious in dogs and swine., stomach tube only

1% zinc sulfate : swine and dogs only, less reliable than copper sulfate

Freshly ground mustard seeds: half to one teaspoonfull/half cup water is also used as emetic

Neutral salts (sodium chloride, sodium bicarbonate): placed or thrown into the pharynx; salt crystals: half teaspoonful in half cup warm water , placed on back of tongue; vomition occurs within 15 mins. O verdosage/ repetitive doses are to be avoided as excessive absorption of ions may occur. Saturated sodium chloride solution: good efficacy in dogs, must be given by stomach tube; 1-3tsp oral, warm saturated solution, vomition within 15mins; Cerebral oedema-, convulsions are the – adverse effects

Syrup of ipecac: Cephaelis ipecacuanha- plant source; contains cephaline and emetine, toxic alkaloid that produces vomiting by acting as a stomach irritant.. 1-2mlper kg oral-D, 3.3ml per kg-Cat ; to be used only once.

Toxic to heart, liver, kidney ; recover by gastric lavage if emesis does not occur If repeated use fails to induce emesis, then gastric lavage is necessary to remove the emetine to prevent additional toxicosis.

Hydrogen peroxide (3%) stimulates vomiting via the ninth cranial nerve.

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• Small doses (5-10 mL) of hydrogen peroxide can be administered via oral syringe until emesis occurs squirt into oro-pharynx, rather difficult to accomplish.

• 1-5ml per kg, not more than 5oml- D: 10ml –C; Caution, especially in cats -aspiration of foam causes severe aspiration pneumonia.

2. Central acting emetics

Mechanism is by - stimulation of chemoreceptor trigger zone (CRTZ) and/or direct stimulation of emetic center.

Also, Centrally stimulated vomition can result from by

intracranial stimuli (head trauma, increased intracranial pressure, or psychic stimuli) stimulation of the vestibular apparatus (motion sickness, vestibulitis). toxins or drugs, such as digoxin and anticancer drugs, directly stimulate the chemoreceptor

trigger zone (CTZ) because it is not protected by a complete blood-brain barrier. Acetylcholine is the primary neurotransmitter acting on the VC

CTZ is stimulated by dopamine, α2 –adrenergic drugs, serotonin and histamine

Apomorphine: stimulates CRTZ, then depression of emetic center

o reflex can only be triggered once o if no emesis occurs, recover by gastric lavage o depression of CNS in most species , excitement in cats

most effective (reliable) emetic in the dog absolutely ineffective in swine Solution for subcutaneous injection, tablets for injection ,subconjunctival placement of tablet

Contraindications: CNS or respiratory depression;ingestion of strong acid, base & petroleum products;hypoxia and dyspenia ; shock; in the absence ofnormal laryngeal reflexes; coma, seizure; severephysical weakness; apomorphine sensitivity; CNSdepressant toxicity and in unconscious patients

Over dose symptoms: CNS depression; restlessness;respiratory depression; protracted emesis, in thesecases administration of narcotic antagonist ( e.g.Naloxone 0.04mg/kg ) is usefulPhenothiaze derivatives interact and negate emetic effect of apomorphine. Morphine: mechanism as for apomorphine; choose this as pre-med when emesis is desired pre-operatively; otherwise, apomorphine is preferred

Xylazine: stimulation of CRTZ; α 2 agonist: fast acting; good to excellent sedation lastsup to 90-120 min; excellent analgesic activity lasts 15-30 min; α 2 stimulation in CTZ: fast acting(1-5 min after IM administration) effective in cats (0.44 mg/kg) and less effective in dogs ; 0.05mg/kg: emesis without sedatio

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Contraindications: cardiac arrhythmia ; Epinephrine administration especially in the case of Halothaneanesthesia , during 3rd trimester of pregnancy

Syrup of Ipecac (Ipecacuanha) : emetine stimulates CRTZ

III. ANTIEMETICS

Protracted vomiting- causes physically exhaustion, dehydration, acid-base (Metabolic . alkalosis) and electrolyte disturbances(Hyponatremia, H+ loss, hypochloremia), and aspiration pneumonia.

Indications of antiemetics: 1. to control excessive nausea and vomiting induced by drugs, systemic diseases; 2. to prevent motion sickness and psychogenic vomiting,3. to control emesis from radiation and chemotherapy.

Antiemetics may act peripherally to reduce afferent input from receptors or to inhibit efferent components of the vomiting reflex response. OR centrally to block stimulation of the CTZ and emetic center

I. Centrally acting antiemetics:

1. Prokinetic drugs :

Dopamine antagonists: Metoclopramide, Clebopride, Bromopride ,Alizapride, Domperidone

2. Antihistaminics: Cyclizine,Meclizine Promethazine Hydroxyzine , diphenhydramine, dimenhydrinate,

3. Anticholinergics : Scopalamine(Hyoscine),Methscopolamine .Dicyclomine Glycopyrrolate, Propantheline, Isopropamid

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4. Serotonin (5-HT3) antagonists: Ondansetron ,granisetron, aloesetron ,palonosetron, dolasetron , tropisetron

5. Butyrophenone tranquillisers: Butorphanol, Droperidol, Haloperidol

6. Phenothiazine tranquilizers: Acepromazine,Triflupromazine,Chlorpromazine,prochlorperazineTrifluperazine, perphenizine, mephazine

7. Cannabinoids: Cannabis (Marijuana), Dronabinol, Nabilone

8. Benzodiazepines : Midazolam, Lorazepam , Alprazolam

9. Neurokinin type 1 (NK-1) receptor antagonists: Aprepitant , Maropitant citrate, casopitant

II. Peripherally acting antiemetics:

1. Prokinetic drugs - Dopamine antagonists: metoclopramide, domperidone

2.Alimentary demulcents- dextrose, glycerin, kaolin, pectin- limited benefit clinically : may control vomiting associated with pharyngitis, gastritis. poor efficacy (may even stimulate vomiting)

3.Antacids- NaHCO3, Al, Mg, Ca salts- carbonate, hydroxides, oxides: indicated for vomiting associated with excess gastric acidity. However, efficacy is questionable except to prevent recurrence (may stimulate vomiting in acute cases)

4.Antispasmodics/GI sedatives: topical/ local anaesthetics : oxethazine, benzocaine, chlorbutol- indicated for vomiting associated with pharyngitis; poor efficacy, may stimulate vomiting

5. Antimuscarinic antispasmodics /GI sedatives - Scopalamine(Hyoscine), Methscopolamine.Dicyclomine, Glycopyrrolate etc

6. Corticosteroids - Dexamethasone , Betamethasone, methyl prednisolone

7. Others- H2 receptor antagonists( cimetidine, ranitidine, etc) , Trimethobenzamide , Ginger , Propofol, Peppermint

PHENOTHIAZINE TRANQUILIZERS

Broad spectrum antiemetic in small animals; Affect almost all centrally origin emesis except those of labrynithitis , at low doses via anti dopaminergic and at higher doses by .antichilonergic mechanisms They antagonize the CNS stimulatory effects of dopamine, thereby decreasing vomiting from many causes and also have antihistaminic and weak anticholinergic action

Peripheral α blockade: sedation& hypotension and .may need fluid replacement therapy

side effects -hypotension due to α-adrenergic blockade, excessive sedation, extrapyramidal signs, and a lowering of the seizure threshold in epileptics.

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Extrapyramidal signs : involuntary muscle spasms, restlessness and aggression, which can be counteracted with an antihistamine (diphenhydramine).

Note: Pyramidal system: collection of nerve tract within the medulla oblongata enrouting from cerebral cortex to spinal cord. Extrapyramidal system: system of nerve tract and pathways connecting cerebral cortex, basal ganglion, thalamus, cerebellum, reticular formation and spinal neurons in complex circuits. EPS -mainly concerned with the regulation of stereotyped reflex muscular movements.

Butyrophenone derivatives also are potent anti dopaminergic; potent antiemetic& sedative; antipsychotic agents in human and show side effects similar to phenothiazines

ANTICHOLINERGICS

They block cholinergic afferent pathways from the GI tract and the vestibular system to the vomiting center. Alone, they are less effective than the other emetics. brief duration of effect and cause excitement in cats. Peripherally acting anticholinergic drugs include glycopyrrolate, propantheline, and methscopolamine Only isopropamide and propantheline are commonly used in small animals for vomiting related to vestibular stimulation

ANTIHISTAMINICS (H1 receptor antagonists)

Block both cholinergic and histaminergic nerve transmission responsible for transmission of the vestibular stimulus to the vomiting center. The histamine (H1)-blocking drugs include diphenhydramine, dimenhydrinate, promethazine (a phenothiazine with H1 -blocking effects), cyclizine, Cinnarizine and meclizine(Most potent). They may cause mild sedation, especially diphenhydramine, dimenhydrinate, and promethazine. Cyclizine and meclizine are potentially teratogenic at high doses

DOPAMINE ANTAGONISTS

They inhibit the class of receptors that binds dopamine, a hormone and neurotransmitter.

Dopamine is an emetic and can induce nausea, hence blocking dopamine receptors is another treatment of Chemotherapy induced nausea and vomition(CINV). Dopamine antagonists act in the brain and are used to treat nausea and vomiting associated with neoplastic disease, radiation sickness, opioids, cytotoxic drugs and general anaesthetics.

Droperidol, Haloperidol, Chlorpromazine, Promethazine, Prochlorperazine. Some of these drugs though antidopaminergic, are limited in their usefullness by their extra-pyramidal and sedative side-effects. Other specific agents include: domperidone, metoclopramide etc some of which do have prokinetic action

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Note: Prokinetics/Gastrokinetics : are the agents which increase the movement of ingested material through the gastrointestinal I tract , by inducing coordinated motility patterns ; They are useful in the treatment of GI motility disorders

DOMPERIDONE

Antidopaminergic drug, used orally, rectally or intravenously, act on CTZ, not protected by BBB

Chemically similar to- Haloperidol: Pharmacologically similar to - Metoclopramide, but with lower antiemetic efficacy and without EPS signs. Pharmacokinetic action is not blocked by atropine( only D2 receptor involved). Does not cross the blood-brain barrier; thus do not exhibit ExtraPyramidal Signs( EPS)

The hormone prolactin stimulates lactation in humans, and its release is inhibited by the dopamine secreted by the hypothalamus. Domperidone, by acting as an anti-dopaminergic, results in increased prolactin secretion, and thus promotes lactation.

Clinical Uses: It is used alone or together with metoclopramide, cyclizine, and 5HT3 antagonists in the treatment of nausea and vomiting.; in the treatment of gastroparesis and for paediatric Gastroesophageal reflux (infant vomiting). And also used to stimulate lactation. ( Hyper prolactinaemia, fatigue, irritability, depression-side effects) . Dose -0.1 to 0.5mg per kg- oral-

METOCLOPRAMIDE

Act both centrally and peripherally , Readily crosses the blood-brain barrier , thus may show EPS

Exerts antiemetic effects via 3 mechanisms. :

a) Anti dopaminergic (D2) transmission in the CNS; -antiemetic action

b) 5HT4 agonistic action - on GIT- ACh release from myenteric neurons-prokinetic action

c) 5HT3 antagonistic action in CTZ-antiemetic action

Effects: In the upper GI tract, it increases both ACh release from neurons and cholinergic receptor sensitivity to ACh . Metoclopramide stimulates and coordinates esophageal, gastric, pyloric, and duodenal motor activity

It also increases lower esophageal sphincter (LES) tone and stimulates gastric contractions; while relaxing the pylorus and duodenum. (Inadequate cholinergic activity is incriminated in many GI motility disorders; therefore, metoclopramide is most effective in diseases where normal motility is diminished or impaired. )

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It is indicated in Emesis induced by chemotherapy, nausea and vomiting associated with delayed gastric emptying, reflux gastritis, and viral enteritis.

Concurrent use of phenothiazine and butyrophenone tranquilizers to be avoided, because they also have central antidopaminergic activity, so they increase the potential for extrapyramidal reactions.

GI obstruction must be excluded prior to initiating metoclopramide therapy. Atropine and opoid analgesics antagonise the action.( 5HT4- Ach release) Absorption of drugs which mainly absorb in the small intestine: Cimetidine,Aspirin,Diazepam

Tetracycline, Acetaminophen Absorption of drugs which mainly absorb in the stomach: Digoxin Modification of dose or timing of Insulin injection

Indications of metoclopramide

As antiemetic: primarily indicated for the relief of nausea and vomiting associated with post operation, disease, irradiation, drug induced less effective in motion sickness and for GERD(gastro esophageal reflux disease) in humans

As Prokinetic : Gastric Emptying Disorders -Delayed gastric emptying , chronic constipation; ; Small bowel motility disorders- is less effective in the distal small intestine and colon; Disorders of ruminoreticular motility -Bloat (free gas bloat) and ruminal impaction( by LES relaxn and gastric emptying)

Contraindications: GI obstruction/perforation, Epilepsy and patients receiving neuroleptics -phenothiazine and butyrophenone tranquilizers (as EPS signs are potentiated)

Side effects: At high doses or with rapid IV administration, metoclopramide causes CNS excitement by dopamine antagonism (similar to the phenothiazine tranquilizers). Extra pyramidal effects, temporary hypotension& elevated prolactin level and may affect Insulin dose and timing

Extrapyramidal signs- involuntary muscle spasms, restlessness and aggression, which can be counteracted with an antihistamine -diphenhydramine.( by the central anticholinergic action)

Long term sid effects- galactorrhoea, gynaecomastia

Clebopride is a dopamine antagonist drug with antiemetic and prokinetic properties used to treat functional gastrointestinal disorders. Chemically, it is a substituted benzamide, closely related to metoclopramide.

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Bromopride : indicated in the treatment of nausea and vomiting, including postoperative nausea and vomiting (PONV); gastroesophageal reflux disease (GERD/GORD); and as preparation for endoscopy and radiographic studies of the gastrointestinal tract.

Also found useful in hiccups and gastrointestinal adverse effects of radiation therapy.

Adverse effect: somnolence and fatigue. rarely cause extrapyramidal symptoms and, as metoclopramide, may increase prolactin levels.

Alizapride is a dopamine antagonist with prokinetic and antiemetic effects used in the treatment of nausea and vomiting, including postoperative nausea and vomiting. It is structurally related to metoclopramide . Cisapride and mosapride are the prokinetics without antiemetic action

5-HT3 ANTAGONISTS

These compounds effectively block the normal signaling through the 5-HT3 receptor, inhibiting the emetogenic impulses both at peripheral and central origin, from reaching the vomiting centre. They are specific inhibitors of 5-HT 3 (Serotonin) receptors in the CTZ; No blocking of other type of receptors.

Cytotoxic drugs and radiation -release of serotonin from intestinal mucosa and these are the most effective antiemetics in radiation and chemotherapy induced nausea and vomition , not effective for emesis caused by motion sickness .; Efficacy in Post Operative Nausea and Vomition (PONV) is not well established as it is multifactorial

CANNABINOIDS

Drugs that bind to cannabinoid receptors (CB) found throughout the central (CB1) and peripheral (CB1 and CB2) nervous systems. Dronabinol is a naturallu occurring cannabinoid, extracted from Cannabis (Marijuana) plant - Cannabis sativum

Endogenous cannabinoids produced in humans that bind weakly to these receptors. ; Synthetic cannabinoids –nabilone, dronabinol- are ‘Schedule drugs’

The excat antiemetic mechanism of action is not clear. They are thought to act as agonists to the CBs on neurons and vomiting centre. and partially block the release of other neurotransmitters. ,used in patients with cachexia, cytotoxic NV , unresponsive to other antiemetic agents.

NK 1 RECEPTOR ANTAGONIST / BLOCKER.

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They block the Central neurokinin receptors NK1. These are the receptors fro substance P, belonging to tachykinin family of neurotransmitters and is in vagal afferent nerve fibres innervating the somatic nervous system and area postern of brain.

They are effective for Cancer chemotherapy-induced and radiation-induced vomiting. (Better than 5-HT3 for delayed vomiting) and also effective for post-operative vomiting. Maropitant has been approved for motion sickness prevention in dogs, however is extremely expensive

CORTICOSTEROIDS

By suppressing peritumoral inflammation and PG production, given in conjunction with 5-HT3

antagonists to augment their effects in CINV. . NSAIDS have similar beneficial effects in Irradiation induced NV. Dexamethasone and betamethasone are the preferred ones.

BENZODIAZEPINES

Lorazepam and Alprazolam; themselves not effective antiemetics, but their sedative , antianxiety and amnesic effects are helpful in reducing anticipatory component of nausea and vomition.

OTHERS

Ginger (Emetrol) has antiemetic action . Trimethobenzamide.HCl is a Potent antidopaminergic, weak antihistaminergic; suppresses CTZ ,no effect on emetic center Controls emesis due to: radiation sickness disease, drugs, infections, anesthesia and uremia

H 2 receptor antagonists - cimetidine, ranitidine, etc. are indicated in vomiting associated with excess gastric acidity. Injectable dose forms are preferred over oral antacids

Butorphanol – has been used in cisplatin chemotherapy. , show mild sedation.,antiemetic effect on the vomiting center. Propofol (IV) used in an acute care setting in hospital as a rescue therapy for emesis. Peppermint claimed to help nausea or stomach pain.

GASTROINTESTINAL ULCERS

The occurrence of GI ulcers is mainly in association with physiologic stress (endogenous cortisol), dietary management or as a sequela of administration of ulcerogenic drugs.

Helicobacter organisms, - Helicobacter pylori , the most frequent cause of ulcers in humans, appear to be involved in some cases of gastritis in animals

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Potential causes : drugs—NSAID and corticosteroids; neoplasia—lymphosarcoma, adenocarcinoma, gastrinoma (Zollinger-Ellison syndrome), and mastocytosis; systemic disease—renal or hepatic disease, hypovolemic shock, hypoadrenocorticism, sepsis, spinal injury, and pancreatitis; other causes— Helicobacter spp , pyloric outlet obstruction, inflammatory bowel disease, chronic gastritis.

Mild gastric ulcers seen in foals, heal without treatment or clinical signs. The prevalence and severity of ulcers increase as the intensity of work increases and also varies by location of ulcers within the stomach and tends to be highest in the nonglandular squamous mucosa. Abomasal ulcers affect mature cattle and calves and have several different manifestations

Abomasal ulcers are very common in milk-fed calves after they have consumed milk or milk replacer for 4-12 wk. Most of these are subclinical and nonhemorrhagic. Occasionally, milk-fed calves <2 wk old are affected by acute, hemorrhagic abomasal ulcers that may perforate and cause rapid death.

Also arise in association with lymphosarcoma, abomasal disorders (displacement or volvulus), or increased intraluminal pressure causing ischemia of abomasal mucosa; they may also appear to be unrelated to other disease.

Physiology of acid secretion

Aggressive factors/agents: Gastrin (G), ACh (M2), Histamine(H2), Pepsin, H. pylori

Defensive factors: PGE2. PGI2,( cytoprotective) HCO3 and mucous production Gastric epithelial barrier( PL& LP), mucosal blood flow. Whenever there is Imbalance- between these 2 factors------ it results in formation of GASTRIC/ DUODENAL ULCERS

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IV. ANTIULCER DRUGS

1. Acetylcholine M1 Receptor Antagonists: propantheline, telenzepine, pirenzipine, atropine, oxyphenonium etc

2. Antacids : NaHCO3, CaCO3, AlOH3, MgCO3, MgOH etc 3. Histamine (H2)-receptor antagonists: ranitidine, famotidine, nizatidine, roxatidine etc 4. Proton-pump(H+ K+ATPase) inhibitors: omeprazole, lansoprazole, esomprazole,

rabeprazole, pantoprazole etc 5. Cytoprotective/ ulcerhealing drugs: sucralfate, CBS( colloidal bismuth subcitrate) 6. Prostaglandin E1 analogues: misoprostol, enprostil, rioprostil etc

1. ACETYLCHOLINE M1 RECEPTOR ANTAGONISTS

They inhibit acid secretion by antagonizing the muscarinic cholinergic receptor on gastric parietal cells. Most antagonists are nonselective, however, and should not be used as gastric anti-secretory agents.

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Pirenzepine and telenzepine, selective M1 cholinergic antagonists, inhibit cholinergically mediated gastric acid secretion without significant effects on other muscarinic receptors (M2, M3) that mediate GI, airway, and urinary bladder smooth muscle contraction

2. ANTACIDS

An antacid is any substance, generally a base, which counteracts stomach acidity.,i.e.- stomach acid neutralizers.

Mechanism of action-

• they buffer gastric acid, raising the pH to reduce acidity in the stomach., neutralize stomach acid to form water and a neutral salt

• signal pain to the central nervous system, when gastric nerves are exposed to HCl, as in peptic ulcers.

Other mechanisms that contribute- the effect of aluminum ions inhibiting smooth muscle cell contraction and delaying gastric emptying

• Orally taken to relieve heartburn, the major symptom of gastroesophageal reflux disease or acid indigestion.

• symptomatic and only justified for minor symptoms. Peptic ulcers may require H2-receptor antagonists or proton pump inhibitors.

• Only neutralise, do not decrease acid production

• Decrease pepsin activity, binding to bile acids in the stomach and stimulating local prostaglandin (PGE1) production

• Frequently interfere with the GI absorption of concurrently administered drugs (eg, digoxin, tetracyclines, fluoroquinolones).

• Not to be given within 2 hours of other oral medications

• Used with meal to avoid “Acid Rebound”- due to negative feedback gastrin release

• Alginates form a raft that floats on the surface of the stomach contents and provide a physical barrier to gastro-oesophageal reflux. are found in preparations combined with an antacid

• Simethicone (activated dimethicone) is frequently added to antacids as 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 in humans .

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Indications: 1. Symptomatic relief of dyspepsia (indigestion) and heartburn, as and when required 2. Gastro-oesophageal reflux disease (GORD/ GERD) in infants and pregnancy 3. Gastritis 4. Gastric/ peptic ulcer 5. bloat, ruminal acidosis, grain overload in ruminants

a.Systemic antacids: eg: sodium bicarbonate (Baking Soda, Soda Mint), Na citrate, Na acetate

These are highly soluble in gastric fluids; once dissolved, they are absorbed readily; They have a rapid onset, short duration of action (transcient/temporary) lasting for only 1-2 hours

Most likely to cause acid-base and electrolyte disturbances. May cause metabolic alkalosis especially when used in high dose or in renal insufficiency or for prolonged period.

Being water soluble, it may result in rapid CO2 liberation – results in belching and this stimulates/ sends negative feedback to release more gastrin secretion with a secondary rise in acid secretion referred as ‘Rebound hyperacidity’ ; leading to perforation/ ulcer. To avoid thie rebound hyper acidity, usually these agents are administered with a meal/food

Long term use can result in cause metabolic alkalosis , Produced NaCl may cause water retention in cardiac &renal insufficiency, hypertension cases

b. Non systemic antacids eg: Aluminum carbonate ,Aluminum hydroxide Aluminum phosphate, Calcium carbonate , Dihydroxy-aluminum sodium carbonate , Mag aldrate , Magnesium Hydroxide (Milk of Magnesia, MOM), Magnesium oxide, Sodium carboxy methyl cellulose

-most useful agents for long-term therapy

- although a small proportion of the antacid may be absorbed, most of the dose remains in the GI tract and will not alter systemic acid base balance or electrolyte levels

-caution must be used in administering magnesium-containing antacids to clients with impaired renal function

Most non-systemic antacids will cause either constipation or diarrhea Not absorbed systemically., transcient action (1-2 hrs) Combinations of magnesium hydroxide and aluminium hydroxide; optimize the buffering capabilities of each compound and balance the constipating effect (from aluminum hydroxide) and the laxative effect (from magnesium hydroxide). In ruminants, magnesium hydroxide -as a laxative in the treatment of rumen overload syndrome, acidosis. Difficult to administer and require frequent dosing in small animals, thus they are not as popular as newer therapeutic agents for gastritis/acidity

Antacids interactions:

Chelation -Chemical binding, or inactivation, of another drug Chemical inactivation Produces insoluble complexes Result: reduced drug absorption

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Increased stomach pH: Increased absorption of basic drugs a nd Decreased absorption of acidic drugs

Increased urinary pH: Increased excretion of acidic drugs and Decreased excretion of basic drugs

Side effects:

Al salts : formation of insoluble aluminum-phosphate-complexes, hypophosphatemia and

osteomalacia., accumulation may occur in presence of renal insufficiency. ; cause constipation. Often used with magnesium to counteract constipation

Mg salts: Mg may accumulate in patients with renal failure leading to hypermagnesemia, with cardiovascular and neurological complications. Commonly cause a laxative effect. Usually used with other agents to counteract this effect

CO3 : regular high doses may cause alkalosis, which in turn may result in altered excretion of other drugs, and kidney stones.; rebound hyperacidity

Ca salts: may increase calcium output in the urine, which might be associated to renal stones. ;Constipative. May cause constipation. Their use may result in kidney stones. Long duration of acid action may cause increased gastric acid secretion (hyperacidity rebound)

Na: increased intake - deleterious for arterial hypertension, heart failure and renal diseases.

3.HISTAMINE (H2) RECEPTOR ANTAGONISTS

Competitive inhibitors of histamine at the parietal cell H2 receptor; effectively block gastric acid secretion from parietal cells by blocking the H2 receptor

They suppress the normal secretion of acid by parietal cells and the meal-stimulated secretion of acid. by two mechanisms:

a) histamine released by ECL cells in the stomach is blocked from binding on parietal cell H2

receptors which stimulate acid secretion, b) other substances that promote acid secretion (such as gastrin and acetylcholine) have a

reduced effect on parietal cells when the H2 receptors are blocked

Potencywise: Famotidine >Nizatidine >Ranitidine >Cimetidine

Food delays the absorption of cimetidine, minimal effect on ranitidine, enhances absorption of famotidine . These agents have antiulcerogenic effects, with no direct effect on gastric/ oesophageal motility

Indications:

1. Peptic Ulcer Disease (PUD), Gastroesophageal Reflux Disease (GERD), Dyspepsia,Stress Ulcer Prophylaxis 2. Gastric ulcers in canines, foals, and pigs. 3.Prolonged inappetence

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in ruminants 4. Abomasal ulcers in cattle and calves -Specific H2 receptors mediated gastric acid secretion in abomasums (true stomach) is blocked

Abomasal ulcers are common in high-producing cows within the first 6 wk after parturition. The most likely cause is prolonged inappetence, which results in sustained periods of low abomasal pH.Patients with heartburn (GERD) infrequently antacids or H2-receptor antagonists preferred.

The advantages of H2-antagonists over antacids –

• longer duration of action (6–12 hours v/s 1–2 hours for antacids), greater efficacy, and ability to be used prophylactically before meals to reduce the chance of heartburn occurring

Cimetidine has many adverse effects and drug interactions, because of which it is nless frequently used clinically . the adverse effects of cimetidine include: hypotension. headache, tiredness, dizziness, confusion, diarrhea, constipation, and rash, may also cause gynecomastia in males, loss of libido, and impotence,( antiandrogenic) which are reversible upon discontinuation

Drug interactions

Antacids reduce the absorption of al H2 receptor antagonists. Therefore they should be administered at least 1hour before or after H2 receptor antagonists

Cimetidine in particular interferes with mechanisms of drug metabolism and elimination through the liver , cytochrome P450 pathway. It is an inhibitor of the hepatic microsomal P450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. By reducing the metabolism of drugs through these enzymes, cimetidine may increase their serum concentrations to toxic levels.

Examples of drugs affected : warfarin, theophylline, phenytoin, lidocaine, quinidine, propranolol, labetalol, metoprolol, tricyclic antidepressants, benzodiazepines, dihydropyridine calcium channel blockers, sulfonylureas, metronidazole.

Contraindications: sensitivity to drug, in pediatrics and those patients with severe hepatic& renal insufficiency

Relapse of gasrtoduodenal ulcers, may be due to rebound hyper secretion .Famotidine& Nizatidine : less likelihood of rebound hyper secretion while Cimetidine has the most potential for rebound hyper secretion

4. PROTON PUMP INHIBITORS (H+ K+ATPase Inhibitors)

These agents inhibit the sodium/potassium proton pump (H+ K +ATPase) at the luminal surface of the parietal cell that secretes hydrogen ions into the gastric lumen.

The parietal cells release positive hydrogen H+ ions (protons) during HCl production. This process is called the “proton pump.” H2 blockers and antihistamines do not stop the action of this pump

Mechanism of action : Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or more commonly referred as t

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gastric proton pump) of the gastric parietal cell. This bond prevents the movement of hydrogen ions from the parietal cell into the stomach. The Result is : Achlorohydria—gastric acid secretion is blocked. In order to return to normal acid secretion, the parietal cell must synthesize new H+/K+ ATPase.

The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion. (“Irreversibility” refers to the effect on a single copy of the enzyme; the effect on the overall human digestive system is reversible, as the enzymes are naturally destroyed and replaced with new copies.)

Targeting the terminal-step in acid production, as well as the irreversible nature of the inhibition, these class of drugs are significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%.

The lack of the acid in the stomach though will aid in the healing of duodenal ulcers, and reduces the pain from indigestion and heartburn, the disadvantage of PPIs is that lack of sufficient hydrochloric acid,/ HCl. (called hypochlorhydria) .Hydrochloric acid is required for the digestion of proteins and for the absorption of nutrients, particularly of vitamin B12 and of calcium.

The proton pump inhibitors are given in an inactive form. They are unstable in acidic environment thus are encapsulated in enteric coated granules. The inactive form is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (like the parietal cell canaliculus) that have acidic environments.

In an acid environment, the inactive drug is protonated and rearranges into its active form. As described above, the active form will covalently and irreversibly bind to the gastric proton pump, deactivating it

Omeprazole is (30 times > potent than Cimetidine) a weak base, acid labile , inactive enteric coated capsule or slow release formulation, absorption takes place in intestine

Omeprazole is the racemate, containing a tricoordinated sulfur atom in a pyramidal structure and therefore can exist in equal amounts of both the S and R enantiomers. In the acidic conditions(pH< 5) of the stomach, both are converted to sulphonic acid and sulphenamide configuration, which reacts covalently with SH group in H+/K+ ATPase, thereby destroying the ability of the parietal cells to produce gastric acid.

Food decreases bioavailability up to 50%, should be administered 1 hour before meal It Inhibits cytochrome P.450 hepatic enzymes : decreases metabolism of :Diazepam,Phenytoin,warfarin

Increases gastric PH and decreases absorption of drugs that need low PH for absorption : Ketoconazole, ester and metal salts of Ampicillin

The Advantages of PPIs include : Faster onset of action (1 hour); Long lasting acid suppression effect (resumes only after 3-5 days of stopping the drug; limited ADRs; single oral dose daily and More effective than H2 blockers as less likely to involve in drug interactions

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Side effects : Generally Well tolerated in human, dog and cat with mild GIT disturbances: anorexia, colic, nausea& emesis, bloat, diarrhea. GIT infections, proteinurea, CNS disturbances(Hematological abnormalities( rare in human), Decrease in absorption and serum level of Vit.B12

Duration of treatment: dog 4weeks up to to 90days, minal pain, nausea,dizziness, Omeprazole - mucosal cell hyperplasia, hypertrophy and development of carcinoids ; avoided in condition of bleeding ulcers.

Absorption : in small intestine ,completed within 3-6 hours. The systemic bioavailability after repeated dose - 60%. . Concomitant intake of food has no influence on the bioavailability.

Metabolism : cytochrome P450 system, mainly in the liver. metabolites - sulfone, the sulfide and hydroxy-omeprazole Excretion- urine . feces, primarily originating from bile

Indications of PPIs : Stress ulcers, peptic ulcers, NSAID induced ulcerations, GERD, ZES :Zollinger –Ellison syndrome in humans, Integral component of H,Pylori therapy kit together with antibiotics and antiprotozoal agents

5.ULCER PROTECTIVES / ULCER HEALING DRUGS

Sucralfate : cytoprotective alkalinizing drug composed of sulfated sucrose and polyaluminum hydroxide. In the acidic environment of the stomach, sucralfate is extensively cross-polymerized to form a viscous gel that binds to the necrotic tissue proteins in an ulcer. -act as a diffusion barrier .

It has Local effects > systemic effects. That is it has got Least systemic absorption after oral administration. Reacts with gastric HCl, forms a insoluble pasty complex , bind to exudates protein of the damaged tissue (anions of the GIT epithelium cell membrane) which forms a barrier in the damaged area and protects the damaged tissue .form more injuries by acid, bile and pepsin It also binds with and inactivates bile acids & pepsin

It has no acid neutralising action, but additional beneficial effects - stimulation of PG production, adsorption of bile salts, and inactivation of gastric pepsins

Binds with &accumulates epidermal growth factor.in damaged area. Stimulates local production of PGI2,PGE2 & nitric oxide which leads to increase in mucosal blood .flow

.Directly stimulates mucosal angiogenesis, also has Some antacid activity, may decrease gastric emptying rate

Minimal oral absorption, . Combination therapy (sucralfate + histamine H2 antagonist, or sucralfate + H+, K+ - ATPase inhibitor) is frequently employed

• It is the effective and safest drug in treating gastric erosion/ulcer and patients receiving NSAID therapy

Colloidal Bismuth Subcitrate: It is not an antacid particularly; thought to act by increasing HCO3 ,PGE2 mucous production by unclear mechanism

Carbenoxolone sodium: Glycerrhiza glabra ( Liquorice)triterpenoid derivative, decreases pepsin action and prolong gastric epithelial cell lifespan. Increase mucus production . Side efft- Na, Water retention (Mineral . Corticoid like action)

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6. CYTOPROTECTIVE AGENTS

Endogenously produced prostaglandins (PGE) promote gastric mucosal defense mechanisms by inhibiting parietal cell acid secretion and by stimulating mucosal blood flow, bicarbonate secretion, mucus secretion, and epithelial cell renewal.

Prostaglandin E 2 (PGE1 ?)Analogues: similarly, Promote gastric mucosal defense mechanisms, inhibiting parietal cell acid secretion,stimulating mucosal blood flow ,bicarbonate secretion, mucus secretion and epithelial cell renewal

Misoprostol – methyl PGE2 (PGE1 ?)ester; poorer in releiving ulcer pain. It has shorter Duration of action; Slow healing rate; It is mainly Employed for GI bleeding and ulceration from NSAID therapy.

It is less efficacious than H2blockers for treatment of ulcers not associated with NSAIDs Increases mucus ,bicarbonate secretion& mucosal blood flow ,enhances re epithelialization Stabilizes mast cell membrane damaged by ulcerogenic agents

Side effects - diarrhea and flatulence Contraindication : pregnancy

Note: Anti H. pylori kit consists of combination of Antimicrobials , Antiprotozoals and PPIs in a single kit to be taken orally at three different times of a day for a minimum of 2-4 weeks . The most commonly used agents in a kit are : Antimicrobials- tetracycline, amoxycillin, clarithromycin etc; Antiprotozoals- metronidazole, tinidazole, secnidazole etc and PPIs- omeprazole. Lansoprazole, rabeprazole etc

V. PROKINETICS / GASTROKINETICS

Agents which increase the movement of ingested material through the GI tract by inducing coordinated motility patterns

1.Dopaminergic drugs: Dopamine inhibitors / D2 receptor antagonists

a. Metoclopramide : stimulates and coordinates esophageal, gastric, pyloric, and duodenal motor activity. increases lower esophageal sphincter (LES) tone ; stimulates gastric contractions and relaxes the pylorus and duodenum

Indications : Gastric Emptying Disorders -Delayed gastric emptying , Small bowel motility disorders- is less effective in the distal small intestine and colon, Bloat (free gas ) and ruminal impaction and Disorders of ruminoreticular motility

b. Cisapride : without antidopaminergic effects (antiemetic action) and no extrapyramidal effects ( as it does not cross BBB). It has more potent and broader prokinetic activity, 5HT 4 agonistic action than metoclopramide; increases the motility of the colon, as well as that of the

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esophagus, stomach, and small intestine improves coordination of the ileocecal-colonic junction. It is withdrawn from international market in abroad ( though available still in India)– due to the potent cardiovascular side effects- heart rhythm disorders in humans.

Indications : a) Gastric stasis,, gastroesophageal reflux, postoperative ileus (horse) and intestinal pseudo-obstruction (dogs and cats);

b)In idiopathic megaesophagus (dogs) that continue to regurgitate frequently despite a carefully managed, elevated feeding program

c) Rational agent in the treatment of idiopathic constipation (cats)

d) Cis-platinum chemotherapy Induced Emesis-it antagonizes 5-HT3 receptors but with less potency than 5-HT3 antagonists

Contraindications : obstruction, perforation &bleeding of the GIT. May have anticoagulant effects

Intensifies sedative effects of alcohol&benzodiazepines It should not be administered with : Ketoconazole,Itaconazole&Tetracycline due to risk of ventricular arrhythmia

Two new 5-HT4 agonist drugs - prucalopride and tegaserod, used in IBS ( Irritable bowel syndrome)

c. Domperidone : regulates the motility of gastric and small intestinal smooth muscle; very little physiologic effect in the colon. It is superior to metoclopramide in stimulating antral contractions

2. Motilin- like drugs

Motilin is an intestinal peptide that stimulates contraction of gut smooth muscle. Motilin is secreted by endocrine M cells that are numerous in crypts of the small intestine, especially in the duodenum and jejunum. Because of its ability to stimulate gastric activity, it was named "Motilin". The main function of motilin is to increase the migrating myoelectric complex component of gastrointestinal motility and stimulate the production of pepsin.

Motilin receptor is a G protein-coupled receptor that binds motilin. Motilin receptors are found in the gastrointestinal tracts of humans, pigs, rats, cows and cats and in the central nervous system of rabbits.

Macrolide antibiotics Erythromycin and Clarithromycin – are motilin receptor agonists; they stimulate cholinergic and noncholinergic neuronal pathways to stimulate motility, at much lower than their antimicrobial doses. They have been indicated in gastroesophageal reflux and reflux esophagitis, gastric emptying disorders and post-operative ileus. Both of them are metabolized by the hepatic microsomal cytochrome P450 enzyme system and inhibit the hepatic metabolism of pther drugs including theophylline, cyclosporine and cisapride.

3. Acetyl Cholinesterase (AChE) Inhibitors

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Neostigmine (cattle: 0.02 mg/kg, SC; sheep: 0.01-0.02 mg/kg, SC) is recommended for use in large animals for treatment of paralytic ileus; but may cause increased secretion into the GI tract, hence contraindicated in small-intestinal disease. I

t is also indicated in , ruminoreticular atony, paresis. However, it tends to increase frequency, rather than strength, of ruminoreticular contractions which is particularly true in ruminal atony. The 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

In horses, it may decrease small-intestinal propulsive contractions and delay gastric emptying

H2 receptotr antagonists: Only Ranitidine and nizatidine have prokinetic activity which is is due to acetylcholinesterase inhibition with the greatest activity in the proximal GIT. They stimulate GI motility by increasing the amount of AChE available to bind smooth muscle muscarinic receptors. Also stimulate colonic smooth muscle contraction in cats by cholinergic mechanism

4. Cholinergic agents

Bethanechol: Choline ester selectively binds M2 receptors with GIT and urinary activity Increases peristalsis and tone of lower esophageal sphincter, gastric and intestinal peristaltic activity , gastric and pancreatic secretions, tone of detrusor muscle

Over dose : increases bronchial contraction & secretion,miosis,salivation and lacrimation

Indications Large animals: stimulation of gastrointestinal activity, post operative gastrointestinal ileus, stimulation of urination, enhancement of gastric emptying and minimizing gasrtoesophageal reflux in foals Feline dysautonomia for promotion of urination

Contraindications: Obstruction of urinary outlets, hyperthyroidism, peptic ulcer or inflammatory condition of the GIT, recent surgery of the GIT with anatomists/resection, GIT obstruction, seizure, asthma, hypotension, sever bradycardia, co administration with other cholinergic agents

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VI. DRUGS USED IN THE TREATMENT OF DIARRHOEA

Three approaches fro treating diarrhoea

• Fluid and electrolyte supplementation-:oral and IV rehydration therapy- NaCl, KCl, Na citrate, glucose, Na lactate, Na acetate ORS (oral rehydrate salt) IV fluids 5% dextrose & normal saline KCl &/or Na HCO3

• Antiparasitic drugs- albendazole, fenbendazole Antimicrobial (antiinfective) agents-Erythromycin, clindamycin, tylosin, tetracycline, chloramphenicol., metronidazole, amoxicillin, ampicillin, fluoroquinolones, cephalosporin plus an aminoglycoside .

• Nonantimicrobial antidiarrhoeal agents- Adsorbents, Astringents, Antimotility and Antisecretory agents

NON ANTIMICROBIAL ANTIDIARRHOEAL AGENTS

1. MUCOSAL PROTECTANTS AND ADSORBENTS

Protectant & Absorbents: No oral absorption, used commonly in anti diarrheal agentsProtectants: make a lining layer to protect GIT epithelium form further irritation by noxious agentsAbsorbents: bind physically with chemicals and hinder their absorptionMg. trisilicate, Kaolin, Pectin, bismuth salts ,Ca2+ carbonate, activated charcoal , Al.trisilicate, Al.hydroxide, Al. phosphateIn nonspecific diarrhoea, they adsorb microorganisms, , toxins and protect the mucosa

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Eg: Kaolin, pectin , Activated charcoal, Chalk (CaCO3), Cholysteramine (bile derivative, Ion exchange resine.), isapgullha, (psyllium), methylcellulose, Bismuth subsalicylate

Kaolin –Pectin: Absorbent& demulcent ,line the GIT epithelium,improve feces consistency. Kaolin is a potent coagulant agent, can be useful in treatment of diarrhea related to mucosal erosion and bleeding; Can cause constipation especially in dehydrated patients

Kaolin-pectin (Pectin source; Citrus limon; citrus aurantiium) formulations act as demulcent and adsorbent in the treatment of diarrhea It may change the consistency of the feces but neither decreases the fluid or electrolyte loss, nor shortens the duration of the illness. Nevertheless, it is often administered to small animals, foals, calves, lambs, and kids. Kaolin-pectin products may adsorb or bind other drugs administered PO and reduce bioavailability

Bismuth salts: Bismuth sub salicylate, bismuth sub nitrate, bismuth sub carbonate

Bismuth sub salicylate: absorbent, anti endotoxin,weak antibacterial; Hydrolyzed to Bismuth carbonate & salicylate,while most effect are related to bismuth, salicylate plays role as anti Prostaglandin to control secretory diarrhea.

Bismuth subsalicylate is considered to be the symptomatic treatment of choice for acute diarrhea in humans. (enterotoxigenic Escherichia coli or “traveller’s diarrhea”). Bismuth adsorbs bacterial enterotoxins and endotoxins and has a GI protective effect. The salicylate component has antiprostaglandin activity.

Main indication is : control of diarrhea, By making a protective lining layer & formation of insoluble complexes with noxious agents can be useful in improving mal indigestion

Useful in the treatment of flatulence and its bad smell . Contraindicated in salicylate hypersensitivity

Fecal discoloration : Radiopaque and may interferes with GIT radiography Interferes with oral absorption of other drugs e.g. Tetracycline

Chronic use: encephalopathy& osteodytrophy . Cats are so sensitive to salicylates toxicity (salicylism); specially in conditions of intestinal inflammation

Activated charcoal: The broadest spectrum ,rapid acting absorbent useful in the emergency treatment of intoxications; Forms stable complexes with noxious agents& enhances their excretion

It is effective for adsorbing bacterial enterotoxins and endotoxins that cause some types of diarrhea. It also adsorbs many drugs and toxins and prevents GI absorption, so it is a common nonspecific treatment for intoxications.

Administration every 6 h for 1-2 days increases elimination of systemic absorbed toxins; Usually administered with a laxative or emetic agent with gastric lavage. Optimal ratio to toxin: 10 to 1used in 6 hours . Food decreases its efficiency.

Best results in toxicity with: Acetaminophen, Atropine, cardiac glycosides, phenytoin, strychnine,morphine& ethylene glycol;

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It is not effective in toxicity with: cyanides, mineral acids, basic corrosive agents, organic solvents,ethanol, lead, iron & methanol. Ipecac syrup negates its absorbent effect.

It is also indicated for : absorption of intestinal gasses in bloat, gastric dilation and indigestion

Cholestyramine resin: Basic anion exchange resin Non specific absorbent, decreases absorption of bileacids, lipoproteins, cholesterol& neutral acids . Indication: symptomatic treatment of diarrhea, specific treatment of pruritus related to increase in bile acids

Side effects: nausea , constipation, decrease in absorption of the fat soluble vitamins, steatorrhea; Should be administered with food or water

Astringents- Vegetable- tannins: tannic acid, (source: Quercus infectoria) catechu (Acacia catechu), kino, krameria, thealbin, cassia, cinnamon,rubus(blackberry fruit) - Intestinal astringents: .

Metalic- Fe, Cu salts; AlNO3, Pb, Zn, AgNO3, BiCO3, Bismuth sub nitrate, Bi sub salicyalte

2. MOTILITY-MODIFYING DRUGS / ANTIMOTILITY AGENTS :

a) Anticholinergic drugs: are common ingredients in antidiarrhoeal preparations as they significantly decrease intestinal motility and secretions.

Their parasympatholytic effects decrease segmental and propulsive intestinal smooth muscle contractions and relax spasms of smooth muscle.

They reduce the abdominal cramping associated with hypermotility.. also produce profound systemic pharmacologic effects.

Intestinal motility is already impaired in many animals with diarrhoea, and these drugs may actually worsen the diarrhea. The anticholinergic drugs also have profound systemic pharmacologic effects. Possible side effects include severe ileus, xerostomia, urine retention, cycloplegia, tachycardia, and CNS excitement and intestinal atony.

Atropine ,because of its systemic effects, is not used for an antidiarrheal effect. To avoid CNS excitement, quaternary amines such as hyoscine, aminopentamide, isopropamide, and propantheline dicyclomine are preferred since they do not cross the blood-brain barrier.

b) Opiates have antisecretory and antimotility effects eg: diphenoxylate and loperamdie

They decrease propulsive intestinal contractions and increase segmentation for an overall constipating effect.

stimulate absorption of fluid, electrolytes, and glucose. Effective in secretory diarrhea due to inhibition of calcium influx and decreased calmodulin activity.

Morphine and codeine - not used clinically as antidiarrheal drugs

Paregoric is a tincture of opium product and a controlled substance

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Diphenoxylate and Loperamide are two synthetic opiates that have specific action on the GI tract, without other systemic effects is used in small animals and neonates.

They are contraindicated in infectious diarrhea as slowing GI transit time may increase the absorption of bacterial toxins.. Diphenoxylate formulation contains atropine at subtherapeutic doses to discourage its abuse

Loperamide Overdose/ Adverse effects include : In dogs, constipation and bloat , abnormal pupillary response to light,circling, constantvocalization, head pressing, mydriasis ; Paralytic ileus, toxic megacolon, pancreatitis, and CNS effects in cats.

Paregoric (tincture of opium)- is occasionally preferred for small dogs, though loperamide is probably the drug of choice.

3.ANTISECRETORY AGENTS

Reduce intestinal mucosal secretion ; provide relief in ulcerative colitis and related inflammotory bowel diseases

Eg: Sulfasalazine, Mesalazine, Basalazine, Olsalazine, Bismuth subsalicylate, atropine, Octreotide, Chlorpromazine, aspirin, corticosteroids (prednisolone), immunosuppressants- methotrexate, cyclosporine, opoids

Sulfasalazine : is composed of sulfapyridine and 5-aminosalicylic acid (5-ASA),(mesalamine) joined by an azo bond, which is broken by bacteria in the colon to release the 2 drugs. 5-ASA inhibits cyclo-oxygenase & lipo-oxygenase & also reduce synthesis of PGs & leukotrienes

Clinical use: Both azo-compounds & mesalamine are first line drugs for treatment of mild to moderate ulcerative or idiopathic colitis in small animals and humans & Chron’s disease in colon or rectum .Mesalamine also useful for treatment mild to moderate Chron’s disease or ulcerative colitis in small intestine

The sulfonamide component (sulfapyridine) is absorbed into the circulation, while the salicylic acid component is clinically active with local antiinflammatory action in GIT

NSAIDs : Prostaglandins are important intracellular messengers for stimulating hypersecretion by the intestinal mucosa, possibly by stimulating an increase in cAMP . Antiprostaglandin activity of NSAIDS is beneficial with some types of diarrhea and may be important in the treatment of septicemia or endotoxemia. Meloxicam, analgin- are used sometimes . NSAIDs -directly inhibit fluid and electrolyte hypersecretion by the intestinal cells . Adverse GI, hepatic, and renal effects of NSAIDS should be kept in mind before using them

Note: Probiotics; use in diarrhea, is based on the theory that some forms of diarrhea are caused by disruption of the normal bacterial flora of the GI tract and examples of this are : Lactobacillus acidophilus, (in curd) Saccharomyces cervisiae

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VII. LAXATIVES

Agents that promote the evacuation of bowels by increasing the frequency of defecation, fecal volume or consistency . They increase the motility of the intestine or increase the bulk of feces.

The distinction is made according to the intensity of their action as Laxatives or Purgatives.

Aperient (laxative)- milder action, elimination of soft but formed stools ; -many agents in low dosages act as laxatives

Purgative(Cathartic)- stronger action, more fluid evacuation with stools; many drugs/agents/laxatives in larger dose act as purgatives

Superpurgation- refers to overdosage of purgative or ideosyncracy to purgative, extreme continued intestinal activity, painful fluid evacuation with dysentry causing shock, dehydration , collapse and death. (Horses more susceptible)

Indicatons of laxatives: a) to increase passage of gut contents associated with intestinal impaction, b) diagnostic purposes : to cleanse the bowel before radiography or endoscopy, surgery, c) to eliminate toxins from the GI tract, d) to soften feces after intestinal or anal surgery. e) Functional constipation(Spastic or atonic) f) to avoid straining of stool in hernia, CV disease, eye surgery, pile, fissures, after some anthelmintic therapy,

General adverse effects of laxatives on chronic use : abuse/ dependance- emotional or physical on long term use; fluid and electrolyte imbalance-Hypo kalemia, dehydration,Water loss; steatorrhoea, malabsorption syndrome; protein losing enteropathy and are dangerous if given in Inflammatory bowel disease (IBD), obstructions, undiagnosed abdominal pain

Classification

1. LUBRICANT / EMOLLIENT / MECHANICAL LAXATIVES

Eg: Mineral oil ( Liquid paraffin), white yellow soft paraffin,

Anionic Surfactants (Fecal/ stool softeners) - Docusates: Dioctylsodium sulfosuccinate, (DOSS) Dioctylcalcium sulfosuccinate , Dioctylpotassiumsulfosuccinate (Docusate Na, docusate Ca and docusate K)

They are Chemically inert substances, act by coating the surface of the feces with a water-immiscible film and by increasing the water content of the feces to provide a lubricant action.- to smoothen passage , Reduce water absorption

Fecal/ stool softeners ( eg: Docusates) -non-irritating soaps that facilitate movement of water into fecal mass. These are classically referred to as "stool-softeners". Can be given as enemas or by mouth

They decrease the surface tension and allow water to accumulate in the feces. increases cAMP in colonic mucosal cells, which increases ion secretion and fluid permeability.

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If used concurrently with mineral oil, soaps are formed and mineral oil absorption is increased. no foreign body reactions

These may facilitate absorption of mineral oil when the two are given together

Disadvantages/ adverse effects of lubricant laxatives: Chronic use - reduce intestinal absorption of Fat Soluble Vitamins, nutrients

• Chronic constipation due to reduced irritability int. mucosa- granulomatous enteritis. ;Chance of aspiration –pneumonia

• May bypass obstruction- as in fecoliths- can be misleading

2. BULK LAXATIVES

a. Simple bulk laxatives- methylcellulose, psyllium(isapghula), prunes, wheat bran, and canned pumpkin- in SA, with Foreign body ingestion

b. Saline bulk (Osmotic) laxative- Mg salts- MgSO4(Epsom salt, not for horse), MgO. MgOH, Mgcitrate,MgCO3, NaCl, Na2SO4(Glaubers salt),NaPO4, KNa tartrate, sugar alcohols -mannitol, sorbitol, Lactulose

Hydrophilic in nature, poorly absorbed from the GIT and Unabsorbed electrolytes which exert an osmotic effect (and) water moves from circulation, draw fluid into the intestine by osmosis.

The fluid content of the feces increases, which causes intestinal distention and promotes peristalsis

Relatively safe, overdoses result in - excessive fluid loss and dehydration, so adequate water intake.

Indicated in conditions of ingested poisoning/ intoxication ti enhance the excretion of the poison

Sodium sulfate -most effective on a molar basis and must be administered by stomach tube

Magnesium salts (oxide, hydroxide, sulfate) : most are also used as antacids and are generally balanced with aluminum salts (aluminum constipates) when used for antacid action only. Magnesium toxicity only with increased GI transit times or renal dysfunction . it is suitable for dogs, cats, foals, calves, cattle. piglets . only should not be used in horses. 20% Mg is systemically absorbed and eliminated by the kidneys. If absorption is excessive -severe hyperMg and met. alkalosis

Na salts: biphosphate or phosphate enemas. not be used in cats because fatal hyperP, hypoCa, and hyperNa

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Sugar alcohols mannitol, sorbitol, - poorly absorbed and fermented in the terminal ileum and large intestine.

Lactulose - synthetic disaccharide that is fermented in the large intestine to produce acetic, lactic, and other organic acids that lower pH of colonic content and exert osmotic effect, with colonic peristalsis.

Uses: chronic constipation in cats with megacolon.

• the management of hepatic encephalopathy, in which acidification of the large intestine promotes formation of nonabsorbable ammonium ions and quaternary amines, thereby reducing the need for detoxification by the liver.

• for diagnostic purposes of colon conditions

Colloid laxatives (methylcellulose, psyllium, prunes, wheat bran) composed of non absorbed synthetic or natural polysaccharide cellulose derivatives; imbibe water and increase the mass of nondigestible material in the intestine. Isapghula (Isabgol): viscous soluble fibres, husk, contain mucilage and hemicellulose

3.STIMULANT / IRRITANT/ CONTACT LAXATIVES

a. Vegetable oils- castor oil, linseed oil, olive oil, glycerine

b. Diphenylmethanes- Phenolphthalein , bisacodyl

c. Anthraquinone / anthracene derivatives (Emodin laxatives)- Aloes, senna, cascara sagrada , rhubarb, frangula,. Myrobalan , Synthetic anthracene – Danthrone

Mechanism:

stimulate intestinal motility via an irritant effect on the mucosa or stimulation of intramural nerve plexi. And activate secretory mechanisms, provoking fluid accumulation in the GI lumen.

potent effects, and excessive fluid and electrolyte loss can result.

act directly or indirectly (if a metabolic conversion is necessary before the compound is active).

Contraindications ;Colitis, enteritis, obstruction. ; They may induce parturition in late pregnancy; most are secreted in milk may purge suckling offspring

Drastic purgatives : castor oil, jalap, colocynth, croton oil, Phenolphthalein, Aloes, senna, cascara sagrada ,podophyllin, frangula,, Ipomea roots, mercurials( toxic) , Glycosides from cucurbitaceae; All result in GRIPE ( pinching spasmodic pain of bowels) pain

Phenolphthalein- indicated only in swine and primates , 6 - 8 hour delay, pink urine (if alkaline

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Anthracene derivatives : Emodin is an irritant glycoside - an active ingredient and Chrysophanic acid

hydrolized in colon, variable onset (6 - 12 hour delay), unreliable and produce considerable discomfort. Action is limited to the large intestine, longer latent pd for action, for the hydrolysis in LI . Repeat dosages should be avoided in horses because of the long latent period and risk of severe superpurgation.

Bisacodyl -inhibit glucose absorption and Na+/K+ -ATPase activity and alter the motor activity of visceral smooth muscle. Also administered by mouth or by enema, and only 5% of dose is absorbed. hydrolyzed in small intestine to produce irritating sodium and potassium salts and is more predictable and reliable than arthroquinone

Vegetable oils- are indirect-acting cathartics. ; hydrolyzed by pancreatic lipase in the small intestine to irritating fatty acids.

Castor oil - potent cathartic. It is hydrolyzed to release ricinoleic acid, which causes increased water secretion in the small intestine; used mainly in nonruminants and preruminant calves.

Raw linseed oil (cooked linseed oil is toxic) is hydrolyzed to release linoleates, which are less irritating than ricinoleic acid. In smaller daily doses, linseed oil is a mild lubricant laxative and a source of fatty acids for horse

4.NEUROMUSCULAR PURGATIVES

Cholinergic agents (Parsympathomimetics) with muscarinic action- - arecholine, carbachol, bethanecol, Cholinesterase Inhibitors: physostigmine, neostigmine

Cholinergic Drugs: They are rationale Cholinergic drugs are used for symptomatic treatment for diminished gastrointestinal motility (ruminal atony, abomasal displacement, ileus). But they produce an uncoordinated increase in motility with manifestations of abdominal pain, cramping without actually improving patient condition

Pilocarpine has marked effects on all muscarinic sites and is readily antagonized by atropine

Bethanechol - (Urecholine) – si selective for smooth muscle stimulation; readily antagonized by atropine terminated by elimination (not by cholinesterases)

Carbachol - relatively selective for smooth muscle ; may stimulate nicotinic receptors at therapeutic doses ; muscle fasciculations ; sympathetic stimulation - antagonizes smooth muscle actions; poorly anholinesterase inhibitors

Cholinesterase inhibitors: These agents increase concentrations of acetycholine at the nerve terminal. The net effect is the same as if a direct-acting cholinergic agent were administered though the ultimate effect may be less predictable.

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Physostigmine (tertiary amine) -oral absorption possible but variable and dose vs response is unreliable

Neostigmine (quarternary amine) has no oral absorption and may stimulate cholinergic receptors directly and is the most reliable of the two cholinesterase inhibitors

5. PROKINETIC AGENTS

As discussed earlier, care the agents which increase the movement of ingested material through the GI tract by inducing coordinated motility patterns

Eg: 5HT4 agonists : (metoclopramide, cisapride, mosapride) and opoid receptor antagonists

Endogenous substances such as oxytocin, Vasopressin,, PGF2 alpha, other PG analogs also have laxative action to some extent.

Note: ENEMA: introduction of solution or suppositories in to rectum to initiate defecation reflex is a simple method to correct constipation. Also, for removal of impacted rectal and colonic contents or in the treatment of colic, it is preferable to infuse large volume of warm fluids per rectum rather than administering purgatives. Soap water (soft anionic), isotonic/hypertonic saline, sorbitol, bisacodyl, glycerol, sodium lauryl sulfate, mineral oil, olive oil are the agents commonly used for enema . Also

VIII. RUMINORETICULAR ANTACIDS/ ALKALISERS

Indicated in ruminal acidosis. Magnesium 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

IX. RUMINORETICULAR ACIDIFYING AGENTS/ ACIDIFIERS

Indicated in ruminal alaklosis as in conditions of urea/ 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), or 13ml glacial acetic acid

X. RUMENOTORICS

Agents which increase the ruminal contractions and stimulate rumuinal motility. Indictaed in ruminal indigestion, ruminal. Atony, Impaction, loss of appetite. Fresh ruminal fluid is considered to

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be the best available “ruminotoric” as it contains viable ruminal bacteria and protozoa as well as many useful fermentation factors (volatile fatty acids, microbial protein, minerals, vitamins, buffers). Strained fresh ruminal juice (at least 3 L; 8-16 L is ideal in cattle; sheep require ~1 L) given PO or by tube is indicated in cases of ruminoreticular stasis

Others- MgOH, DSS, DPS, DCS, Formulations that contain glucogenic substrates, minerals, cofactors, and bitters (eg, nux vomica) , antimony potassium tartarate, Cobalt sulphate, Cobalt chloride, ferrous sulphate, Copper sulphate, Thiamine, Manganese sulphate, Drie yeast, sodium acid phosphate,. Zinc sulphate, brassica, antihistaminics, and prokinetics are the other examples.

Mineral oil (1-2 L) or dioctyl sodium sulfosuccinate (DSS, 90-120 mL in 1-2 L of water) administered PO or via nasogastric tube followed by gentle ruminal massage- helpful in promoting the dissolution and passage of impacted fibrous ruminal contents. DSS can markedly depress rumen protozoa ruminal transfaunation should follow the use of this agent if ruminal hypomotility continues

XI. SALIVARY STIMULANTS/SIALICS/ SIALOGOGUES

Increase the volume and fluidity of saliva, with the intention iof thereby increasing the appetite or digestibility of food.

Egg: Bitters: gentian, quassia, calumba, cascara, nux vomica, cinchona, calumba, ; Turpentine oil; Cholinergis: choline esters, cholinomimetic alkaloids, cholinesterase inhibitors; alpha adrenergic drugs; nicotine; mercurials, iodine , alcohol etc

XII. ANTISIALOGOGUES

Antimuscarinics(atropine, hyoscyamine, glycopyrrolets), neuroleptics (chlorpromazine, trifluperazine, prochlorpromazine), anticonvulsants (carbamazepine), antihisatminics (promethazine, diphenhydramibne, dimenhydrinate) and astringents (alum, potassium sulphate) )are tha examples. Indicated mainly as preanaesthetic medicants andin some poisoning cases

XIII. CARMINATIVES (ANTIFLATULENTS)

Agents which cause expulsion of gases from the stomach, oindicated in treatment of free gas bloat/tympany

Examples: pure volatile oils (turpentine oil, peppermint oil, eucalyptus oil; Ginger, powdered aniseed/anise; volatile compounds( alcohol, ethr, chloroform,a mmonia,)s camphor, menthol; cardamom, cinnamom, coriander, pepper, dill seeds, nutmeg, sodium bicarbonate, asafetida, simethicone, dimethylpolysiloxane etc

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XIV. ANTIZYMOTICS

Agents which prevent or reduce the bacterial/enzymatic fermentation in rumen. Mainly used for the prevention of further gas production in the rumen in conditions of bloat in ruminants and flatulent colic in horses.

Eg: turpentine oil, linseed oil, formalin, phenolic compounds, chloroform, surfactants/ antifoaming/antifrothing agents: a) organic silicones – Poloxalene, methyl silicone, Polymerized methyl silicone, PMS, dimethyl poly siloxane, silica in dimethicone (SIMETHICONE); b) Docusate sodium in emulsified soybean oil (6-12 fl oz containing 240 mg/mL) ; c) Vegetable oils such as peanut oil, sunflower oil, or soybean oil (cattle: 60 mL; sheep: 10-15 mL); d) Ionophores (such as monensin sodium ) in the ration

XV. ALIMENTARY DEMULCENTS

The agents coat, protect, lubricate and soothen the inflamed oral, pharyngeal, esophageal, gastric mucosa; are used to lessen the irritation of the abraded mucosa. Also indicated to mask the unpleasant taste/odor of the medicines

Eg: syrups (syrup of squill, jaggery syrup); honey , starch, glycerol, Gums (gum tragacanth, gum acacia, gum arabica, guargum,) ; methyl cellulose, agar, Glycerrhiza (liquorice), liquid paraffin , linseed oil, sesame oil etc.

XVI. DIGESTANTS

These agents promote the digestion of food especially in monogastric animlas.. a number of proteolytic, amylolytic and lipolytic enzymes are used as appetite stimulant , health tonics and digestants.

Eg: Proteolytic enzymes (papain, trypsin, chymotrypsin, enterokinase, carboxypeptidase);amylolytic enzymes (diastase, takadiastase);

Pancreatic enzymes (pancreatin (mixture of amylase, trypsin and lipase), pancreolipase) are also indicated in chronic pancreatitis, exocrine pancreatic insufficiency

XVII. CHOLAGOGUE AND CHOLERETICS

The substances which cause gall bladder contraction are cholagogues; and the substances which increase the bile secretion are choleretics. They are indicated in gall bladder disease, cholestasis, biliary fistula, gall bladder stones, biliary cirrhosis

Ceruletide, gastrin, cholecystominin- cholagogues. Natural bile salts: glycocholate, taurocholate; ursodeoxy cholic acid/ursodil, chenodeoxy cholic acid/chenodiol,tocamphyl, flovantyrone are the examples fro choleretics.