Drugs that affect the

endocrine system
Drugs for diabetes
contd
• Diabetes: a heterogeneous group of complex metabolic disorders that
share common alterations in glucose metabolism
• Differ in age at onset, genetic predisposition, treatment options, and
the complications developed
• Diabetes mellitus(DM) is classified broadly as:
1) Type 1(formerly, insulin dependent diabetes mellitus) which
typically occurs in younger people who can not secrete insulin
2) Type 2(formerly non-insulin dependent diabetes mellitus) which
typically occurs in older , often obese, people who retain capacity to
secrete insulin but who are resistant to its action
contd
• Insulin: Synthesized and stored in granules in the beta-islets cells of
the pancreas
• Daily secretion amounts to 30-40 units
• Principal factor that evokes insulin secretion is high blood glucose
concentration
• Human insulin is made either by enzyme modification of porcine
insulin, or by using recombinant DNA to synthesize the pro-insulin
precursor molecule for insulin This is done by artificially introducing
the DNA into either Escherichia coli or yeast
contd
• Insulin analogues have small numbers of modifications to either alpha
or beta chains
• As a result analogues with more rapid onset and offset of action, and
• Analogues slower onset and offset of action than the naturally
occurring insulin are produced
• Insulin receptors: insulin binds to beta subunit of its receptors
• Beta subunit is a tyrosine kinase that is activated by insulin binding
and is autophosphorylated
• Tyrosine kinase also phosphorylates other substrates so that a
contd
signaling cascade is initiated & biological response ensues
• Insulin receptors are found on surface of the target cells(mostly liver,
muscle, fat)
• Insulin receptors vary in number inversely with the insulin concentration
• With high insulin concentration the number of receptors declines(down-
regulation) and responsiveness to insulin also declines(insulin resistance)
• With low insulin concentration the number of receptors increases(up-
regulation) and responsiveness to insulin increases
contd
• Patients with type 2 diabetes have insulin resistance
• Hyperinsulinemia predates the onset of type 2 diabetes and the
resistance is secondary to down-regulation of insulin receptors as well
as post-receptor intracellular events
• Obesity is a major factor in the development of insulin resistance
• Patients may recover insulin responsiveness as a result of dieting so
that insulin secretion decreases, cellular receptors increase and
insulin sensitivity is restored
contd
• Actions of insulin:
 Glucose transport into muscle and fat cells
 Increased glycogen synthesis
 Inhibition of gluconeogenesis
 Inhibition of lipolysis and increased formation of triglycerides
 Stimulation of membrane bound energy-dependent ion
transporters(e.g. sodium/potassium ATPase)
 Stimulation of cell growth
contd
• Pharmacokinetics:
• Insulin is destroyed in the gut and must be given parenterally
• In conventional use, insulin is injected s.c. or i.v.
• It is degraded in the liver and kidney with a half-life of 5-10 minutes
• Uses of insulin:
 Diabetes mellitus is the main indication
 Correction of hyperkalemia( insulin promotes the passage of
potassium simultaneously with glucose into cells)
contd
• Types of insulin preparations( with different time-course of action):
1) Short duration of action(and rapid onset): soluble or regular insulin,
insulin lispro, insulin aspart
• Regular insulin(onset approx. 30 min; duration of action 6-8 hours)
• Insulin lispro(onset approx. 15 min; duration 2-5 hours
• Insulin aspart(onset 10-20 min; duration 3-5 hours)
2) Intermediate duration of action(and slower onset)
• Isophane(NPH) insulin, insulin zinc suspension(onset 1-2hrs; duration
12-24 hours)
contd
3) Longer duration of action(protamine zinc, insulin glargine, insulin
detemir)
• Protamine zinc onset 4-6 hours; duration 24-36 hours
• Insulin glargine and insulin detemir( onset 2.5 hours; duration 24
hours)
4) Mixed: mixture of soluble and isophane insulin officially called as
biphasic insulins or short-acting analogue insulins with isophane
insulins
• Only regular insulin should be injected i.v.
contd
• Standard strength of insulin preparations is 100 units/mL
• Inhaled insulin is also available. Bioavailability is only 15%
• In conjunction with injected insulins can be used to maintain glycemic
control
• Conventional therapy of insulin involves two injections a day of
biphasic insulin
• If using biphasic insulin, two-thirds of the daily dose may be given in
the morning and one-third in the evening
• Initial daily dose requirement 16-20 units daily
contd
• Adverse effects of insulin: mainly of overdose and include
hypoglycemia, coma, convulsions, and even death(as brain relies on
glucose as its source of energy)
• Sleep disturbance and headache also result due to hypoglycemia
• Treatment of hypoglycemia is to give sugar by mouth or
glucose(dextrose) i.v
contd
• Oral antidiabetic drugs: the term oral hypoglycemic may be used but
some drugs do not cause hypoglycemia
• Chemically classified in to:
1) Sulfonylureas: tolbutamide, chlorpropamide, glibenclamide,
glipizide, gliclazide,..
2) Biguanides: Metformin
3) Thiazolidinediones: rosiglitazone, pioglitazone
4) Meglitinides: repaglinde, nateglinide
5) Alpha-glucosidase inhibitors: acarbose
contd
• Sulfonylureas: act primarily by stimulating pancreatic beta cells to
secrete more insulin
• Block the ATP-sensitive potassium channels on the beta-islet cell plasma
membrane
• This results in release of stored insulin in response to glucose
• Do not stimulate insulin synthesis
• Functioning pancreatic tissue(at least 30%) is therefore necessary for
their action
• Additionally, they inhibit both gluconeogenesis and insulin degradation
in the liver
contd
• Enhance insulin action on liver, muscle, and adipose tissue by
increasing insulin receptor number
• Principal result is decreased hepatic glucose output and increased
glucose uptake
• Main adverse effects: hypoglycemia and weight gain
• Less commonly: allergic reactions(rashes), GI symptoms, bone
marrow suppression
• Drug interactions: alcohol can enhance the hypoglycemic effect of
sulfonylureas and also that of insulin
contd
• Sulphonamides including co-trimoxazole enhance the hypoglycemic
effect of sulfonylureas
• Secondary failure(after months or years) occurs due to declining beta-
cell function and to insulin resistance
• Clinical use and dose: majority of patients(type 2 DM) are started with
a short half-life drugs(e.g. glibenclamide t1/2, 6 hr, 5mg bid or tid);
glipizide t1/2, 4 hr, 5 mg bid or tid)
• Tolbutamide has long half-life(36 hr) increased risk of hypoglycemia
therefore not preferred esp. in elderly/renal or cardiac failure
contd
• Biguanides: Exact mechanism of action uncertain but the following
effects are likely to contribute:
Decreased glucose absorption from the gut
Reduction of hepatic glucose production
Enhancement of peripheral insulin sensitivity increasing glucose entry
to cells
Anorectic effects(helps to reduce weight in obese patients)
• Ineffective in the absence of insulin
• Pharmacokinetics: excreted unchanged by the kidney
contd
• Its chief use is in the obese patients with type 2 diabetes alone or in
combination with sulfonylureas
• Frequent adverse effects related to the GIT: nausea, vomiting,
diarrhea
• More serious, but rare adverse effect is lactic acidosis, when it occurs
it should be contraindicated in renal impairment, cardiogenic shock,
liver failure
• During pregnancy it should be substituted by insulin
• Lactic acidosis is treated with large(i.v.) doses of isotonic sodium
bicarbonate
contd
• Usual adult dose: 0.5-1 gm 8 hourly; duration of action 8-12 hours
• Thiazolidinediones: pioglitazone is indicated once daily in patients not
controlled by metformin alone
• Activate a nuclear receptor that regulates gene transcription, resulting
in expression of proteins that improve insulin action in the cell
• This action leads to increased utilization of available insulin by the
liver and muscle cells and also in adipose tissue
• Additionally, hepatic glucose production can be reduced
contd
• Do not produce hypoglycemia unlike sulfonylureas
• Main adverse effects are weight gain and edema
• Dose: 15-30 mg once daily; duration of action 16-24 hours
• Meglitinides: repaglinide, nateglinide
• Are short-acting insulin secretagogues
• Close ATP-sensitive potassium channels in the beta cell membrane
• Potassium channel blockade depolarizes the beta cell and leads to
opening of calcium channels
• This resultant influx of calcium increases the secretion of insulin
contd
• Have short duration of action (2-4 hours)
• Most useful in patients whose primary glucose alteration is
postprandial hyperglycemia
• They do not directly affect fasting blood glucose levels
• Dose: repaglinide 0.5-16 mg t.i.d
contd
• Alpha-glucosidase inhibitors: acarbose
• Reduces digestion of complex carbohydrates and slows their
absorption from the gut
• Reduces glycemia after meals and may improve overall glycemic
control
• Usual dose: 50-300 mg/day
• Adverse effects are mainly flatulence and diarrhea, which lead to high
discontinuation rate
• May be combined with sulfonylureas
contd
• Treatment of DM:
• All Type 1 patients need immediate insulin therapy(age below 30
years)
• Initial therapy in Type 2 patients should be by dietary means alone for
2-3 months, but most patients will need oral antidiabetic drugs in
addition
• Type 1 patients are initially underweight whereas the reverse is true
for Type 2
• Older overweight diabetics have a relative deficiency of insulin but
seldom develop ketosis, hypocaloric diet is vital
contd
• Younger patients with Type 1 are often underweight and need insulin to restore
normal weight, calorie restriction is not required initially in these patients
• The blood of these younger diabetics contains negligible insulin and they
readily become ketotic
• Stepped therapy in Type 2:
Diet alone
Diet plus oral agents
Diet plus insulin
Diet plus oral agent(metformin) plus insulin
For ketoacidosis: soluble insulin urgently
contd
• About a third of type 2 patients will be adequately managed with diet
alone
• When diet alone has failed to control Type 2 diabetes, add an oral
agent such as:
Metformin for obese patient
Sulphonylureas for a non-obese patient, if control is incomplete
metformin may be added
• When oral therapy fails, insulin treatment should be used alone or in
combination with metformin
contd
• Well controlled diabetic is less liable to ketosis and infections
• Good control of glycemia mitigates the serious microvascular
complications of:
• retinopathy,
• nephropathy,
• neuropathy and cataract
contd
• Interactions with non-diabetes drugs:
1) Beta-adrenoceptor blocking drugs
 impair the sympathetically mediated release of glucose from the liver
in response to hypoglycemia
Adrenergically mediated symptoms of hypoglycemia(except sweating)
are reduced
Thus insulin-caused hypoglycemia is more prolonged and less
noticeable
A diabetic needing beta blocker should be given a beta1 blocker,e.g
bisoprolol, metoprolol
contd
2) Thiazide diuretics at higher dose can precipitate diabetes
3) Hepatic enzyme inducers(e.g. rifampicin, phenobarbital) can
enhance the metabolism of sulfonylureas
4) Hepatic enzyme inhibitors(e.g. cimetidine) can increase plasma
concentration and effect of metformin
5) Monoamine oxidase inhibitors potentiate effects of oral drugs and
insulin
6) Alcohol may cause hypoglycemia with any antidiabetic drug
7) Salicylates(aspirin) can increase insulin sensitivity
contd
• Diabetic emergencies:
1) Hypoglycemic coma: coma can present with a wide range of
neurological signs; capillary glucose should be checked
• Coma is precipitated by missing a meal, unaccustomed exercise, or
taking too much insulin or sulfonylureas
• Treatment: 50 mL of 50% dextrose is given intravenously, and
repeated as necessary
• Alternatively, 1 mg glucagon is given intravenously or i.m
contd
2) Ketoacidosis: Infections, MI, trauma and inadequate insulin are some
of the causes
• Clinical features; dehydration, hyperventilation, impaired
consciousness, blood glucose is markedly elevated, body potassium
content is decreased although plasma potassium is high
• Treatment:
 Fluid(isotonic saline)d to replace dehydration
Insulin(soluble insulin i.v.) to control hyperglycemia(cont. infusion or
intermittent injection)
Potassium to counter hypokalemia
contd
 Bicarbonate to counter acidosis
• Infections, if any, should be treated
contd
3) Hyperosmolar diabetic coma: characterized by dehydration, very
high blood glucose level, and lack of ketosis and acidosis
• Sodium is raised and plasma osmolality increased
• Occurs chiefly in non-insulin dependent diabetics
• Cause is obscure
• Treatment:
 Isotonic saline or half normal if plasma sodium is above 150 mmol
Give insulin as for ketoacidosis, but insulin requirement is lesser
 Heparin may be needed as these patients are prone to thrombosis
Drugs for GI diseases
• Drugs for peptic ulcer: peptic ulcer occurs when there is an imbalance
between aggressive and protective factors in the upper GIT(stomach
and duodenal mucosa)
• Aggressors: acid, pepsin, H. Pylori, NSAIDs
• Protectors: mucus, bicarbonate, prostaglandins, mucosal blood flow
• Exact mechanisms are still poorly understood
• Use of non-steroidal anti-inflammatory drugs are major causes of
ulcer particularly in elderly
• Smoking is a major environmental factor
contd
• Strategies for drug treatment of peptic ulcer:
 Neutralization of secreted acid
Reduction of acid secretion
Enhancing mucosal resistance
Eradication of Helicobacter pylori
• Almost all patients with duodenal ulcer, and most patients with
gastric ulcer have H. pylori infection
• H.pylori stimulates increased gastrin release and thereby increased
acid secretion
contd
• Gastric acid is secreted by the parietal cells in gastric mucosa
• Three main stimulants of acid secretion: gastrin, histamine, and
acetylcholine
• They stimulate their own receptors located on basolateral membranes
of parietal cells
• Though their second messengers, eventually stimulate the gastric
acid(proton) pump which is the final common pathway for acid
secretion
• The pump is H+ / K+ - ATPase, uses energy(ATP) to transport H+ out of
contd
parietal cells in exchange for potassium
• Hydrogen ions combine with chloride ions to form hydrochloric
acid(HCl) which is secreted into the gastric lumen
• Drugs antagonizing the actions of endogenous acid secretagogues and
inhibitors of proton pump reduce acid secretion
• Antacids are basic substances that reduce gastric acidity by
neutralizing hydrochloric acid
• The hydroxide is the most common base, but trisilicate, carbonate
and bicarbonate are also used
contd
• Antacids: sodium bicarbonate, magnesium hydroxide, magnesium
trisilicate, aluminum hydroxide, calcium carbonate
• Sodium bicarbonate is systemic antacid whereas others not
• Differ from each other in onset of action, acid neutralizing capacity,
duration of action, adverse effects
• Antacids protect the gastric mucosa against acid(by neutralization)
and pepsin(which is inactive above pH 5) and which in addition is
inactivated by aluminum and magnesium
• Antacids also stimulate mucosal repair mechanisms around ulcers,
contd
possibly by stimulating local prostaglandin release
• Antacids are generally used to relieve dyspeptic symptoms and they
are taken intermittently when symptoms occur
• Are used mainly for symptomatic relief in patients with peptic ulcer,
gastroesophageal reflux disease, or non-ulcer dyspepsia
• Side effects and inconvenience limit their use as ulcer healing agents
(must be given frequently and in high doses for healing ulcers)
• Antacids which contain aluminum tend to cause constipation
• Those containing magnesium cause diarrhea
contd
• Sodium bicarbonate is absorbed and causes alkalosis(short-term use
can not be a problem)
• It also releases carbon dioxide in the stomach to cause discomfort and
belching
• Antacid combinations e.g. magnesium hydroxide and aluminum
hydroxide is advantageous than giving either alone(enables to cancel
out the side effects of each, combines quick action of magnesium
salts with long-lasting action of aluminum salts)
• Interactions: antacids may reduce the absorption of a number of
different drugs(e.g. tetracyclines, quinolones,etc.)
contd
• Antacids should be given at least 2 hours apart with drugs intended
for systemic effect
• Antacids with high sodium content should be avoided in patients with
impaired cardiac function or chronic liver disease
• Calcium carbonate is not commonly used because it causes marked
rebound acid secretion upon withdrawal
• It also releases carbon dioxide in the stomach causing discomfort and
belching
contd
• Drugs that inhibit gastric acid secretion:
 H2 –receptor antagonists
 Proton pump inhibitors
 Anticholinergics
 Synthetic prostaglandin analogues
contd
• H2 receptor antagonists: cimetidine, ranitidine, famotidine, nizatidine
• Are competitive antagonists of histamine at the H2 receptors on the
basolateral membrane of parietal cells
• Additionally inhibit gastrin and acetylcholine-mediated acid secretion
• Peptic ulcer healing correlates best suppression of nocturnal acid
secretion(single evening dose may be considered)
• The usual ulcer healing course is 8 weeks
• High gastrin levels may reduce their effect(less effective in reducing
food-stimulated acid secretion)
contd
• Cimetidine was the first and prototype
• Least potent of the group
• All are well-absorbed following oral administration, have relatively short
half-lives are mainly excreted by kidneys
• H2 receptor antagonists can heal duodenal ulcers and benign gastric ulcers,
can be effective in mild cases of GERD
• Around 90% of DU and 80% of GU should have healed by 8 weeks
• Should be given at least twice daily
• In critically ill patients, used prophylactically to prevent stress-related
gastric mucosal bleeding
contd
• H2 receptor antagonists are well tolerated at therapeutic doses
• Cimetidine( but not other H2 blockers) has antiandrogenic
action(displaces dihydrotestosterone from its cytoplasmic receptors),
release prolactin, and inhibits degradation of estradiol by liver
• Thus, higher doses given for long periods have produced
gynecomastia, loss of libido, and impotence in men
• Drug interactions: cimetidine inhibits cytochrome P450 isoenzymes
with prolonged use
• This increases the effect other co-administered drug especially those
with low margin of safety(e.g. warfarin, phenytoin)
contd
• Recommended doses for DU and GU:
• Cimetidine 400 mg twice daily or 800 mg in the evening
• Rantidine 150 mg twice daily or 300 mg in the evening
• Nizatidine 300 mg in the evening
• Famotidine 40 mg in the evening
• Ranitidine, famotidine, nizatidine do not inhibit hepatic microsomal
enzymes
contd
• Proton pump inhibitors: omeprazole, esomeprazole, lansoprazole,
pantoprazole
• Inhibit irreversibly the proton pump in parietal cells
• All are similar in efficacy and mode of action
• All PPIs are prodrugs, it becomes activated in acid milieu of the
secretary canaliculus and binds to H+ /K+ -ATP ase
• Reduce acid secretion markedly, a single 20 mg dose can inhibit
gastric acid output by 90% over 24 hours
• Omeprazole is degraded at low pH, given in enteric coated granules
contd
• Omeprazole has short half-life(1-2 hours) but has a prolonged
pharmacologic effect
• PPIs used for:
 DU omeprazole 20 mg daily will heal DU around 90% in 4 weeks
GU same dose but treatment for 8 weeks recommended
Bleeding peptic ulcer
Stress ulcers
Gastroesophageal reflex disease
Zollinger-Ellison syndrome
contd
• Adverse effects: nausea, headache, diarrhea, constipation
• Omeprazole inhibits hepatic microsomal enzymes with prolonged use
• Risk of gastric neoplasia and infections due to achlorhydria seen on
experimental animals after prolonged use
contd
• Anticholinergics e.g. pirenzepine are weak inhibitors of gastric acid
secretion
• Their use is not recommended

• Synthetic prostaglandins: misoprostol inhibit acid secretion(but weak)

and exert cytoprotective effect on gastric or duodenal mucosa
• Main clinical use: prevention of gastric ulcer in patients on NSAIDs
Enhancing Mucosal Resistance
• Drugs can increase mucosal resistance by:
Protecting the base of a peptic ulcer(e.g. bismuth chelate, sucralfate)
Cytoprotection(e.g. misoprostol)
• Bismuth chelate: bismuth subcitrate, tripotassium
dicitratobismuthate
• Bismuth chelate act:
1) Chelating with protein in the ulcer base to form a coating that
protects the ulcer from the adverse influences of acid, pepsin, and bile
2) Suppression of the growth of H. pyori
contd
• Their therapeutic efficacy against benign DU and GU is equivalent to
that of H2 receptor antagonists
• But ulcers remain healed for longer after bismuth chelate than H2
receptor antagonists
• This may due to their ability to eradicate H. pylori
• Bismuth chelates are almost not absorbed and no systemic adverse
effects
• But the liquid formulation darkens the tongue, teeth and stool
• The effects are less likely with the tablet formulations
contd
• Bismuth is excreted by the kidney; it is prudent to avoid giving the
drug to patients with impaired renal function
• Sucralfate: is a complex salt of sucrose sulfate and aluminum
hydroxide
• Binds to protein molecules of the damaged mucosa, forms a viscous
paste that adheres selectively and protectively to the ulcer base
• It also binds to and inactivates pepsin and bile acids
• Its ulcer healing efficacy is equivalent to H2 receptor antagonists
• Sucralfate may cause constipation but otherwise well tolerated
contd
• Sucralfate is effective in acidic conditions(antacids should not be used
concomitantly)
• Sucralfate interferes with the absorption of ciprofloxacin, digoxin,
theophylline, phenytoin, and amitiptylline by binding
• Misoprostol: Misoprostol is a synthetic analogue of prostaglandin E1
• Protects against the formation of GU and DU in patients taking
NSAIDs
• Endogenous prostaglandins contribute to the integrity of the
gastrointestinal mucosa by a number of related mechanisms
contd
• Misoprostol also contributes to healing GU and DU possibly related to
antisecretory properties
• Adverse effects: transient diarrhea and abdominal pain
• Contraindicated in pregnancy(increased risk of abortion)
• This action has led its illicit use as abortifacient in parts of the world
where provision of contraceptive services is poor
Helicobacter pylori Eradication
• H. pylori role in the development of GU and DU is well established
• This close association is not seen with NSAID-induced ulcer, non-ulcer
dyspepsia, and GERD
• It is not known how H. pylori predisposes to peptic ulcer
• But chronic infection with the organism is associated with
hypergastrinemia and hyperacidity
• Other possible effect of long-term infection with H. pylori include
gastric carcinoma and lymphoma
• Eradication of the organism leads to resolution of peptic ulcers
contd
and particularly lymphoma
• Successful eradication of H. pylori usually results in long-term
remission of the ulcer
• Drugs used for eradication: metronidazole, amoxicillin, clarithromycin,
tetracycline and bismuth salts
• Efficacy of antimicrobials can be increased by co-administration of a
proton pump inhibitor
• The following regimens are recommended:
 Proton pump inhibitor in full dose + clarithromycin 500 mg b.i.d +
contd
amoxicillin 1 gm b.i.d. for 7- 14 days
 Proton pump inhibitor in full dose + clarithromycin 250 mg b.i.d. +
metronidazole 400 mg b.i.d for 7-14 days
• Treatment for two weeks is recommended
• Indicated for GU and DU not associated with NSAIDs, and gastric
lymphoma
• Not indicated for GERD
• Equivocal in value for non-ulcer dyspepsia, after incidental detection,
and for prophylaxis of gastric ulcer
NSAIDs-induced ulcers
• NSAIDs(e.g. aspirin) induced ulcers: occur in up to 5% of patients
taking these drugs
• Exert their anti-inflammatory effects by inhibiting the enzyme cyclo-
oxygenases(COX 1 & COX 2)
• Cyclo-oxygenase 1 is an enzyme involved in the production of
prostaglandins, which protect the gastric mucosa
• Inhibition of COX 1 has a potential for gastric mucosal injury
• Because NSAIDs are weak acids, enter into gastric mucosa,
accumulate inside the cell and can damage the cell
contd
• Treatment of NSAIDs-induced ulcers:
 Withdrawal of NSAIDs, and
 Acid suppression with standard doses of antisecretory drugs
• Inappropriate prescription of NSAIDs should be avoided if the
condition can be controlled with paracetamol
• When co-administered with NSAIDs, misoprostol reduces ulcers by
about 40% unless adverse effects limit its use
• PPIs in healing doses also have similar efficacy for prophylaxis
• H2 receptor antag. have limited effect against DU but none for GU
Gastroesophageal reflux disease(GERD)
• GERD develops with prolonged exposure esophageal mucosa to acid
and pepsin
• Factors contributing to GERD:
 Incompetence of gastro-esophageal sphincter
Delayed esophageal clearance of acid
Delayed gastric emptying
• The commonest symptom is heartburn
• In severe cases, acute or chronic bleeding occurs, esophageal
carcinoma may ensue
contd
• Drug treatment include:
 Antacids: Antacids combined with alginate are useful, it blocks the
reflux and protectively coats the esophagus
 acid suppression: PPIs are the most effective drugs at conventional
ulcer healing doses
Pro-kinetic drugs: anti-dopaminerigic drugs metoclopramide and
domperidone alleviate GERD symptoms
 Act by increasing gastro-esophageal sphincter and stimulating gastric
emptying(additionally exhibit central antiemetic effect)
Antiemesis drugs
• Useful vomiting occurs as a protective mechanism for eliminating irritant or
harmful substances from the upper GIT
• Act of vomiting is controlled by the vomiting center, which receives input from the
gut, higher cortical centers, and the vestibular apparatus
• Drugs used in treatment of vomiting:
 Anticholinergic drugs: hyoscine
• Competes with acetylcholine at muscarinic receptors in the gut and CNS
• Has also antispasmodic action in the gut wall
contd
• Adverse effects: typical anticholinergic effects such as dry mouth,
blurred vision, difficulty in micturition, drowsiness,etc.
• Uses: motion sickness prophylaxis(0.3-0.6 mg 1 hr before journey)
 Antihistamines: promethazine, cyclizine, dimenhydrinate
• Are competitive antagonists of histamine at H1 receptors mainly on
the vomiting center
• Used for motion sickness in addition to their wide use as antiallergic
drugs(promethazine dose of 25 mg q 8 hourly)
• Adverse effect: mainly sedation
contd
Dopamine antagonists: metoclopramide, chlorpromazine
• Have dopamine receptor antagonist properties and act mainly on the
chemoreceptor trigger zone
• Block stimuli to the CTZ
• Chorpromazine additionally has anticholinergic effects
• Metoclopramide has also pro-kinetic effects
• Uses: vomiting due to variety of conditions such as disease-induced,
cytotoxic therapy, morning sickness), but not effective for motion
sickness(metoclopramide dose: 10- 20 mg 4-8 hourly)
contd
 Serotonin antagonists: ondansetron
• Antagonizes serotonin at 5-HT3 receptors
• Has both central and peripheral actions
• Uses: treatment of nausea and vomiting associated with cytotoxic
therapy or radiotherapy
• Dose depends on the severity of the problem
• Adverse effects: constipation, headache, flushing
Drugs used for diarrhea
• Diarrhea: too frequent passage of poorly formed stools
• Important to identify and eliminate a cause where possible
• Rational management depends on establishing cause and instituting
specific therapy(only if necessary)
• Most diarrhea are self-limiting
• Therapeutic measures may grouped into:
 Treatment of fluid depletion, shock and acidosis
Maintenance of nutrition
Drug therapy
contd
 Treatment of dehydration: oral rehydration can be instituted from
the very beginning depending on the severity
• The rationale is to make up the losses in stool
• New formula of WHO-ORS:
NaCl: 2.6 g
KCl: 1.5 g
 Trisodium citrate: 2.9 g
Glucose: 13.5 g
Water: 1L
contd
• ORT is not designed to stop diarrhea, but to restore and maintain
hydration, electrolyte and pH balance until diarrhea ceases
 Maintenance of nutrition: contrary to the traditional view patients of
diarrhea should not be starved
• Fasting decreases brush border disaccharidase enzymes and reduces
absorption of salt, water and nutrients, and may lead to malnutrition
• Feeding during diarrhea increases intestinal digestive enzymes and
cell proliferation in mucosa
• Simple foods like breast milk, boiled potato, rice, banana, etc be given
contd
 Drug therapy: consists of:
 Specific antimicrobial drugs
Nonspecific antidiarrheal drugs
• Antimicrobial therapy should not be started for the mere presence of
pathogens(e.g. rota virus, Salmonella enteritidis)
• Antimicrobials are needed in invasive organisms like Shigella, Salmonella
typhimurium, E. histolytica, Closti. Difficile, E. coli,etc
• Selection of drugs depends on the susceptibility of the organism
• Co-trimoxazole, Quinolones, doxycycline, macrolides, metronidazole are
among commonly used drugs
contd
• Nonspecific antidiarrheal therapy include:
1) Antisecretory drugs: sulfasalazine, masalazine, prednisolone
• therapeutic effect in inflammatory bowel disease related diarrhea
2) Antimotility drugs: diphenoxylate, loperamide
• Reduce propulsive movements and diminish intestinal secretions
while enhancing absorption
• Abdominal cramps and rashes are common adverse effects
• Utility of antimotility drugs is limited to noninfective diarrhea because
they delay the clearance of the pathogen from intestine
contd
• Contraindicated in irritable bowel syndrome because they increase
intraluminal pressure

• Can be used to induce deliberate short-term constipation(e.g. after

anal surgery, colostomy patients)
Drugs used for constipation
• Medications that promote defaecations largely by reducing the
viscosity of the contents of lower colon are classified as:
1) Stool bulking agents
2) Osmotic laxatives
3) Fecal softners
4) Stimulant laxatives
• Laxative, purgative, cathartic, aperient, evacuant are synonymous
• Stool bulking agents include dietary fiber, bran, methylcellulose
contd
• Act by retaining water, increasing the volume and lowering the
viscosity which encourages normal reflex bowel activity
2) Osmotic laxatives: magnesium hydroxide, magnesium sulfate,
lactulose
• Retain water osmotically when given as a hypertonic solution
• Used frequently to clear the colon for diagnostic procedures or
surgery
3) Fecal softners: docusate
• Softens feces by lowering the surface tension fluids in the bowel
contd
• Allows more water to remain in the feces
• Useful in the management of anal fissure and hemorrhoids
4) Stimulant laxatives: bisacodyl, sena, cascara, castor oil
• Increase intestinal motility by various mechanisms
• Used to relive constipation and to empty the bowel for investigative
procedures
• May cause abdominal cramps
• Should be used with caution in pregnancy and never where intestinal
obstruction is suspected
contd
• Drastic purgatives such as cascara, castor oil are obsolete for use in
constipation
• May be indicated in the management of poisoning
• Laxative dependence(abuse) is a clinical problem
• Users should be informed about the bowel habit properly
• Prolonged abuse can damage gut nerves and lead to an atonic colon
• Excessive use of stimulant laxatives can lead to severe water and
electrolyte depletion