Systemic Pharmacology- Lecture Notes Dr.S.

Sakthikarthikeyan

Drugs acting on digestive system:

Drugs acting on digestive system:

Stomachics, antacids
Antiulcers, Prokinetics
Carminatives, antizymotics, emetics and antiemetics
Purgatives
Antidiarrhoeals, cholerectics and cholagogues
Rumen pharmacology

Rumen pharmacology:

Rumen function starts at 3-6 weeks and is complete at 9-13 weeks

Normal Intraruminal pH 5.5 – 7

Oesophageal Groove:

The oesophageal groove is present in newborn ruminants. It is a channel taking milk from
the oesophagus into the abomasum, bypassing the rumen, reticulum and omasum.

The oesophageal groove reflex is well developed in suckling neonates but becomes less reliable in
older animals.

Suckling is a strong stimulus for this reflex even in adults. It is best to allow sick calves and lambs
to drink medicated milk from a nipple to assure abomasal delivery and rapid absorption.

Advantages of Closure of Oesophageal groove or by passing rumen- reticulum:

It bypasses rumino-reticulum pathway, which allows faster and complete absorption of drugs from
abomasum than that from rumino reticulum.

1
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

It increases efficacy of many drugs by not allowing their metabolism in rumen by ruminal
microflora.

More over drugs may be degraded by ruminal microflora (eg: chloramphenicol and digitalis
glycoside) or the drugs may be harmful to the beneficial microbes (eg; tetracyclines, penicillin and
sulfonamides).

Agents for Closure of esophageal groove:

Oral administration of medicaments intended for the local intestinal effect (eg: purgatives,
antidiarrhoeals, contrast media and some anthelmintics) should be preceded by administration of
an appropriate of salt solution to close the reticular groove to avoid ruminoreticular dispersion.

 5% copper sulphate,
 5% zinc sulphate,
 10% sodium bicarbonate or 10% sodium sulphate

Any one of the above can be administer at 60ml in cattle to bring about closure of oesophageal
groove.

 1-2% copper sulphate is useful in sheep. Onset of reflex response takes about 5-10seconds
and the groove may remain closed for up to 60 seconds.
 Milk, sodium bicarbonate (10% to calves) or copper sulphate (5% to calves, 2% to
lambs) but not water may be used to induce esophageal groove closure.

Ruminotorics

 Ruminotorics are agents which stimulates rumino reticular contractions and cause
improvement in general functioning of rumen or agent which promotes forestomach
function (fermentation and motility)
 Typically such mixtures consist bitters like nuxvomica to stimulate salivation and perhaps
ruminal contractions,alkalinizing compounds like magnesium oxide to elevate a low
ruminal fluid pH,galactogenic substance like glycerol,minerals like cobalt as co-factors for
microbial enzyme function andsalts like phosphate as buffers to maintain osmolality.
 Bitters: (e.g: nux vomica, ginger, capsicum)- stimulate salivation which may enhance
rumen function, however, the efficacy of bitters is minimal. Bitters are administered orally.
 Cholinergics (e.g: neostigmine, bethenachol)- transiently increase the frequency, but not
the strength, of contractions in rumen atony. Cholinergics are administered
subcutaneously.
 Opiate antagonists (e.g: naloxone)- stimulate extrinsic contractions when administered
parenterally. Opiate antagonists are useful for the treatment of endotoxin-induced rumen
stasis.
 Rumen fluid transfer – Fresh ruminal fluid (5- 10 L) which contains viable rumen bacteria
and protozoa is the most effective means of restoring rumen function following correction
of the primary cause of stasis.

2
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Rumen Antacids:

 Correction of intraruminal acidosis (pH< 5.0) due to grain engorgement or soluble

carbohydrate overload with ruminal alkalinizing agent to treat depressed ruminoreticular
motility and functions.
 Rumen antacids e.g: sodium bicarbonate, ammonium carbonate and also

magnesium hydroxide calcium hydroxide aluminium hydroxide

magnesium oxide
magnesium carbonate calcium carbonate, aluminium carbonate

Antacids are used to treat mild cases of lactic acidosis resulting from carbohydrate engorgement.

These agents are administered orally every 8-12 hours’ Systemic alkalosis may result from
overdose especially of magnesium oxide.

Rumen Acidifiers

 In ruminal Stasis, intraruminal pH often increases to > 7.5 because of constant inflow of
bicarbonate rich saliva in absence of active ruminal fermentation and formation of volatile
fatty acids.
 Rumen acidifiers (e.g: vinegar, 4-5% acetic acid)
 Rumen acidifiers may be used to treat simple indigestion, in which a constant inflow of
bicarbonate rich saliva raises the pH of the rumen.
 They are used in the treatment of acute urea poisoning, because they decrease ammonia
absorption via formation of ammonium ion and inhibit urease activity of rumen microflora.
 Rumen acidifiers are mixed with several liters of cold water and administered via stomach
tube every 6-8 hours.

Antibloat agents (Viscosity altering agents)

Ruminal bloat or tympany is the accumulation of excess gas in the rumen as a result of impaired
elimination, not excess production.

Ruminal gases may be in the form of free form or entrapped in froth. Passage of a ruminal tube
will alleviate the free gas bloat but viscosity altering agents are required for the treatment of frothy
bloat.

Antibloat agents -Mechanism of action:

Anti-bloat agents alter the surface tension of froth and break up the bubbles which contain
entrapped gases.

3
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Administration:

Anti-bloat agents are administered via drench or stomach tube

 It can be relieved by giving antizymotic agents such as turpentine oil which reduce the
fermentation process in the forestomach.
 Admixing small quantities of turpentine oil, formalin with ground nut oil or trocarisation
will help overcome simple bloat
 Antibloat agents include Poloxalene (25-50 g in cattle), polymerized methyl silicone (3 %
emulsions ; 30-60 ml in cattle), mineral oil and vegetable oil (e.g: soybean, peanut,
sunflower oil) 60 ml in cattle; 10-15 ml in sheep.

Ulcer Mangement:

Gastrin: It is a Peptide hormone that stimulates secretion of gastric acid by parietal cells of stomach
and aids in gastric motility.

Pepsin: It is an endopeptidase (Digestive enzymes) which breaks Protein in to smaller particles. It

is produced by gastric chief cells of stomach lining

Factors

 Factors that play a role in peptic ulcer formation in gastric and duodenal ulcers:
Ulcerogenic factors include
 acid hypersecretion
 pepsin
 drugs (NSAIDs, corticosteroids, ethanol, chemotherapeutic agents)
 infection
 tumors
 stress - head trauma, shock/sepsis, emotional
 alteration of protective factors
 disruption of mucosal integrity and
 decreased bicarbonate secretion
 Symptoms of ulcers are due to a combined effect of hydrochloric acid and pepsin.
 Acid causes pain but not tissue damage.
 Pepsin, which is activated in acid environment, digests mucosal, muscular and vascular
layers of stomach & intestines.
 Gastric (stomach) ulcers are not due to too much acid.
 Alkaline reflux from intestines may inflame gastric mucosa.
 Duodenal (intestinal) ulcers are due to increased acid secretion in stomach.
 When stomach empties into intestines there is too much acid for pancreatic secretions to
neutralize and this acid erodes tissues.
 Most common causes are H. pylori and NSAIDs as well as gastrin hypersecretion.

4
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Goals of drug therapy for ulcers include

 neutralize existing gastric acid - antacids

 inhibit acid secretion - H2 antagonists, proton pump inhibitors
 treat infection (H. pylori) - antibiotics, bismuth subsalicylate
 protect ulcer from further damage – sucralfate

Antacids:

 Antacids are agents which neutralize excess acid.

 Some of the commonly used antacids include sodium bicarbonate, aluminium hydroxide
and dihydroxy-aluminium, calcium carbonate and magnesium hydroxide.
 The weak base reacts with the gastric hydrochloric acid to form a salt and water.
 This reaction causes an increase in the gastric pH and above pH 4, pepsin is inactive.

Sodium bicarbonate

 It has a rapid onset of action.

 But it is not an ideal antacid due to the rebound acidity i.e., stimulation of acid production
once the pH exceeds 4, due to gastrin secretion.
 As sodium bicarbonate is readily absorbed into systemic circulation, it alters systemic pH
and produces electrolyte disturbances.
 This in turn may lead to edema, hypertension or heart failure.

Aluminium hydroxide

 The insoluble aluminum chloride that is formed due to the reaction of hydrochloric acid
and aluminium hydroxide often causes constipation.
 It also binds with tetracycline to inhibit its absorption.

Calcium carbonate

 The absorption of ~10% of calcium chloride may result in hypercalcemia (muscle

weakness, kidney stone formation) and rebound gastric acidity.
 Constipation may occur with high doses.

Magnesium hydroxide

 This causes prolonged neutralizing effect due to slow stomach emptying.

 Poor absorption of magnesium salts may result in diarrhoea .
 Combinations of aluminum or calcium containing antacids with magnesium containing
antacids can nullify the adverse effects on bowel function.

H2 Receptor Antagonists

5
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

 Endogenous histamine released from paracrine enterochromaffin-like cells or mast cells

stimulates parietal H2 receptors.
 Histamine activates a cyclic AMP pathway, activates H+_ K+-ATPase and leads to
increased H+ in gastric lumen. H2 receptor antagonists can block this histamine induced
secretion and are helpful reducing acid secretion during ulcers.
 Examples of H2 receptor antagonists include cimetidine, ranitidine, famotidine, nizatidine
etc.
 In general, these drugs are well tolerated with few side effects (less than 3% with
cimetidine and <1% with other drugs).
 Cimetidine exhibits antiandrogenic properties leading to decreased sperm count,
gynecomastia and also inhibits hepatic drug metabolism.
 Inhibition of cytochrome P450 activity by cimetidine leads to potential drug interactions.
 This feature is not seen with ranitidine, famotidine and nizatidine.

Sucralfate

 It is a complex of sulfated sucrose and aluminum hydroxide and is known as gastric band
aid.
 Sucralfate polymerizes to a viscous gel at a pH less than 4.
 It combines with proteins and adheres to ulcer forming a barrier resistant to acid and pepsin
and binds to bile salts which are implicated in ulcer pathogenesis.
 It precipitates surface proteins at the ulcer base and acts as a physical barrier preventing
acid, pepsin and bile from coming in contact with the ulcer base.
 It does not decrease gastric acid secretion or neutralize acid or stimulate healing.
 The drug requires an acidic environment to be more effective.
 It is as effective as cimetidine or antacids at healing peptic ulcers and is useful in treating
gastric reflux.
 It is a Gastric protective.

Use: Sucralfate is used in the treatment of gastric and duodenal ulcers in dogs, cats and foals.

Adverse effect:

Constipation may occur with long term therapy. It interacts with many drugs and shown to
interfere with absorption of tetracyclines, fluoroquinolones, cimitidine,phenytoin and digoxin.

Proton Pump Antagonists

 Proton pump inhibitors are also called as acid blockers. Examples of this group of drugs
are omeprazole, lansoprazole, pantoprazole etc.
 These drugs irreversibly inhibit K+H+-ATPase proton pumpin gastrointestinal parietal
cells i.e. inhibits entry of H+ ion entry into lumen.
 These drugs also appear to have antimicrobial activity against H. pylori.
 These drugs break down in the acid environment of the stomach and must be given orally
as enteric coatedpreparations and they have short plasma half-lives but are long acting.
 They inhibit hepatic drug metabolism and are very well tolerated.

6
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

 These drugs heal duodenal ulcers more rapidly than H2 antagonists.

 They are used primarily for ulcers refractory to other treatments and are also used for reflux
esophagitis and management of gastrinomas.

Cytoprotective Drugs

 Misoprostol, an analogue of prostaglandin (PGE1) analog is used as a cytoprotective drug.

 Prostaglandins (membrane derived second messengers) have protective actions on gastric
mucosa.
 They increase mucosa formation and increases release of bicarbonate (HCO3-).
 Adverse effects are not common except diarrhoea and abdominal cramping.
 As this drug may cause abortion, it is not recommended for use in pregnant animals.
 It is used for short-term management of peptic ulcers and also to reduce gastrointestinal
irritation associated with NSAID (aspirin-like drugs) therapy.

Drugs that eradicate Helicobacter pylori bacteria

 multiple antibiotics (metronidazole + amoxicillin or tetracycline)

 bismuth subsalicylate
 most effective treatment is a combination of...
o multiple antibiotics
o bismuth subsalicylate
o H2 antagonist or proton pump inhibitor for 6 months

Sialagogues

 Sialogogues are agents that increase the volume of saliva, thereby increasing the
appetite and the digestability of food.
 Such remedies are used in large animal practice as ‘tonics’.
 Increased salivation is obtained by administering substances that stimulate taste buds like
the vegetable bitters.
 Substances with this type of activity include gentian, quassia and nuxvomica.
 Increase in salivation is also achieved on administration of parasympathomimetics.

Antisialagogues

 Antisialagogues (antisialics) are agents that decrease the volume of salivary secretions.
 The antisialagogue effect may be required during surgery of the mouth or after excision of
salivary cysts.
 Parasympatholytic drugs have antisialagogue effect. Atropine or glycopyrrolate are
commonly used to reduce secretions as a premedicant during surgery to reduce salivary
and bronchial secretions.

Appetite Stimulants

7
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

 Inappetance or anorexia is common in disease states and the resultant malnutrition can
delay recovery and may aggravate the underlying disease.
 The various ways by which appetite can be improved are:
o Enteral alimentation with liquid supplements is useful in small animals
o Small amounts of palatable food should be offered at frequent intervals. Warming
the food may enhance appetite in carnivores
o Various drugs are used for the short-term stimulation of appetite.

Benzodiazepines – e.g., Diazepam, Oxazepam

The antiserotonergic effect depresses the satiety center in the
hypothalamus.
Benzodiazipines are used most frequently in cats and less frequently in
horses, dogs and goats for a short-term stimulation of appetite after
which the effects diminish.
Diazepam can be administered orally, intravenously, intramuscularly
once or twice daily,
Oxazepam can administered once daily orally.
The adverse effects include sedation and ataxia.
Cyproheptadine
Cyproheptadine acts as a serotonin and a histamine (H1) antagonist
and suppresses the satiety center in the hypothalamus.
Cyproheptadine stimulates appetite in cats and in humans, but not in
dogs.
Adverse effects includes CNS excitement and marked aggressive
behaviour in cats.
Glucocorticoids-e.g., Prednisolone, Dexamethasone
Glucocorticoids stimulate appetite due to glucocorticoid-induced
euphoria.
In small animals prednisolone or dexamethasone is administered
intramuscularly once daily or every other day where as in large animals
it is administered intramuscularly once daily.
Adverse effects of glucocorticoids include immunosuppression and
gastric ulceration.
Bitters like plant derived compounds such as nux vomica, chiretta, ginger
These are used as salivary stimulants and their effect on appetite is
questionable.
However, bitters are a component of tonics for appetite stimulation in
large animals in traditional medicine.

Emetics

Emetics are agents that induce vomition and are classified as

centrally acting and
reflex acting emetics.
The main area in the brain responsible for vomiting is the vomiting center. This area is located
in the lateral reticular formation of the medulla.

8
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

It receives input from many areas like:

Chemoreceptor trigger zone: This is located in the floor of the fourth ventricle and it
picks up circulating chemicals/toxins in the blood (e.g. bacterial food poisoning toxins,
drugs used for chemotherapy) and cause vomiting.
Vestibular apparatus
Tractussolitarius - vagal afferents from the gut, heart and testes
Direct input from gut (reflex)
The neurotransmitters involved in the emetic response are
On the CTZ: 5HT3, D2
On the vagal afferents: 5HT3
In the vomiting center: Muscarinic, H1 receptors

Centrally acting emetics

 This includes:
 Apomorphine is a D2 agonist that acts on the CTZ to cause vomiting.
o Apomorphine is contraindicated in cats as it may cause extreme excitement in cat.
o Apomorphine can be administered subcutaneously or as a lamella (eye tablet) in
the conjunctival sac.
o Since apomorphine depresses the emetic centre, repeated dosing is not
recommended when the initial dosing is ineffective.
 Xylazine is used as an emetic in cats.
 Syrup of Ipecacunha is also used as an emetic.
o It acts both centrally and locally (reflexly) as an emetic.
o It irritates the gastric mucosa and within 15-30 minutes after administration emesis
is observed.
o It produces a toxic metabolite and hence if emesis does not occur after
administering the syrup, it should be removed by administering a gastric lavage.
o High concentrations of ipecac are cardiotoxic.
o Animals with ipecac overdose may exhibit arrhythmias, hypotension and
myocarditis.
o Activated charcoal ( a constituent of universal antidote) should not be administered
with ipecac as the charcoal adsorbs the syrup of ipecac and prevents it from
irritating the gastric mucosa and in turn producing emesis.

Locally acting emetics

 Warm water
 Warm saturated sodium chloride solution
 Sodium chloride crystals placed at the back of the tongue
 Sodium carbonate as crystals
 Copper sulphate 50 ml of a 1% solution
 Zinc sulphate 50 ml as a 1% solution
 Freshly ground mustard paste
 Hydrogen peroxide as a 3% solution

9
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Clinical uses of emetics include

 removal of ingested poison (except when corrosive poisons of petroleum products have
been ingested)
 emptying the stomach contents in emergency surgery
 Emetics should not be administered in an unconscious patient, weak and debilitated patient
and patients with clinical circumstances like pregnancy, bowel obstructions and hernia.
Antiemetics

 Antiemetics are agents that are used to control emesis

 Species like the horses, rabbits and rodents are unable to vomit.
 Protracted vomiting is undesirable in dogs, cats and other species.
 Vomiting usually occurs secondary to another disease process. If the primary cause is
treated then vomiting disappears.
 Antiemetics are useful in motion sickness, uremia, liver disease, endotoxemia, canine
parvovial gastroenteritis and in cancer chemotherapy.
 Use of antiemetics may mask the primary disease.
 Prolonged vomiting leads to electrolyte and acid base imbalances and dehydration.
Antiemetics may also be locally acting or centrally acting.

Centrally acting antiemetics

Phenothiazine derivatives

 A number of phenothiazine derivatives (chlorpromazine, promethazine, prochlorperazine,

trifluopromazine etc.) are classified as broad spectrum antiemetics.
 They act by blocking the chemoreceptor trigger zone at low doses and the emetic centre in
the brain at higher doses.
 Promethazine is a H1 antagonist (classical antihistaminic) which also has antimuscarinic
actions. It is very effective at preventing motion sickness (since the vestibular afferents
input in the vomiting center which has H1 and muscarinic receptors).
 Prochlorperazine is a D2 antagonist and has no antipsychotic effects. It is useful as an
antiemetic as well as for dizziness. It has minor anticholinergic effects. Since it blocks
D2receptors elsewhere (e.g. substantia nigra), it may cause extrapyramidal effects.
 Chlorpromazine, another phenothiazine, can also be used as an antiemetic, although it tends
to be sedative. It also has antipsychotic effects.
 Hyoscine (scopolamine) is a muscarinic antagonist (M2). It is used as a patch behind the
ear for controlling CTZ mediated vomiting.
 Metoclopromide is a D2 antagonist which is also a weak 5HT3 antagonist. It increases the
motility of the gut in the upper regions (does not cause diarrhoea - only facilitates gastric
emptying). It is useful in gastric stasis in a number of species including the cattle and
horses. Metoclopromide will help the absorption of drugs because it stimulates gastric
emptying. This drug is useful in vomiting associated with vagal afferents (gut disorders,
heart, testes, gut irritants - all stimulate the 5HT3 receptor on the vagal afferents) .
 Ondansetron is a 5HT3 antagonist and is a potent antiemetic. It is very effective in patients
receiving cancer chemotherapy. It can also be used for CTZ nausea.

10
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Locally acting antiemetics

 H2 antagonists like cimetidine, ranitidine etc. These drugs reduce the acid output and hence
decrease the irritating effects on acid stomach lining. As a consequence, afferent signals to
vomiting centres are decreased. Antacids like sodium bicarbonate are also useful.

Purgatives:

 Purgatives are drugs which cause marked intensification of intestinal activity and results
in the expulsion of intestinal content from the colon and rectum.
 The terms aperient and cathartic are also applied to describe the purgatives. A distinction
is made according to the intensity of action.
 Laxative or aperient: are milder in action, elimination of soft but formed stools
 Purgatives or cathartic: are stronger action resulting in more fluid evacuation.

Laxatives:

General considerations:

Laxatives Promote evacuation of the bowel through stimulation of fluid and electrolyte transport
and increase in propulsive motility. Specific indications for the use of laxative in dogs and cats
are:

1. To relieve constipation or obstipation which is causing faecal impaction. Constipation

common in cats.
2. To increase intestine motility to eliminate toxins from GI tract
3. To evacuate large bowel prior to surgery, radiographic procedures, endoscopic procedures

Hyperosmotic laxatives:

MOA: This are non-absorbable or poorly absorbable salts or polymers which osmotically retain
water in the intestinal lumen.
This have rapid onset of action which begins in small intestine.
Examples: Lactulose, Polyethylene, Magnesium sulfate

Magnesium sulfate: Epsom salts or Magnesium oxide (Milk of magnesia)- Oral route
Not to be used in renal disease condition.
Not to be used in feline constipation or megacolon

Lactulose: Organic acid produced from lactulose fermentation stimulate colonic fluid secretion
and propulsive motility. Given at 0.5 ml/kg body wt, 2 or 3 times a day

Polyethylene glycol: safe in cats

Bulk Laxative:

11
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

It comprises poorly digestible polysaccharides which adsorb water and increase fecal bulk that
stimulates large bowel peristalsis.
These products reduce tenesmus associated with large bowel dysfunction (e.g. colitis, Fiber-
responsive diarrhea)
These products are dietary fiber supplements.
They act in large bowel, so the onset of action is slow- Normally 1-3 days.
Eg. Methylcellulose, wheat bran or Psyllium

Administration: Methylcellulose, wheat bran or Psyllium is added to the diet.

Dietary fiber is more preferable because well tolerated, more effective, more physiologic than
other laxatives. Do not use in dehydrated animals.

Used in dogs and cats for mild constipationor to reduce clinical signs of colitis.

Lubricants and surfactants:

Mineral oil: or Liquid Petrolatum and white petrolatum lubricate are used to soften fecal mass.
These should be given via rectal route to avoid aspiration by oral route.

Docusate: Anionic surfactant which hydrates and softens stools by an emulsifying action.

Emollients laxatives:

MOA: These are anionic detergents that increase miscibility of water and lipid in digesta, thus
enhancing lipid absorption and impairing water absorption.

Dioctyl sodium sulfosuccinate and dioctyl calcium sulfosuccinate are 2 common emollients in
oral formulations. Dose: 50 mg oral/once daily in cat and dog.

Stimulant laxatives:

MOA: Stimulant cathartics derived from plants which are activated in GI tract to release irritant
derivatives which stimulate myentric neurons and smooth muscles to increase gut motility.

Castor oil: Cleaved by pancreatic lipases in small intestine to yield irritant ricinoleates. These
stimulate peristalsis throughout intestine and reduce fluid absorption. Used mainly in calves and
foals.

Anthraquinone: (Emodin) laxatives include aloe, Senna, Cascara sagrada. These contains
glycosides which are hydrolysed in large intestine to yield irritant anthraquinones which
stimulate myentric plexuses and increase colonic motility. Onset of action is slow, since they act
in large intestine. Used mainly in Horses.

Antidiarrheal agents:

General Considerations:

12
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Diarrhea is defined as an increase in fecal water content resulting in increased frequency,

volume, or fluidity of feces.

General causes of Diarrhea:

a. Increased secretion of fluid and electrolytes (Secretory diarrhea)- Ex: EnterotoxigenicE.coli
infection
b. Increased intestinal permeability – Ex: Mucosal inflammation (Inflammatory Bowel Disease)
and canine losing enteropathy.
c. Osmotic diarrhea- Ex: Exocrine pancreatic insufficiency
d. alterations in intestinal motility – Uncommon. Acute diarrhea – respond to symptomatic
therapy with antidiarrheal drugs but chronic diarrhea requires in-depth diagnostic evaluation.

Oral rehydration:

This therapy with glucose- electrolyte solutions represents significant advance in treating
secretory diarrheal disease in absence of vomiting.
Sodium –glucose or fructose and sodium –amino acid linked absorption by the enterocyte
remains intact even in the presence of moderate loss of villus structure.
This provide driving forces for water and electrolyte absorption from the lumen to replace fecal
losses.

In addition to glucose or aminoacid, solution containing Nacl, Kcl, NaH2Co3 and Potassium
Phosphate are used.

1. Motility modifying drugs (Opioids)

MOA: Opioids increase the GI rhythmic segmentation and decrease propulsive motility via
reduced Ach release.
They slow the transit of luminal contents and increase the water absorption.
They directly stimulate the net absorption of fluid and electrolytes via µ opioid receptors in CNS
and intestinal mucosa.
Therapeutic uses: For short term (5-7 days) symptomatic treatment of acute diarrhea in dogs.
Contraindicated with infectious diarrhea because slowing the GI transit may increase absorption
of bacterial toxins and enhance the bacterial growth in intestinal lumen.

Administration:
a.Paregoric (camphorated tincture of opium) is given orally 2 or 3 times a day in dogs or cats and
once a day in calves and foals. Use of antidiarrheal opioids in cats is controversial because of
potential excitatory effect.
b.Diphenoxylate: It is a Synthetic congener of Meperidine (Pethidine-synthetic opioid). It is
combined with atropine as a commercial prepration Lomotil® and given orally 2 to 3 times a day
to dog.
c.Loperamide: Synthetic piperidine opioid with action limited to the gut. Given once in dog @
0.08 mg/kg b.wt

13
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Adverse effects: Constipation, Bloat and Sedation.

2.Anticholinergic agents:

Mechanism of action: It inhibits GI motility, both propulsive and non-propulsive. The rationale
use of this antidiarrheals is questionable since hypomotility of the gut is common, especially in
diarrheal diseases.
This are infrequently used as antidiarrheals and GI spasmodics.
Ex: Isopropamide, Methoscopolamine

3.Protectants and adsorbents:

Mechanism of action: Protectants and adsorbents adsorb toxins and provide a protective coating
on the inflamed mucosa.
Symptomatic therapy of acute diarrhea
a.Kaolin/Pectin-Kaolin:
b.Bismuth subsalicylate:It as anti-prostaglandin action and Protective/ adsorbent properties.
It is also used as a component of triple therapy for treatment of helicobacteriosis.
Adverse effects: Bismuth subsalicylate may produce dark stools which should not be confused
with melena.

4. Antisecretory:

Sulfasalazine, Mesalazine, Bismuth subsalicylate, Atropine, Octreoxide

Anti-obesity drugs:

Obesity characterized by excessive accumulation and storage of fat in the body. Obesity can be
defined as exceeding ideal body weight by 20% or more.
Most common cause – Over consumption of food with inadequate exercise.

Dirlotapide
MOA: It is a selective microsomal triglyceride transfer protein (MTP) inhibitor that blocks
the assembly and release of lipoprotein particles in to the blood stream (via the lymphatic
system) in dogs. It provides weight loss by reducing appetite and by decreasing fat absorption.
Dose: Initial dose- 0.05 mg/kg b.wt O.I.D, orally, for first 14 days. 0.1 mg/kg for next 14 days,
O.I.D, orally.

Adverse effects: Vomitting, Diarrhea, anorexia, Lethargy.

Prokinetic Drugs:

Prokinetic drugs act to increase GI motility by stimulating smooth muscle contractions.

GI transit disorders include both structural (Mechanical obstruction) and functional (defective
propulsion associated with mucosal inflammation) diseases.

14
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

1. Cisapride : It is a Serotonergic 5-HT4 agonist and Dopaminergic D2 antagonist, 5HT3

antagonist 5HT4 agonist enhance release of Ach from vagus nerve but does not induce nicotinic
or muscarinic receptor stimulation.
Not commercially available.

2. Metoclopromide: It is a Serotonergic 5-HT4 agonist and Dopaminergic D2 antagonist, 5HT3

antagonist 5HT4 agonist enhance release of Ach from vagus nerve

Stimulates motility of proximal GI tract, especially Lower Oesophageal Sphincter and stomach.
Clinically used for reflux esophagitis and gastric stasis or hypomotility

3. Ranitidine: In addition to its antisecretory activity, it stimulates GI motility by inhibiting

acetylcholinesterase activity.

As a parasympathetic potentiating agent, it stimulates gastric emptying (by gastric motility) and
small intestinal and colonic motility.

4. Erythromycin: It stimulates motility by means of direct motilin –receptor activation and

indirect cholinergic and neurokinin activation (in dogs)
Sub-antimicrobial doses (0.5 -1 mg/kg) are orally administered to induce prokinetic activity in
dogs and cats. GI motility in proximal GI tract.

Digestants:

Pancrelipase: Consist of pancreatic enzymes including lipase, amylase, protease derived from
porcine pancreas. Pancrelipase powder mixed with food to treat exocrine pancreatic insufficiency
in dogs and cats. 1 tsp/meal of dogs for 20-30 kg B.wt.

Cholagogue
Promotes the flow of bile into the intestine, as a result of contraction of gall bladder
E.g. Dietary fat, concentrated magnesium sulphate

Choleretic

Stimulates the production of bile in the liver

E.g. Bile salts: ursodeoxycholic acid, chenodeoxycholic acid
Enhances fat absorption and stimulate biliary secretion

Carminatives:

Promote expulsion of gases from GI tract

Mild relaxation of oesophageal sphincter and eructation of gas
Relieve the feeling of discomfort and distension of stomach

15
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

E.g. Asafoetida(Perungayam), Cardamom (Elakkai), Coriander (kothamalli), Ginger (Inji),

Menthol, Peppermint

Stomachics:

Agents that serves to tone the stomach, improving its function and increase appetite.
Stimulate the appetite by increasing the gastric secretions

Bitters stimulate the taste buds, thus producing reflex secretion of gastric juices.
Eg. Gentian, Nux vomica

Drugs acting on the Urogenital system:

Diuretics:

These are drugs which cause a net loss of Na+ and water in urine.

Classification of Diuretics:

1. High efficacy Diuretics (Inhibitors of Na+ K+2Cl- co transport)

Ex: Furosemide, Bumetanide, Torasemide

2. Medium Efficacy Diuretics (Inhibitors of Na+ Cl- Symport)

Ex: Thiazides (Hydrochlorthiazide, Benzthiazide)

Thiazide like (Chlorthalidone, Metolazone, Indapamide)

3. Weak or adjunctive Diuretics

a) Carbonic anhydrase inhibitors-Ex. Acetazolamide

b) Potassium sparing Diuretics
i) Aldosterone antagonist- Ex. Spironolactone
ii) Inhibitors of renal epithelial Na+ Channel- Triamterene, Amiloride
c) Osmotic diuretics: Ex. Mannitol, Isosorbide, Glycerol

It can also be classified as:

Cardiac diuretics - Xanthines

Osmotic diuretics - Mannitol, Isosorbide, Urea
Natriuretics - Mercurials, Thiazides, Acetazolamide

16
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Refer Class notes for Diagram- Mechanism of action

1. High efficacy Diuretics (Inhibitors of Na+ K+2Cl- co transport)

Furosemide:
Maximal Natriuretic effect than other classes
Active even in renal failure patients
Major Site of action: Thick Ascending loop of Henle where furosemide inhibit Na+ K+2Cl- co
transport
Aministration: Oral and IV route
It Increases excretion of Ca 2+ and Mg 2+
It increases blood uric acid level.

Molecular Mechanism of action:

Thick Ascending loop of Henle’s- luminal membrane epithelium having Na+ K+2Cl- co
transporter (glycoprotein) used for secretory or absorbing function.
Furosemide binds to Cl- binding site of this protein to inhibit its transport function.

Bumetanide: 40 times more potent than Furosemide.

Uses:
In Edema of Cardiac, Hepatic and Renal origin.
Hypertension, only in renal insufficiency, CHF cases
Hypercalcemia and renal calcium stones.

2. Thiazide and related diuretics: (Inhibitors of Na+ Cl- Symport)

Medium Efficacy
Site of action: Early Distal Tubule or Cortical diluting segment which inhibit Na+ Cl- Symport at
luminal membrane.
Aministration: Oral

Molecular Mechanism of action:

Distal tubule- luminal membrane epithelium having Na+ Cl- symporter (glycoprotein) used for
secretory or absorbing function binds to Thiazides
Some thiazides have CAase inhibitory action in PT.
It Increases excretion of Mg 2+ but decreases Ca 2+ excretion.

Extrarenal action of thiazides- Slowly developing fall in BP in Hypertensives.and elevation of

sugar in some pateints.

Chlorthalidone: Long acting used as antihypertensive.

Metolazone: Given along with Loop diuretics
Indapamide: Antihypertensives.

17
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Uses:
Cardiac oedema
Hypertension
Diabetes insipidus
Hpercalciuria

Note: Long term use of loop diuretics causes distal nephron hypertrophy which lead to resistance
or refractoriness. Addition of metolazone or to some extent a thiazide which act on DT overcome
the refractoriness.

Carbonic anhydrase inhibitors:

Carbonic anhydrase is an enzyme which catalyses the reversible reaction

H2O + CO2 CA H2CO3

H2CO3 CA H2O + CO2

Location of Carbonic anhydrase

Renal Tubular Cells (PT)

Gastric Mucosa
Exocrine Pancreas
Ciliary body of Eye
Brain
RBC

Acetazolamide:

It is a Sulfonamide.
It is a non-competitive, reversible inhibitors of CAase in PT cells which lead to as follows
1. In PT cells inhibiton of CAase lead to Slowing of Hydration of Co2, so decreased availability
of H+ to exchange with luminal Na+ through Na+-H+ antiporter.
2. Inhibtion of brush border CAase at lumen side retards dehydration of H2CO3 in the tubular
fluid, so that less Co2 diffuses back in to the cells.
3. The net effect is inhibition of HCO3- (and accompanying Na+) reabsorption in PT. So prompt
but mild alkaline diuresis ensues.

When CAase inhibitors are given, the distal Na+ exchange takes place only with K+ which is
lost in excess.
Urine produced under acetazolamide action is alkaline and rich in HCO3- and causes acidosis.

Extrarenal Effects:

18
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Lowering of intraocular pressure due to decreased formation of aqueous humour (it is rich in
HCO3-
Raised level of Co2 in brain and lowering of pH, lead to sedation and elevation of seizure
threshold.

Uses:
It is not used as Diuretic because of acidosis and hypokalemia,
a. Glaucoma – Topical CAase inhibitors are in use.
b. To alkalinize urine
c. Epilepsy- as adjuvant therapy, if primary drugs are not effective
d, Acute mountain sickness, for symptomatic relief, due to decreased CSF formation as well as
lowering of CSF and Brain pH.

Potassium Sparing Diuretics:

They are either aldosterone antagonist or directly inhibit Na+ Channels in DT and CD cells to
indirectly conserve K+.

Spironolactone:

It is a steroid, chemically related to mineralocorticoid aldosterone.

Spironolactone converted to canrenone, which is active metabolite involved in ½-2/3 in vivo
action.

MOA:
Aldosterone acts on late DT and CD cells by combining with intracellular mineralocorticoid
receptor MR which induces the formation of AIP (aldosterone induced proteins) which promote
Na+ reabsorption by following mechanism:

a.AIP include Na+K+ATP-ase and amiloride sensitive Na+ Channels. AIP also activate Na+
Channel, translocate Na+ Channels from cytosolic site to luminal membrane and Na+K+ATP-
ase to basolateral membrane, increase ATP production by mitochondria.
All these changes promote Na+ reabsorption. So, more K+ and H+ is secreted indirectly.

Spironolactone binds to MR, prevents AL action and produces opposite effects.

Amiloride approaches the Na+ channel from the luminal side and blocks it, reducing the lumen
negative transepithelial potential difference which governs K+ and H+ secretion.

Uses:
It’s a weak diuretic so used in combination with other diuretics.
Refractory oedema (Breaks the resistance to thiazide diuretics)
To counteract K+ loss due to thiazide and loop diuretics.
Hypertension
CHF

19
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Inhibitors of renal epithelial Na+ Channel:

Traimterene and amiloride are 2 non steroidal organic bases with identical actions.
It decrease K+ excretion.

MOA:
Luminal Membrane of Late DT and CD cells expresses a distinct ‘amiloride sensitive’ or ‘renal
epithelial’ Na+ Channel through which Na+ enters the cell down its electrochemical gradient
which is generated by Na+ K+ ATPase operating at the basolateral membrane.
This sodium entry partially depolarizes the luminal membrane creating a -15 mV transepithelial
potential difference which promotes secretion of K+ in to the lumen through K+ channels.

All diuretics acting proximally (loop diuretics, Thiazides,CAase inhibitors) promote K+

secretion.
Amiloride and Triamterene block the luminal Na+ channels, indirectly inhibit K+ excretion,
while the net excess loss of Na+ is minor.
Both Amiloride and Triamterene used in conjunction with thiazide type or high ceiling diuretics
to prevent hypokalemia.
Amiloride and Triamterene main adverse effect- Hyperkalemia.
Amiloride blocks entry of Li+ through Na+ channels in the CD cells and mitigates diabetes
insipidus induced by lithium.

Osmotic diuretics:

Mannitol is a non electrolyte, pharmacologically inert

Given to increase the osmolarity of plasma and tubular fluid.
It is not metabolized in the body, freely filtered at the glomerulus and undergoes limited
reabsorption .

Mannitol limit the tubular water and electrolyte reabsorption by the following ways.
a. Retains water isoosmoticaly in PT- dilutes luminal fluid which opposes Nacl reabsorption.
b.Inhibits transport process in thich Ascending loop of henle
c.Expands extracellular fluid volume (because it does not enter cells, mannitol draws water from
the intracellular compartment)- increase GFR and inhibits renin release.

Primary action of mannitol is to increase the urinary volume, excretion of all cations and anion is
also enhanced.

Administration: Only IV route as 10-20 % solution.

Uses:
Acute congestive glaucoma, Head injury, Stroke etc.
Before and after ocular and brain surgery
To counteract low osmolality of plasma/ECF due to rapid haemodialysis or peritoneal dialysis.

20
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Methylxanthines:

Ex: Aminophylline, Theophylline, Caffeine, Theobromine

Diuretic effect is due to increased renal blood flow and glomerular filtration rate and to
inhibition of Na+ reabsorbtion in the proximal convoluted tubule.

Also produce bronchodilation by inhibition of adenosine receptors and are CNS stimulants.

Rarely used as diuretic but increased urine output noticed when Aminophylline or Theophylline
used as bronchodilator in respiratory disease therapy.

Acidifying salts:

MOA: Acidifying salts such as ammonium chloride (NH4Cl) lower the pH of extracellular fluid
and urine.
Liver converts NH4Cl to urea, H+ and Cl-
H+ is buffered by Hco3- in plasma and leads to acidosis.
Increased load to the kidney produces urinary loss of Na+ and Cl- and a mild diuresis.

Uses: NH4Cl is used for urinary acidification to dissolve uroliths or to prevent their formation,
Renal excretion of ionizable drugs or poisons by ion trapping in the urine.
In IV route as acidifying agent for treatment of metabolic alkalosis.

Alkalinisation of urine
 Alkalinising agents reduce the irritation of an inflamed urinary tract and discourage the
growth of certain organisms like E.coli.
 Urine can be made alkaline by sodium bicarbonate intravenous administration or by
potassium citrate oral administration.
 Sodium or potassium citrate is metabolised to form a stable cation (Na+ or K+) and a labile
anion (citrate).
 Citrate is taken up for use by the TCA. The Na+ or K+ is excreted with the most common
anion (HCO3-.
 Hence, there will be alkaline urine.
Administration and use
 To decrease the adverse effects of sulphonamidesalkalinisation is useful. Sulphonamides
are generally insoluble in acid urine. They may thus precipitate out and crystallise.
Therefore, to increase solubility, the urine is made more alkaline.
 To increase the excretion of acidic drugs like Aspirin, salicylates and barbiturates.
 Alkalinisation of urine increases the antibacterial activity of aminoglycosides in urinary
tract infection.
 Alkalinisation of the urine in usually recommended to prevent the recurrence of urate
stones in dogs after cystotomy. Sodium bicarbonate at 0.5 to 1.0 g is given orally thrice
daily.

Ecbolics

21
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

These are agents that bring about increase in uterine contractions.

Oxytocin: It is hormone of the posterior pituitary received from the hypothalamus. It has a major
physiological role in milk let down and labor initiation.
Clinical uses of oxytocin:
1. For labor induction. Given by slow I/v in dextrose solution.
2. For milk let down. Only in agalactic animals
3. For treatment of uterine inertia and for rapid involution of uterus.
4. To arrest post parturient haemorrhage.
5. For expulsion of retained placenta.
The dose of oxytocin is 5 - 25 units in bitch, 75 - 100 units in cow / mare and 30 - 50 units in sow
/ ewe.
Oxytocics:
Other agents which perform similar functions are also called oxytocics.
Ergot alkaloids: Alkaloids from the fungus Claviceps purpurea viz. ergometrine, ergonovine
have prominent effect on the uterus. Not preferred for induction of labour. Generally indicated for
post parturient haemorrhage, rapid involution of uterus, retained placenta.
PGF 2 alpha: Exerts potent stimulant action on myometrium. It is also popularly used for its
luteolytic effect.
Tocolytics
These are agents that inhibit uterine contractions. They relax uterine smooth muscle and may be
used to delay labor and to stop threatened abortion.
Beta2 agonists: Salbutamol, terbutaline, isoxsuprine
Calcium channel blockers: Nifedipine, diltiazem
Oxytocin antagonist: Atosiban

Respiratory Pharmacology

Introduction:

The primary function of the respiratory system is gas exchange between the inspired air and the
pulmonary artery blood.

Because of the large surface area of the alveoli and exposure to the environment, this organ system
is prone to antigen–allergy responses and infection.

22
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

The defenses of the respiratory system include hypersecretion of mucus, sneezing and coughing
reflexes, bronchoconstriction, and macrophage activation and inflammation.
Pharmacology of the respiratory system centers around these defense mechanisms and can be
simplified into seven categories: (1) elimination of excess secretions and membrane congestion,
(2) bronchiole dilation when excessive constriction has occurred, (3) cough suppression when it is
nonproductive and detrimental to the animal, (4) control of infection and inflammation, (5)
decrease pulmonary hypertension, (6) stimulate the peripheral chemoreceptors and the central
respiratory center, and (7) exogenous surfactant.
Mucolytic agents- Increasing or facilitating the removal of excess, accumulated secretions
1. N-Acetylcysteine (N-acetyl-l-cysteine) is a derivative of l-cysteine and acts as a mucolytic drug.
N-Acetylcysteine (NAC) breaks the disulfide bonds within the mucus molecules and decreases
the viscosity.
NAC will not only alter the viscosity of normal mucus but also the thick mucus that results from
the addition of bacterial and neutrophil cellular debris.
This drug is usually aerosolized and inhaled by the patient, but a powder form is available and can
be formulated for oral use.
2. Bromhexine HCl is a frequently prescribed mucolytic.
Enhances the hydrolysis of acid mucopolysaccharides that significantly contributes to mucus
viscosity.
Does not alter protein in the mucus, which originates from bacteria or neutrophil cellular debris.
May increase the concentration of certain antibiotics in the alveoli by altering the permeability of
the alveolar/capillary membranes.
Expectorants
Theoretically make the bronchiole secretions less viscous but their efficacy is questionable.
1. Potassium iodide is an oral saline expectorant, which causes irritation to the gastric mucosa that
in turn increases bronchiole secretion through a vagal reflex.
2. Guaifenesin is a guaiacol (wood tar) derivative that acts as an expectorant and increases airway
particle clearance in humans.
Guaifenesin may stimulate the gastric mucosa and increase respiratory tract secretions via reflex.
The volume and viscosity of secretions does not appear to change.
This compound is primarily found in over-the-counter human cough preparations.
Decongestants shrink the nasal mucosa and allow air to pass more freely.
Sinusitis or reverse sneezing are other indications for decongestants.

23
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

1. H1-antihistamines are commonly used for allergic-induced symptoms and chronic rhinitis in
people but efficacy in animals is not documented. (See Chapter 3 for the pharmacology of H1-
antihistamines.) a. Diphenhydramine b. Dimenhydrinate c. Chlorpheniramine d. Hydroxyzine
2. Sympathomimetic drugs (α-receptor agonists) may be given orally or topically as nasal sprays
to avoid their systemic effects. However, nasal sprays are not well tolerated in animals. Their
primary effect is to constrict the precapillary arterioles, reduce blood flow, and reduce the
extracellular fluid in the nasal mucosa. Nasal discharge consequently will be reduced and
resistance to airflow through the nasal cavity will decrease.
Ex: a. Ephedrine b. Pseudoephedrine c. Phenylephrine.
Control of Infection And Inflammation.
Antibiotic choice should ideally be based on culture and sensitivity or cytology with a Gram’s
stain.
A. Antibacterial drugs that have a good spectrum of activity.
1. Upper airway disease—Gram-positive spectrum is best.
2. Lower airway disease—Gram-negative spectrum is best. a. Cephalosporins b. Potentiated
sulfonamides c. Amoxicillin d. Amoxicillin/clavulanate e. Fluoroquinolones
3. Aerosolized antibiotics may be helpful in selected cases of infectious tracheobronchitis
B. Glucocorticoids
1. Corticosteroids are important for the treatment of antigen-induced inflammatory bronchial
disease such as chronic obstructive pulmonary disease (heaves) in horses and feline bronchial
disease (asthma), as well as chronic bronchitis in dogs.
Glucocorticoids reduce mucus hypersecretion, bronchial mucosal thickening, and airway smooth
muscle constriction.
a. Oral intermediate-acting steroids are preferred for ease of dosage adjustments. (1) Prednisolone
(2) Prednisone
b. Fluticasone is an inhaled glucocorticoid that is being used more frequently in animals. (1) It is
available in a multidose inhaler (MDI) for human inhalation. (2) An animal mask and spacer are
needed for administration. (3) It has 18× the affinity of dexamethasone for human glucocorticoid
receptors. (4) Only 30% of the administered dose reaches the airways of the lung. (5) It may take
1–2 weeks of administration to see the maximum effects.
C. Leukotriene receptor antagonists
It is a new type of therapy. Leukotrienes are potent bronchoconstrictors and trigger inflammatory
responses such as edema formation.

24
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

1. These modulators of inflammation can be used instead of corticosteroids.

2. Drugs that antagonize leukotriene receptors are zafirlukast, zileuton, and montelukast.
D. Nonsteroidal anti-inflammatory drugs:
NSAID are seldom used to treat inflammatory respiratory diseases because they tend to inhibit
cyclooxygenase more than lipooxygenase enzymes. Aspirin has been used in the treatment of
thromboembolism in cases of heartworm disease.
E. Serotonin receptor inhibition may be beneficial for feline “asthma.” Cyproheptadine is the
only drug in this category currently thought to be beneficial.
F. Mast cell stabilizers are used in human medicine to treat allergic asthma. These cromones,
cromoglycate and nedocromil, prevent the release of inflammatory mediators from mast cells by
inhibiting the influx of calcium. They are administered by inhalation and efficacy in animals is not
documented.
Cough:
Coughing is the sudden and loud ejection of air from the lungs.
It is a normal protective reflex that is necessary in the diseased animal. The sensory receptors for
the reflex cough are sub epithelial irritant or stretch receptors that are numerous in large airways
and innervated by the vagus nerve.
Antitussives decrease the severity and frequency of coughing.
a. Peripherally acting antitussives include anti-inflammatory drugs, mucolytics, and
bronchodilators.
b. Central acting opioid and nonopioid drugs reduce the sensitivity of the cough center to afferent
stimuli.
The opioid cough suppressants may cause sedation, nausea, and constipation.
(1) Codeine—dogs and cats. One of the most effective with an antitussive effect that is much
greater than its analgesic effect.
(2) Hydrocodone—commonly used in the dog. More potent antitussive than codeine.
(3) Butorphanol—100× more effective as an antitussive than codeine. Can be given orally or
parenterally to dogs and cats. It has a short duration analgesia but longer sedative effect and
minimal respiratory depression with a half-life of 1.7 hours.
(4) Dextromethorphan is a semisynthetic opioid that is found in many over-the counter human
cough preparations.
Bronchial Dilation is beneficial to decrease resistance to airflow when excessive constriction is
present.

25
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Bronchodilators are common treatments for airway disease. The horse benefits the most from these
drugs.
Parasympathetic system—provides innervation to the entire tracheobronchial tree.
M3 muscarinic receptor subtypes mediate airway smooth muscle constriction, plus vasodilation
and mucus secretion.
Anticholinergic drugs will cause bronchodilation even in the normal healthy animal.
1. Atropine—injectable 2. Glycopyrrolate—injectable 3. Ipratropium—aerosol by metered dose
inhaler (MDI) 4. The parenterally administered anticholinergic drugs have significant side effects,
including decreased GI peristalsis, dry mucous membranes, tachycardia, and urinary bladder
relaxation.
These side effects limit the chronic use of parenteral anticholinergic drugs and favor the aerosol
administration of ipratropium directly to the lungs.
Adrenergic Agonist:
1. Adrenergic agonists
a. Nonselective (α+β1+β2) agents may be used for the acute treatment of bronchoconstriction. (1)
Epinephrine (2) Ephedrine (3) Isoproterenol
b. β2-Selective agonists produce fewer undesirable α- and β1-effects.
(1) Terbutaline—orally or parenterally for severe bronchoconstriction in cats.
(2) Isoetharine—has been aerosolized and used in small animals.
(3) Albuterol—has been aerosolized and used in horses and small animals.
(4) Clenbuterol - Approved for use in horses with airway obstruction such as chronic obstructive
pulmonary disease (heaves).
Methylxanthines:
It has been used for many years in veterinary medicine as a bronchodilator.
1. Mechanism of action. Methylxanthines are phosphodiesterase inhibitors, which induce
bronchodilation by blocking the degradation of cAMP by phosphodiesterase in airway smooth
muscle cells and inhibition of light chain myosin kinase.
The increase of cAMP levels in mast cells inhibits the release of histamine and other autacoids,
for example, leukotrienes which may reduce ongoing bronchoconstriction.
The increase of cAMP levels in the chromaffin cells of the adrenal medulla promotes the release
of catecholamines which bronchodilate by stimulating noninnervated β2-receptors in the lung.

26
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

The other benefits of the methylxanthines are increased mucociliary clearance, improvement in
diaphragmatic contractility, decreased pulmonary artery pressure, increased CNS sensitivity to
PaCO2, and stabilization of mast cells.
In addition, methylxanthines are adenosine receptor antagonists. Adenosine receptors are coupled
to Gi/o protein, which mediate the decrease in cAMP formation by inhibiting adenylyl cyclase.
Thus, adenosine receptor antagonists increase cAMP levels as well.

Theophylline

a. Therapeutic uses.

Theophylline is administered orally. It is used primarily to induce bronchodilation for the treatment
of obstructive small airway diseases.

It is used often in patients with heart failure and/or pulmonary edema. Theophylline must be used
cautiously because of its adverse effects

(1) The GI absorption is ∼100% after oral administration of a non-sustained release product. The
GI absorption of sustained release products yielded 30–80% bioavailability.

(2) Theophylline is distributed widely in the body and penetrates the blood– brain barrier. The
plasma binding activity of theophylline is low

Aerosol administration of drugs

1. Optimal particle size for delivery to the trachea is 2–20 microns and to the distal airways is 0.5–
5 microns.

2. The benefits of aerosol therapy are that of limiting systemic absorption of the drug and
introducing the drug close to the site of the problem.

3. Used primarily to treat chronic obstructive airway disease of horses, lower airway disease in
felines, chronic bronchitis in dogs, and kennel cough complex in young dogs.

4. Small animal and equine specific products for administering these agents using a facemask and
spacer are commercially available.

27
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

5. Bronchodilators, an anticholinergic, corticosteroids, and some antibiotics (e.g.,

aminoglycosides) are the primary drugs administered by this route.

Sildenafil

It is a phosphodiesterase type V inhibitor, has been administered orally to induce vasodilation and
reduce pulmonary hypertension in dogs and humans.

Doxapram hydrochloride

It is an analeptic and a centrally acting respiratory stimulant that also increases the sensitivity of
the peripheral chemoreceptors located in the carotid bodies.

When injected IV to dogs, the respiratory rate and tidal volume (minute ventilation) increase.

Exogenous Surfactant

It can be administered directly into the respiratory tract of foals or calves that are born prematurely
and show signs of respiratory distress.

Surfactant is normally produced by the alveolar type II cells and is a complex mixture of
phospholipids and protein.

Surfactant is necessary in the alveoli to reduce the surface tension during inspiration and stabilizes
alveoli during the resting phase after expiration.

Animals born prematurely may lack surfactant production, and breathing requires an increase in
effort and work.

One treatment option is to inject exogenous surfactant into the lungs. Several products for human
use are derived from animals.

Beractant is lipid extract of bovine lung with synthetic lipids.

Calfactant is a lipid extract of calf lung lavage fluid.

28
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Drugs acting on Cardiovascular system

The effect of drugs on the heart may be expressed as

Inotropic effect if it affects the contractility

Chronotropic if it affects the rhythmicity
Dromotropic if it affects the conductivity
Bathmotropic if it affects the excitability
Tonotropic if it affects the tonicity.

Cardiotonic drugs or Cardiac Stimulants

Drugs which increase the force of contraction of heart or agent that has a strengthening effect on
the heart or that can increase cardiac output or drugs which increase the contraction of cardiac
muscles without increase in the myocardial oxygen demand or Positive Inotropic effect are called
cardiotonic drugs.

Classification:

1. Cardiac Glycosides: Ex. Digoxin, Digitoxin

2. Symapthetic drug: Ex. Adrenaline, Dopamine, Isoprenaline, Dobutamine
3. Anticholinergic drugs: Ex.Atropine, Scopolamine
4.Xanthines: Ex. Theophylline, Theobromine
5. Inhibitors of Phosphodiesterase III: Ex. Amrinone, Milrinone, Vesnarinone
2,3,4,5 are Non- Glycoside Cardiotonics.

Congestive heart failure (CHF)

CHF is a condition where the heart is incapable of providing adequate blood flow (and oxygen) to
the peripheral tissues either at rest or during exercise.

Cardiac glycoside Sources

The main source of cardiac glycosides is from the foxglove family.

Their effectiveness in cardiac failure was, described by William Withering in 1775. He published
his classic monograph ‘An account of the foxglove and some of its medicinal uses: with practical
remarks on dropsy on used by an old woman of Shorpshireand other diseases’ in 1785.

29
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Initially kidney was thought to be the target organ

The cardiac glycosides are unique in that they not only improve the contractility of the
myocardium, but also reduce the heart’s demand for energy and oxygen.

These drugs also decrease the conduction of certain impulses within the heart and therefore
decrease the heart rate.

Cardiac glycoside Sources

Plant Parts Glycoside

Digitalis purpurea Leaf Digitoxin, Gitoxin, Gitalin

Digitalis lanata Leaf Digoxin, Digitoxin, Gitoxin

Strophanthus gratus Seeds Ouabain

Strophanthus kombe Seeds Strophanthin

Chemistry of Cardiac Glycosides

Cardiac glycosides that contain an aglycone (genine) and a sugar moiety.

The sugar moiety consists of one to four sugar residues.
The pharmacological activity rests with the aglycone and the sugar helps in the
pharmacokinetic properties.
The aglycone consists of a cyclopentanoperhydrophenantherene ring structure attached to a
5 or 6 membered unsaturated lactone

Glycoside Sugar (Glycone) Non-sugar

(Aglycone / Genin)
Digitoxin Digitoxose Digitoxigenin

Gitoxin Digitoxose Gitoxigenin

Gitalin Digitoxose Gitaligenin

30
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Digoxin Digitoxose Digoxigenin

Ouabain Rhamnose Ouabagenin

Strophanthin Cymarose Strophanthidin

Mechanisms of inotropic action of cardiac glycosides

Cardiac glycosides produce their action by inhibition of Na+, K+ transport system (Na+, K+ -
ATPase)

Inhibition of this sodium pump results in increased intracellular Na+ concentration

Normally sodium is brought into the cell in exchange for Calcium during the plateau phase

Because of the elevated intracellular Na+, sodium - calcium exchanger is not functional,
leading to elevated intracellular Ca++ levels

Ca++ forms a complex with troponin and tropomyosin allowing actin and myosin filaments to
come together

Muscle contracts

Altered Na+, K+ and Ca++ levels are the basis for both the therapeutic and toxic effects of the
cardiac glycosides.

Pharmacological Effects of Cardiac Glycosides

Positive inotropic effect is noticed by improved emptying and reduction in size of the dilated
failing heart.

The muscle contracts more quickly and more powerfully for the same filling stimulus and for the
same oxygen consumption.

So venous pressure is reduced, oedema fluid is reabsorbed and blood pressure increases.

Negative chronotropic effects by direct stimulation of the vagal centre and by slowing the rate of
passage of impulses through the conducting system.

Diuretic effect due to increased blood flow and increased glomerular filtration rate.

Pharmacokinetics:

31
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Absorption differs among the digoxin preparations.

Prepared digitalis causes local irritation and vomiting in pig and dog and for these species digitalis
glycoside should be given.

In ruminants, oral administration of glycosides leads to destruction of the drug and hence it is
preferable to give the drug parenterally.

Plasma protein binding is high with digitoxin.

Excretion of the drug is by the kidneys.

Enterohepatic recycling increases the duration of action of the drug.

The use of these drugs in dogs and cats is not uncommon.

However, the absorption of digoxin from the gastrointestinal tract though adequate may differ
somewhat among animals and can be influenced by feeding times.

Therapeutic Uses:

Congestive heart failure.

Arrhythmias by depressing the AV nodal conductivity and increasing refractoriness.

Digitalization

Cardiac glycosides have narrow margin of safety.

For ex: 10 mg/kg b.wt dose, 11 mg/kg b.wt lead to toxic effect
To overcome this, a larger loading dose in fractions over a period of 24 – 48 hours is administered.
This is called digitalisation dose or loading dose. Given by oral or IV route.
Loading Dose: The dose of digitalis required to acquire the initial response.
Maintenance dose: Daily dose required to maintain the therapeutic effect.
Loading dose
Slow method- 5 equal parts for 48hrs (Zero hr, 12th hr, 24th hr, 36th hr, 48th hr)
Rapid method- 3 equal parts @ 6hr interval (Zero hr, 6th hr, 12th hr)
Intensive method- half dose initially, one fourth after 6hrs and one eighth each after 4 hr intervals
Digitoxin- 0.11 – 0.22mg/kg total loading dose
Maintenance dose-0.011mg/kg @12hr intervals

32
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

There is a considerable, individual variation in response to these glycosides.

Effective concentration of digitalis is reached only slowly if the drug is given by mouth.
Adverse reaction of Cardiac glycosides:
Risk of toxicity is greater in patients with advanced heart disease.
Factors that promote excessive digitalis accumulation include, high dosage and decreased
excretion due to renal disease, age and hypothyroidism.
Factors that increase myocardial sensitivity to digitalis toxicity include, myocardial disease or
ischemia, hypokalemia, high serum calcium and low serum magnesium.
Symptoms of toxicity can be grouped as cardiac symptoms and non-cardiac symptoms.
Cardiac symptoms of toxicity – Sinus bradycardia, S-A block, A-V block, tachycardia, premature
ventricular contraction.
Non-cardiac symptoms of toxicity –
Gastrointestinal disturbances like anorexia, nausea, vomiting fatigue and muscle weakness
CNS effects like confusion, hallucination, restlessness, insomnia, drowsiness and occasionally
overt psychoses
Visual effects like hazy vision, difficulty in reading, photophobia, chromatopsia (yellow or green
colour appearance)
Gynaecomastia (antiadrenergic effect).

Treatment of cardiac glycoside toxicity:

Withhold cardiac glycosides
Withhold potassium depleting diuretics
Administer potassium salts
Administer antiarrhythmics if arrhythmias appear to be life threatening
Administer agents like activated charcoal to bind digoxin in the gastrointestinal tract.
Precautions and Contraindications
Hypokalemia will lead to increased digitalis toxicity
In elderly patients and in patients with renal and severe hepatic disease the toxicity will be higher
Thyrotoxicosis reduces the responsiveness to digitalis
Myxoedema increases the responsiveness to digitalis
Partial A-V block may be converted to complete A-V block

33
Systemic Pharmacology- Lecture Notes Dr.S.Sakthikarthikeyan

Drug Interactions
Diuretics – potassium depleting diuretics precipitate digitalis toxicity while potassium sparing
diuretics reduce the renal excretion of digitalis
Calcium precipitates digitalis toxicity
Quinidine reduces binding to proteins and thereby increase the concentration and toxicity of
digitalis
Verapamil and diltiazem increase plasma concentrations of digoxin
Antacids and neomycin reduce absorption of digitalis.
Other Drugs Used in CHF
Phosphodiesterase inhibitors like theophylline.
Diuretics like furosemide to increase water and sodium excretion, decrease preload and relieve
symptoms of pulmonary and systemic congestion
Vasodilators like hydralazine
ACE inhibitors like enalapril, lisinopril etc.
Adrenergic alpha1 agonists like prazosin
Calcium channel blockers like nifedipine

34