Categories
4. Drugs acting on Gestrointestinal tract

Chelating Agents

Chelating agents are the drugs or agents used to prevent or reverse the toxic effects of heavy metals on enzymes or accelerate elimination of metals from body.

The term “chelate is derived from the Greek word “ Chele” meaning “Crab’s Claw”. It is used to describe those complexes in which the ligand molecule binds through at least two donor groups so that a ring system is formed. Ligands having potential to form such rings are called chelating agents.

Chelating agent:

A flexible molecule with two or more electronegative groups that form stable coordinate bonds with a cationic metal atom.

Metals having Physiological Importance

  • Cr
  • Cu
  • Fe
  • Mg
  • Mn
  • Se
  • Zn

Clinically Important Metals

  • Au
  • Bi
  • F
  • Ga
  • Li
  • Pt

Toxic Metals

  • Al
  • As
  • Cd
  • Co
  • Pb
  • Hg
  • Hg-CH3
  • Ni

Positively charged metal ion binds with functional groups (OH-SH-NH) of enzymes, proteins, co-enzymes and membranes, inactivate the enzymes.

Classification

  • Desferrioxamine      Fe, Al, Ga
  • Deferasirox (oral)    Fe
  • Deferiprone (oral)    Fe
  • Dimercaprol (BAL)    As, Pb, Cu, Au
  • Ethylenediaminetetraacetic acid   Pb Pu
  • Succimer                As, Pb, Hg
  • Penicillamine          Cu, Pb
  • Trientine                Cu

Deferoxamine (Desferrioxamine)

Source Streptomyces pilosus

Affinity Fe++, Ca++, Al+++

Chelate Fe in hemosiderin & ferritin

But Fe in hemoproteins, cytochromes and microsomes is resistant

Pharmacokinetics

  • Oral absorption is poor, as it promotes Fe absorption
  • I/M, I/V – S/C preferred in children (in severe toxicity I/V given, while in moderate cases I/M preferred)
  • Metabolism –metabolized by plasma enzymes but exact mode is not defined.
  • Desferrioxamine metal complex excreted in urine (orange red colour)

The whole bowel irrigation is recommended to flush the un-absorbed iron because activated charcoal does not bind Fe & deferoxamine enhances Fe absorption

Side effects

  • Severe hypotension on rapid I/V infusion, so given slowly
  • Idiosyncratic reactions (Pruritus, Wheals, rashes, dysuria, abdominal pain, diarrhea, fever, leg cramps)
  • Adverse drug reactions on prolonged administration include neurotoxicity
  • Acute respiratory distress syndrome

Contraindications

Not given in patients suffering from renal insufficiency and anuria.

Therapeutic uses

  1. Iron overload
  2. Acute toxicity (oral?)
  3. Chronic Poisoning 1g I/V repeat after 2-4 hours maximum 6g

Management of Thalassemia

Repeated blood transfusions cause accumulation of iron, treated by:

  1. Admit the Patient
  2. 30/40mg/kg S/C abdominal wall
  3. DRC (Doses/Urinary excretion)
  4. Add ascorbic acid in low doses
  5. Repeat for 5 days

Toxicity

  • Local reaction at the site of injection
  • Neurotoxicity 30% children
  • Loss of hearing
  • Ocular damage

Deferasirox

  • Tridentate ligand binds Fe >> Zn, Cu
  • Given orally
  • Bioavailability is 70%
  • Protein binding is 99%
  • Glucuronide conjugation
  • Biliary excretion

Uses

  • Chronic transfusional iron over load
  • Dose 10-20 mg/kg daily
  • Iron excretion is predominant fecal

Dimercaprol

Also known as British Anti Lewisite ( BAL)

Used for the first time during the second world war when British Lewisite gas was used for destruction (caused vesicles), thus Dimercaprol was given as antidote. It is given for treatment of arsenic poisoning.

It is oily, colorless fluid having pungent mercaptan like odour.

Mechanism of action

  • SH groups has affinity for Lewisite, protect the sulfhydryl-containing enzymes of patient
  • Produce a non toxic, stable complex by binding As, Hg, Pb
  • Eliminated in urine
  • Earlier the drug is given, better is the response

Pharmacokinetics

  • Oral absorption is poor
  • Deep I/M 10% peanut oil suspension is used (painful), 100mg/ml, as aqueous solution is unstable so mixed with peanut oil
  • Peak effect 30-60 minutes. T ½ is 4 hours
  • Excreted in urine (at low pH drug/metal complex dissociates nephrotoxicity)
  • Use higher doses 2:1 ratio
  • Alkaline diuresis for rapid excretion from body.

Toxicity

  • Tachycardia, Rise in BP
  • Nausea vomiting, burning sensation in throat lips,
  • Lacrimation, rhinorrhea, salivation, increase in secretions
  • Burning sensation in hand, urinary tract

Used for acute poisoning not for chronic arsenic poisoning as can lead to redistribution of arsenic, which might go to brain.

Edetate Calcium Disodium (EDTA)

  • EDTA, Na2 EDTA, Ca Na2 EDTA
  • Chelate Di & trivalent metal ions both exogenous and endogeneous e.g. Fe Zn Mn
  • Used for acute lead intoxication

Pharmacokinetics

  • Oral  absorption is poor
  • I/M painful (mix with local anesthetic), Bioavailability is  good, T ½ < one hour, little degradation occurs
  • Distribution limited to extra cellular compartment
  • Excreted in urine just like inulin clearance (Asses renal functions before drug therapy)
  • For preventing life threatening calcium depletion, administered as calcium disodium salt.

Side effects

  • Tetany (Slow infusion)
  • Renal toxicity, degeneration of renal tubular cells, reversible. urgency, frequency
  • Malaise, fatigue, chills, fever
  • GIT symptoms –nausea, vomiting, gastric irritation
  • Nasal congestion sneezing
  • Hypotension ECG changes

Mainly used for chelating lead, but also for zinc and manganese.

Succimer (2,3 – dimercaptosuccinic acid)

  • Chemically related to dimercaprol
  • Oral absorption
  • Selectivity to Pb>>> As, Hg, Cd
  • Does not mobilize (Zn, Cu, Fe)
  • Excretion in urine, Bile, Enterohepatic circulation
  • Drug of choice in children Pb>45µg/dl
  • GIT Symptoms

Penicillamine (D – bb– dimethylcysteine)

  • History –in 1953 discovered and isolated from urine of patients on  penicillin treatment, which led to use in Wilson’s disease
  • Chelate Cu, Zn, Hg, Pb
  • Used mostly for Copper.
  • Oral absorption is 40% – 70%
  • Drug is stable in vivo-N acetyl penicillamine > stable used for Hg
  • Biotransformation: Liver complete
  • Excretion in urine, bile

Uses

  1. Wilson’s disease
  2. Hg Pb poisoning
  3. Rheumatoid arthritis –as has effect on immune complex
  4. Cystinuria (cystine –penicillamine soluble complex)
  5. Biliary cirrhosis
  6. Scleroderma

Toxicity

  • Allergy to penicillin also leads to allergy to this
  • Skin lesions 33% urticaria, maculopaplar  rashes, lupus erythematosis, fever
  • Blood aplastic anemia, aggranulocytosis, leukopenia
  • Can aggravate myasthenia gravis
  • GIT symptoms relieved by Cu supplements
Categories
4. Drugs acting on Gestrointestinal tract

Anti Tussives, Mucolytics and Mucokinetics

In most of the cases, anti tussives are combined with mucolytics, mucokinetics and anti histamines (sedatives, anticholinergics are combined as well).

Cough

It is a protective reflex with sudden noisy expulsion of air , expelling sputum & other irritant materials from upper part of airways.

Types

(1)  Productive / Useful Cough

It effectively expels secretions & exudates, from respiratory tract.

(2) Unproductive / Useless Cough

It is due to local irritation, e g smoker’s cough.

Anti-tussive Drugs:

Drugs which suppress cough & are used for symptomatic treatment of cough.

Types:

types according to mechanism of action

1. Centrally acting anti-tussives:

Suppress cough by a direct action on medullary cough center.

2. Peripheral Anti–tussives

They suppress cough reflex by decreasing the input of stimuli from cough receptors in respiratory passages.

Anti-tussive Drugs should be used to suppress unproductive / useless cough.

Classification  of Anti-tussive Drugs

(A)       Central Anti-tussives

(a)        Opioid / Narcotic /Addicting  Anti-tussives

(i)   Less addicting Drugs

  • Codeine phosphate,
  • Pholcodine,
  • Dihydrocodeine tartrate.

(ii)  Potent addicting Drugs

  • Morphine,
  • Dihydromorphinone.

(b) Non-Addicting Anti-tussives

Opioid derivatives :

  • Dextromethorphan,
  • Noscapine.

Non Opioids:

  • Benzonatate,
  • Diphenhydramine –antihistamine 1st gen, having sedative, anticholinergic actions, crosses BBB

(2)  Peripheral Anti-tussives

            (a)  Pharyngeal Demulcents (soothing action on irritating mucosa)

(b)   Steam inhalation

With tincture bezoin / menthol.

(c)   Drugs with Local Anesthetic Activity

  • Benzonatate –has central and peripheral actions, local anesthetic so action on stretch receptors in lung bronchi
  • Lignocaine by nebulizer –not anti tussive, only used in special cases (CA bronchus)

Uses

1)     For dry unproductive cough.

2)     If cough is unduly tiring.

3)     Disturb sleep.

4)     If patient is suffering from hernia, piles or underwent abdominal surgery

Mechanism of action of antitussives

Centrally acting

  1. Depression of medullary centres or associated higher centres.
  2. Increased threshold of cough centre.

Peripherally acting

  1. Interruption of tussle impulses from respiratory tract, having soothing effect.

Opioids:

Codeine

An opium alkaloid.

  • It is more selective for cough centre.
  • Centrally acting anti tussives increase threshold for cough.
  • Suppresses cough for about 6 hours.
  • The antitussive action is blocked by naloxone indicating that its action may be exerted through Opioid receptors in the brain.
  • Cough suppression occur with low doses of opioids than those needed  for analgesia.(sub-analgesic dose 15 mg)
  • Abuse liability is low, but present.

Adverse Effects

  • Constipation.
  • Respiratory depression & drowsiness
  • Driving may be impaired.
  • Contraindicated in asthmatics & in patients with diminished respiratory reserve.

Pholcodeine:

  • Centrally acting, suppresses center in medulla
  • Little/ no analgesic or addicting property.
  • Similar efficacy as antitussive to codeine
  • Is longer acting—–acts for 12 hours or more.
  • Given once or twice daily.
  • Dose: 10-15 mg.

Adverse Effects

  • Nausea
  • Drowsiness.

Non-addicting Anti-tussives:

Noscapine:

  • Depresses cough but has no narcotic, analgesic or dependence inducing properties.
  • Efficacy same as  codeine, specially useful in spasmodic cough.

Adverse Effects

  • Headache & nausea can occur.

Dextromethorphan:

  • A synthetic compound
  • The d-isomer has selective antitussive action (raises threshold for cough & depresses cough center in medulla.).
  • It has been found to enhance the analgesic action of morphine & other μ receptors agonists
  • As effective as codeine, does not depress mucociliary function of the airway mucosa.
  • Devoid of addicting actions.
  • Produces less constipation than codeine.
  • No CNS depression.
  • Antitussive action for 6 hours.
  • Naloxone does not antagonize it, indicating it does not act through opioids receptors.
  • Available as combination with anti asthmatics drugs, bronchodilators, expectorants and anti histamines. Extended release preparation is available which is administered two times daily.

Side effects:

Dizziness, nausea, drowsiness & ataxia.

Dose: 15-30mg three or four times daily

Levopropoxyphene:

Devoid of opioid effect but has some sedative property.

Adverse Effects

Sedation.

Antitussive dose   50-100mg 4 hrly.

Antihistamines

  • 1st generation drugs are used as anti tussives.
  • Many antihistamines have been added to antitussive / expectorant formulations.
  • They relieve cough due to their sedative and anticholinergic actions, but lack selectivity for the cough centre.
  • Useful in allergic cough.
  • They  may  reduce secretions by anticholinergic action (2-5 mg)

Diphenhydramine (15-25 mg) , Promethazine (15-25 mg)  are commonly used.

Only first generation antihistamine are used, 2nd generation drugs cannot cross BBB, so having no sedative effect.

Peripheral Antitussives

Demulcents.

  • They provide relief to throat.
  • promotes salivation & inhibit impulses from inflamed mucosa.

Linctus

Thick liquid preparation containing sucrose and medicinal substance.

These have sedative, demulcent properties.

Throat lozenges:

  •  Small medicated tablets intended to dissolve slowly in mouth
  • They have lubricating and soothing effect on irritated tissue of throat.
  • Lonzenges may contain benzocaine or dextromethorphan.

Bronchodilators

  • If cough is due to bronchospasm, D2 agonists are given.
  • Bronchodilators relieve cough in patients with bronchial hyperreactivity.
  • They shoud be used only when an element of bronchoconstriction is present.

Benzonatate:

Chemically related to Procaine, which is local anesthetic. It has both central and peripheral actions.

Mechanism of Action

  • Exerts its antitussive action on stretch or cough receptor in lungs (Local anaesthetic effect).
  • It has some central effects as well.

Adverse Effects:

  • Headache,
  • Dizziness,
  • Pruritis
  • Nasal Congestion,
  • burning of eyes &
  • tightness in chest.

Mucokinetics/Expectorants:

Definition:

Drugs which ↑ bronchial secretions or reduces its viscosity facilitating its removal by coughing

Expectorants

  • Ipecacuanha
  • Ammonium chloride
  • Ammonium bicarbonate.
  • Terepin hydrate
  • Potassium Iodide
  • Guaiphenesin
  • Sodium or Potassium citrate.

Mechanism of Action of Mucokinetics

a.  Directly acting:-

  • Stimulate secretory cells of resp tract directly & produces demulcent effect by decreasing irritation and viscosity of mucous.
  • Since these drugs stimulate secretion more fluid get produced in resp tract and sputum is diluted, there by helping in easy removal of sputum.

b.  Indirectly/ reflex acting:-

  •  Act indirectly to relieve cough by irritating gastric mucosa and increases resp tract fluid secretion and decreasing viscosity of sputum.

Ammonium salts:

  • Gastric irritants(nauseating) — enhance bronchial secretions.
  • Expectorant doses are subemetic, having unpleasant taste.
  • Used in combination with antitussives.

Ipecacuanha:

  • Used as expectorant in small doses & emetic in large doses.
  • It liquefies thick secretions and relieve  the irritated mucosa.
  • It  also irritates the gastric mucosa and  enhances the expulsion of secretion.
  • It is mainly used for emesis in accidental poisoning.

Guaiphenesin

Mechanism of Action

Decrease sputum viscosity and increase sputum volume thereby decreasing difficulty in expectoration

Only FDA Approved expectorant .

Uses:

For symptomatic relief of dry, non productive cough in the presence of mucus in respiratory tract.

Adverse effects:

Gastric disturbances and drowsiness.

Mucolytics:

Drugs which render sputum less visous so that sputum is more easily cleared from chest.

Classification:

Inhalational:

  • Acetylcysteine,
  • Tyloxapol.

Oral :

  • Acetylcysteine,
  • Bromohexine,
  • Carbocysteine,
  • Methylcysteine.

Mechanism of Action

Acetyl – , Carbo – , & Methyl-cysteine

Split disulphide bonds in mucoprotein present in sputum & reduces its viscosity.

Bromohexine

Reduces viscosity of bronchial secretions by de-polymerization of muco-polysaccharides as well as liberating lysosomal enzymes , network of fibers in tanacious sputum is broken.

Clinical Uses

(1)   Acute & chronic bronchitis.

(2)   Bronchial asthma

Adverse effects

(1)   CNS: Headache, tinnitus.

(2)   GIT: GI disturbances, gastric irritation.

(3)  Skin:    Urticaria

Rhinorrhoea

Lacrimation.

Specific treatment approaches to cough

Etiology of coughTreatment approach
Upper/lower respiratory tract infectionAppropriate antibiotics
Smoking/ chronic bronchitisQuit smoking / avoid Allergens/use antibiotic.
Pulmonary tuberculosisAntitubercular drugs
Asthmatic coughInhaled β2 agonists/ ipratropium / corticosteroids
Postnasal drip due to sinusitisAntibiotic, nasal decongestant, H1 antihistaminic
Postnasal drip due to allergic / perennial rhinitisAvoid the precipitating factor(s), corticosteroid nasal spray
Gastroesophageal refluxBed head elevation, light  dinner, diet modification, Hblockers, omeprazole, metoclopramide
ACE inhibitor associated coughSwitch on to losartan
Categories
4. Drugs acting on Gestrointestinal tract

Purgatives and Laxatives

Laxatives

Laxatives are milder in action and deal with evacuation of rectum. With use of laxatives, there is elimination of formed stools.

Cathartics

Cathartics are severe in action and deal with evacuation of colon. With their use, liquid form of stool is eliminated.

Purgatives

In between the two.

Functions Of Colon

  • Modification of consistency

Maintenance of consistency of stool through reabsorption of water. More water is reabsorbed, stool will harder.

  • Storage of fecal material
  • Evacuation takes place only when it is convenient for person.

Factors affecting function of colon

1.  Diet

Diet rich in fiber content will produce a softer consistency of stool

2.  Water intake

Also plays important role

What is constipation ?

Different in different parts of world. It is based on culture as well e.g. in west, passing 2 stool/week is no constipation, but in the east, passing 1 stool in one day is constipation.

If person is straining hard and consistency of stool is also hard, it is constipation and usually is said that 2 stools /week are constipation.

Causes

  1. Diet

Diet lacking fiber content will lead to constipation

  1. Structural abnormalities

Hemorrhoids and anal fissure. In these, patient is reluctant to pass stool.

  1. Tumors of colon can cause constipation
  2. Intestinal obstruction
  3. Drugs

a.      Opioids
b.      Anticholinergics
c.       TCAs
d.      Calcium channel blockers

  1. Systemic diseases
  • Hypothyroidism
  • Diabetes mellitus
  • Parkinsonism
  1. Idiopathic

Management of constipation

  1. To remove the cause
  2. Diet changes
  3. Use of drugs –mostly wrongly described.

Purgatives

Bulk Purgatives

Hydrophilic colloids

  • Ispaghula Husk
  • Bran
  • Methylcellulose
  • Psyllium seed

Stimulant Purgatives

Anthraquinone derivatives

  • Senna
  • Cascara
  • Aloe

Diphyenyl methane derivatives

  • Bisacodyl
  • Phenolphthalein –withdrawn due to cardiotoxicity

Castor oil

Osmotic Laxatives

Saline Purgatives

  • Magnesium sulfate
  • Magnesium Hydroxide
  • Sodium Phosphate

Non-absorbable Sugars

  • Lactulose
  • Sorbitol

Alcohol

  • Glycerin

Stool Softeners

  • Sodium docusate,
  • Calcium docusate,
  • Potassium docusate
  • Mineral Oil

5 HT4 Receptor Agonist

Tegaserod

Bulk Forming Purgatives

Mechanism of Action

Fiber  in our diet is:

A. Partly fermented

B. Unfermented

Fermented portion is converted into short chain fatty acids which have got prokinetic activity (they increase motility and secretion)

Unfermented portion imbibes water and increases bulk of stool due to this there is distention and increase in peristalsis.

Side Effects

  1. Abdominal discomfort
  2. Allergic reaction (with psyllium seeds)

Uses

  1. Mainly constipation
  2. Irritable bowel syndrome
  3. Diverticulosis
  4. When staining of stool is to be avoided

Stimulant Purgatives

Powerful purgatives

Anthraquinone Purgatives

Mechanism of Action

Contain active principle EMODIN which is a glycoside. It is passed into colon where it is acted upon by bacteria and they liberate ANTHROL which has prokinetic activity

Take a few hours (5-6 hours) to produce their actions.

Side Effects

1. Melanosis coli

Harmless pigmentation of colonic mucosa. It may be due to use of these drugs or due to pigment rich bacteria.

2. Cathartic colon

when used for long period of time, abnormal dilation of colon occurs and haustrations are lost. Damage to muscularis mucosae and neurons of myenteric plexus takes place.

These two adverse effects are reversible in some persons.

Diphenylyl methane Derivatives

Bisacodyl

Mechanism of Action

Hydrolysed in gut through deacetylation and converted to active form which produces low grade inflammation as a result of which motility and secretions are increased.

Take 5-6 hours for action to occur.

Indications

  1. Constipation
  2. Prepration of bowel for Radiographic Studies

Side Effects

  1. Abdominal pain/discomfort
  2. Few allergic reactions (rarely Steven’s Johnsons syndrome)

Castor Oil

Oldest purgative largely used by quacks.

02 components

a. Triglyceride – Glycerol & Ricinoleic acid
b.  Proteins

Triglyceride component is acted upon by pancreatic lipases as result of which glycerol and ricinoleic acid is formed. Ricinoleic acid has prokinetic activity.

Prolonged use is prohibited, it can damage intestinal mucosa as well as intestinal neurons.

Fecal Softeners

Docusate

Softens stool

Cause accumulation of water in the lumen of colon because of which they soften the stool.

Motility of gut

Increased by stimulating cAMP

Emulsifies colonic contents by increasing the penetration of water into stool.

Disrupts mucosal barrier

Interfere with absorption of fat soluble vitamins (A, E and K)

  Can interfere with absorption of different drugs

Side Effects

  Mainly GIT

  Abdominal Cramps, Pain, Nausea, Bitter In Taste

Hepatotoxicity has been feared on prolonged use

Liquid Paraffin

A viscous mixture of petroleum hydrocarbons with a lubricant action

Introduced as laxative at start of 19th century and largely used then.

Taken for about 2-3 days.

Use

Helps in relieving constipation as it coats the stool.

Side Effects

  Unpleasant to swallow

  Interference with absorption of fat soluble vitamin

Osmotic Purgatives

  Not absorbed in small intestine & retain water due to osmolar action

  By absorbing water, increase the bulk of stool because of which there is distention of colon and increase in motility

  Magnesium salts can increase secretion of CCK, which aids in purgative action of Mg.

Uses

  1. Preparation of bowel before surgery
  2. Preparation of bowel before colonoscopy
  3. In food and drug poisoning
  • Glycerine

Given in form of suppository. Acts in 02 ways

  1. Osmotic action
  2. Lubricant action
  • Lactulose

Neither digested nor absorbed. Converted into organic acid, decrease pH of colon, converts ammonium into non-absorbable ammonium ion and thus decreases ammonia absorption.

Uses

Hepatic encephalopathy

Contraindications

Mg salts in renal diseases

Na salts in congestive heart failure and patients suffering from Na retaining conditions

Prolonged use

Electrolyte and fluid imbalance.

  Side Effects

  • Renal and cardiac disease
  • Abdominal distension
  • Flatulence

Tegaserod

  Partial agonist at serotonin 4 receptors and has high affinity for these receptors as compared with 5HT3 receptors.

  Resembles serotonin and increases release of Acetylcholine and  calcitonin Gene Related Peptides by acting on pre-junctional serotonin 4 receptors.

  Increases cAMP dependent chloride efflux thus increases secretion, motility

  Prokinetic activity is seen in stomach and small/large intestine.

Uses

  • In chronic constipation when all other remedies fail.
  • Gastropharesis
  • Irritable bowel syndrome

Adverse Effects

  • Diarrhea
  • Abdominal discomfort
  • Flatulence
  • Headache
Categories
4. Drugs acting on Gestrointestinal tract

Anti Diarrhoeal Drugs

Some Patho-Physiological Aspects Of Diarrhea

Diarrhea means differently to different people.

Definition

Frequent and excessive loss of fluid and electrolytes accompanying:

  • more than 200 grams of stool per day
  • major portion is water à 70-80%

Fluid content and consistency grades

1. Grade I

Solid stool

2. Grade II

Semi solid stool

3. Grade III

Fluid and decal material mixed but its consistency is so much low that it takes shape of any container.

4. Grade IV

Water content and solid material separate.

5.  Grade V

Only water content

For clinicians, grade IV and V are very dangerous, especially in children and elderly, because they rapidly develop dehydration and electrolyte imbalance.

When absorptive capacity is exceeded or less time is provided for absorption, it leads to diarrhea

From Mechanistic prospective

It can be due to:

  1. Increased osmotic load in lumen
  2. Secretion of water and electrolytes in lumen
  3. Exudation of proteins and fluids from mucosa
  4. Increased intestinal motility

All these 4 mechanisms are readily affected by:

  1. Neurohormonal mechanisms
  2. Pathogens
  3. Drugs

Management

Correction  Of Dehydration And Electrolyte Imbalance

  1. Oral rehydration therapy ORT – ORS

ORS basically exploits the nutrient dependent co-transport, which remains intact (Na and Cl transported always with glucose)

In condition where vomiting occurs, oral therapy is not effective:

I/V Rehydration

Normal saline (normotonic solution)

Ringer lactate (hypertonic solution)

So in patients, we start with Ringer’s lactate and then switch to normal saline. Never let the patient to die of hypovolemic shock.

Treat the cause
Symptomatic relief – drugs

Classification Of Anti-Diarrheal Drugs

Opiates

1. Diphenoxylate

2. Diphenoxin

3. Loperamide

Adsorbents

1. Kaolin (attapulgite)

2. Pectin

Miscellaneous

1. Bismuth subsalicylte

2. Bismuth carbonate

3. Octreotide

4. Ispagullah husk and methylcellulose

Diphenoxylate

8-10 times more potent than morphine in decreasing gastrointestinal motility.

Mechanism of Action

Opioids in gut cause decrease in intestinal motility.

So, Diphenoxylate is converted into Diphenoxin/Diphenoxilic acid (active metabolite) producing anti diarrheal effect by three mechanisms:

  1. Inhibit presynaptic cholinergic nerve in submucosal and myenteric plexus by binding to peripheral mew receptors, that results in decreasing motility, leading to increased absorption of water.
  2. Increased tone of anal sphincter
  3. Increased mass colonic movements and gastrocolic reflex.

Side effects

Can cross BBB so adverse effects occur.

  1. CNS depression
  2. Respiratory depression
  3. Addictive potential

To counter addictive potential, it is marketed with small doses of atropine

Lomotil contains 2.5 mg diphenoxylate and 0.25 mg atropine.

Subtherapeutic doses do not have anticholinergic effect on this dose.

Motefen contains 1 mg diphenoxin and 0.025 mg atropine

Rationale of using atropine

So if patient will try to use more and more Lomitil, subtherapeutic doses of atropine are converted into therapeutic doses, producing anticholinergic effects leading to:

  1. Dryness of mouth
  2. Constipation
  3. Urinary retention

Loperamide

Mechanism of Action

Same mechanism of action, 40-50 times more potent than morphine in reducing gut motility.

Differences With Diphenoxylate

LoperamideDiphenoxylate
PotencyMore potentLess potent
BBBDoes not crossCrosses BBB
No CNS depressionCNS depression
No addictive effectWill occur, having analgesic effect in high doses
Does not need atropineNeeds atropine

Contraindications

  1. Ulcerative colitis

If given, increases chances of toxic mega colon (abnormal dilatation of colon) leading to increased risk of perforation and toxicity.

Ineffective diarrhea like:

  1. Acute bacillary dysentery –irritation of GI leading to diarrhea
  2. Amoebic dysentry

Anti motility drugs decrease the motility, leading to increased chances of toxin absorption, producing systemic adverse effects.

So as a rule, not used in children and infants.

Bismuth Subsalicylate

Mechanism of Action

Rapidly dissociates into bismuth and subsalicylate..

Bismuth then reacts with HCl and forms oxichloride which is not absorb at all.

  1. Anti-Bacterial Activity

Anti bacterial effect is by adsorbing bacteria. It binds bacteria and excretes them, very effective in H. pylori infections.

  1. Anti-Inflammatory Action

The other part of subsalicylate is rapidly absorbed and produces anti inflammatory effects by decreasing prostaglandins synthesis.

  1. Anti-secretory activity

Side Effects

Well tolerated drug.

  1. Black stools –darkening of stools, false impression of malena
  2. Dark coating of tongue

Methyl Cellulose & Ispagullah Husk

These two are not true anti diarrheals.

They absorb water and reduce fecal water content, leading to increased consistency of stools and giving false impression of bettering the diarrhea.

Orally proven uses of these are two:

  1. Colostomy
  2. Ileostomy

Kaolin And Pectin

Active form of Kaolin is Attapulgite – hydrated Mg Al disilicate

Pectin – indigestible carbohydrate derived from apple

Mechanism of Action

Both act as absorbants of bacterial toxins and fluids and decrease stool fluidity and frequency.

Side Effect And Caution

Well tolerated.

May cause constipation.

Used cautiously when other drugs are used because they will hamper their absorption.

Octreotide

Synthetic somatostatin analogue – peptide released in GIT & pancreatic d cells, enteric nerves and hypothalamus.

Mechanism of Action

  1. Inhibition of hormonal secretion

Decrease secretion of many hormones and neurotransmitters like gastrin, VIP and glucagon, insulin and CCK

  1. Decreases secretions

Decreases intestinal and pancreatic secretions

  1. Decreases motility

Inhibit contractions of gall bladder

  1. Decreases portal blood flow

By direct vasoconstrictor action

5.  Decrease secretion of anterior pituitary hormones

Somatostatin half life is 2-3 minutes thus has limited clinical use

Octreotide half life is 1.5-2 hours, having the same actions

Uses

  1. Diarrhea due to vagotomy
  2. Short bowel syndrome
  3. AIDs

Octreotide has multiple effects on GI motility:

  1. High dose decreases motility (150-250 mcg/day)
  2. Low dose increases motility
  3. Carcinoid syndrome
  4. Tumors that secrete increased VIP
  5. Varices

Side effects

  1. GIT

a.      Steatorrhea (absorption of fat soluble vitamins is decreased)
b.      Abdominal pain
c.       Flatulence
d.      Diarrhea

On long term use:

  • Acute cholecystitis
  • Hyperglycemia or hypoglycemia because it alters balance between insulin, growth hormone and glucagon.
  • Hypothyroidism
  • Bradycardia
Categories
4. Drugs acting on Gestrointestinal tract

Anti Emetics

Vomiting

Vomiting center is located in the lateral reticular formation of medulla (M1, H1, 5HT3, NK1 and others are involved). Stimulus comes from different areas. Efferents move through vagus nerve.

Important afferents include:

  1. CTZ also known as area postrema located in the floor of 4th ventricle (D2, NK1 and 5HT3 are involved)
  2. Vestibular apparatus –motion sickness is associated (H1, M1, vestibular nerve)
  3. Higher brain stem and cortical centers
  4. Signals from pharynx, stomach via solitary tract nucleus, 5HT3
  5. Visceral afferents from heart, GIT, testes, etc.

Once stimulated, efferents move through the vagus, phrenic and spinal innervation of abdominal muscles.

Events in the process of emesis

  1. Nausea
  2. Decrease of gastric tone
  3. Decrease or absence of peristalsis
  4. Tone of upper small intestine increases
  5. Upper portion of stomach & lower esophageal sphincter relax
  6. Coordinated contraction of diaphragm and abdominal muscles leads to vomiting

Classification of anti- emetics

1. Subtituted benzamides

  • Metoclopramide –commonly used having multiple effects, D2, 5HT3, 5HT4, other effects)
  • Trimethobenzamide

2. Phenothiazines

  • Prochlorperazine
  • Chlorpromazine
  • Thiethyl perazine

3. Butyrophenones

  • Domperidone (mortilium)
  • Droperidol
  • Haloperidol

4. Serotonin receptor blockers

  • Ondansetron
  • Granisetron
  • Dolasetron
  • Palonosetron -40 hrs, highest affinity for 5HT3 receptors

5. Anti-histamines

  • Dimenhydrinate
  • Diphenhydramine
  • Promethazine
  • Cyclizine
  • Meclizine –least cholinergic effects

6. Anti-muscranic agents

  • Hyoscine (scopolamine) important for motion sickness

7. Marijuana derivatives / cannabinoids

  • Dronabinol
  • Nabilone

8. Neurokinin receptor antagonist

  • Aprepitant
  • Fosaprepitant (rapidly converted into aprepitant, once given)

Metoclopramide

Mechanism of Action  (central & peripheral)

A. Anti emetic effect

1. Central effect

Block D2 receptors in CTZ, main action at CNS

Also block 5HT3 receptors in vomiting center and CTZ, weaker action (afferent vagus nerve signals blocked)

2. Peripheral effect

Antiemetic effect by blocking 5HT3, blocking affects of vagus nerve going to CTZ

B. Prokinetic effect

5HT4 agonist effect in periphery

Enterochromaffin cells of GIT secrete 5HT in response to chemical and mechanical stimuli, serotonin has two effects:

  1. Stimulate 5HT receptors, vagus and spinal nerves stimulate
  2. Nor adrenergic and non cholinergic effect, inhibit acetylcholine release

Increasing inhibitory effect decreases acetylcholine while decreasing inhibitory effect increases acetylcholine, which is the prokinetic effect.

5HT4 in myenteric plexus releases acetylcholine, increasing gastric emptying.

Clinical Uses

1. Anti emetic effect
2. Gastro esophageal reflux disease (GERD)

Used because of prokinetic effect, given 30 minutes before meal. Also used adjunct to proton pump inhibitors and H2 blockers.

3. Long standing DM

Used in long standing diabetes mellitus, where diabetic gastroparesis occurs (delayed stomach emptying)

4. Post op conditions

Vagotomy, enterotomy. Decreased gastric emptying

5.  Delayed type chemotherapy

Used in combination in delayed type chemotherapy induced nausea, vomiting along with other drugs

6. Post partum lactation

Since D2 blocker, increases post partum lactation

7. Non peptic non ulcer dysphagia

Also used effectively in non peptic non ulcer dysphagia

8. Hiccups

Uses in persistent type of hiccups

Adverse effects

As crosses blood brain barrier:

  1. Somnolence
  2. Nervousness
  3. Extra pyramidal symptoms -tremors
  4. Galactorrhea & ammenorrhea

Domperidone

Market name is Mortilium

Mechanism of Action

Having both central and peripheral effects, only D2 blocking effects in CTZ and produces anti-emetic effects.

In periphery block D2 receptors like metoclopramide. Disinhibit dopaminergic nerves, producing weak prokinetic effect.

As only D2 blockers, have no 5HT4 effects.

Comparison with metocloperamide

DomeperidoneMetoclopramide
ButyrophenoneSubstituted Benzamide
Does not cross BBBCross BBB
Only D2 blocking effectD2, 5HT3, 5HT4
Weak prokineticStronger prokinetic
No sedative, CNS effectsProduce CNS symptoms
No EPSEPS
Only act CTZHas effects on vomiting center (5HT3)

Uses -same

Cannabinoids

Block CB1 receptor in and around vomiting center. Use is decreasing because of better options.

Also increase appetite

Previously used in cancer chemotherapy induced vomiting.

Currently only used when other agents fail.

Adverse effects

  1. Euphoria,
  2. Dysphoria,
  3. Ataxia,
  4. Drowsiness,
  5. Dry mouth,
  6. Appetite stimulation
  7. Withdrawal symptoms when discontinued.

5HTAntagonists

Mechanism of Action (central & peripheral)

Dual effects.

  1. CNS –block 5HT3 receptors in CTZ and vomiting center
  2. Periphery –block 5HT3 receptors blocking extrinsic stimuli

Serotonin is released from enterochromaffin like cells producing emetic effects

Uses

5HT3 blockers are primary agents in prevention of cancer chemotherapy induced nausea, vomiting and diarrhea, given 30 minutes before chemotherapy.

Slow I/V over 15 minutes time.

  1. In acute phase single drug,
  2. For delayed used in combination with:
  3. Drugs like steroids (dexamethasone)
  4. Neurokinin 1 receptor blockers
  5. 5HT3 receptor blockers
  6. Post radiation nausea, vomiting
  7. Hyper emesis of pregnancy (in 1st trimester no anti emetic is used)
  8. Blocks emesis by vagal stimulation
  9. Post op vomiting

Adverse effects

  1. Headache
  2. Dizziness
  3. Constipation
  4. QT prolongation –Dolasetron has highest effect, not given with other drugs with QT prolongation.

NK1 antagonist

Aprepitant –oral preparation, crosses BBB        

Fosaprepitant –I/V rapidly excreted

Used in combination for preventing delayed type vomiting in cancer chemotherapy.

Extensively metabolized by liver.

CYPA4 enzyme inhibitory effects. Important drug interactions as vincristine, vinblastine are also metabolized by CYPA4, thus dose correction is required.

Adverse effects

  1. Fatigue
  2. Dizziness
  3. diarrhea

Steroids and Benzodiazepines

Benzodiazepines have direct anti-emetic effect used in anticipatory vomiting.

Effects include antianxiety, amnesic and sedative effects.

Categories
4. Drugs acting on Gestrointestinal tract

Drugs Used in Acid Peptic Disease

These drugs are used for:

1. Peptic ulcers (gastric or duodenal)

2. Gastro esophageal reflux disease

3. Hyper secretory conditions –Zollinger Ellison syndrome

Underlying Causes of Ulcers

  • Helicobacter pylori a gram negative bacillus is a major cause of duodenal ulcer.
  • Imbalance between acid/pepsin secretion
  • Decreased secretion and action of mucous/bicarbonates.

Histamine, acetylcholine and gastrin provide stimulus for release. Balance is maintained by opposing effects of mucous, bicarbonates, prostaglandins and superficial layer of epithelial cells. Any disturbance may lead to development of  ulcers.

Drugs can alter the balance towards prevention or healing of Ulcer

  •  Reduction of acid secretion
  •  Neutralization of secreted acid
  •  Eradication of helicobacter pylori
  • Enhanced mucosal resistance

The Control of Gastric Acid Secretion

Gastric acid (HCl) is produced by parietal cells in the stomach and its secretion is regulated by three pathways.

  •  Parasympathetic stimulation occurs via the vagus nerve, the preganglionic fibres of which synapse at ganglia where muscarinic M1 receptors play an important role in neurotransmission.
  •  Gastrin is released from G cells in the antrum of the stomach
  •  There is a local release of histamine from enterochromaffin-like (ECL) cells.

Stimulation of prostanoid receptors PGE2, PGI2 on superficial epithelial cells inhibits HCl secretion.

Imbalance leads to development of peptic ulcer.

H2 receptor antagonists are required in high dose in hypersecretory conditions, so no more used. Large amount of antacids is required.

Drugs Used In Peptic Ulcer

Drugs that Reduce Acid/Pepsin Activity

H2-Receptor Blockers

  • Cimetidine,
  • Ranitidine,
  • Famotidine,
  • Nizatidine

Proton Pump Inhibitors (Benzimidazole Derivatives)

  • Omeprazole,
  • Lansoprazole,
  • Rabeprazole,
  • pantoprazole,
  • Esmoprazole (S isomer omeprazole)

Anti Muscarinics (M1 Selective) (control acid secretion)

  • Pirenzepine,
  • Telenzepine

Gastric Antacids

Systemic

Sodium bicarbonate

Non Systemic

a. Physicochemically acting

  • Aluminium hydroxide,
  • Al  phosphate
  • Magnesium trisilicate,
  • Magaldrate

b. Chemically acting

  • Magnesium hydroxide,
  • Ca carbonate (non ulcer dyspepsia)

Drugs that Increase Mucosal Resistance

Sulfated Sucrose Derivative
Sucralfate

Colloidal bismuth compounds

  • dicitrato tripotassium bismuthate,
  • bismuth subcitrate

Prostaglandin derivative

  • misoprostol,
  • enprostil,
  • rioprostil

Drugs used for the Eradication of Helicobacter Pylori (Antibiotics)

  • Metronidazole
  • Clarithromycin
  • Amoxicillin
  • Tetracycline

Proton Pump Inhibitors

Omeprazole

Mucosal Surface Protectors

Bismuth salts (better options are available)

Antacids

Chemical Composition

AlCl3 is demulcent, forms coating over ulcerated mucosa. Problem is that it has astringent property leading to constipation.

MgCl3 has weak chemical action, there are chances of toxicity with Mg. It is prescribed in combination with Al to increase buffering time.

CaCl2 has complete absorption, neutralization can take place repeatedly, so not preferred because of toxicity.

CO2 causes belching.

Systemic acting are not given, as increase Na load may lead to cardiac problems.

If heart burn occurs, and milk is given along with systemic antacids (soda bicarbonate containing, Ca containing or in renal compromised) can lead to milk alkali syndrome, leading to hypercalcemia and toxicity.

If peptic acid is confirmed, systemic acting are not given because of:

  1. Belching
  2. Milk alkali syndrome
  3. Acid rebound –systemic antacids neutralize gastric pH when taken continuously, poor neutralization reflex gastric secretion, even when stop taking, gastrin is in excess.

H2 Receptor Antagonists

  • Competitively inhibit histamine actions at all H2 receptors
  • Lowers the basal, food stimulated & nocturnal secretions of  gastric acid as histamine release is maximum at night.

Now proton pump inhibitors are the main stay.

  •  Rapidly absorbed after oral administration, oral preparations are preferred, I/V preparation is available as well. Given I/V in stress and gastric bleeding.
  •  under go first pass hepatic metabolism
  •  Bioavailability 50%
  •  Nizatidine has negligible first pass metabolism. Cimetidine undergoes 1st pass metabolism.
  •  Therapeutic levels achieved rapidly after I/V dosing
  •  Duration of action depends on dose given
  •  Excretion by kidneys
  •  Important to reduce dose in patient with decreased creatinine clearance.

Cimetidine is imidazole derivative, nocturnal dose of 800 mg quite sufficient for 24 hour acid secretion.

Ranitidine (zantax) has similar actions, 300 mg nocturnal dose while Famotidine has triazole ring (400 mg). 5 times more potent, mainly used.

Nazitidine has 20 mg dose, not used for nocturnal treatment, used for symptomatic treatment, for short term. NSAIDs are used as these are not cost effective.

CimetidineRanitidine
 5 times potent
Undergoes 1st pass metabolismDoes not undergo (only 10%)
 Action mainly GIT
I/V within 4-5 hours effect6-8 hours levels up to 12 hours remain after I/V admin
Avoid in young adults having adrenergic effects. 
Excretion through kidneys, one has to be careful as renal impairment might occur. 

Adverse Reactions

Well tolerated by most patients, occur in less than 3%

Minor:

a.      Diarrhea, abdominal pain
b.      constipation
c.       head ache,
d.      Drowsiness,
e.       Fatigue,
f.        Muscular pain,

CNS:

a.      Confusion,
b.      delirium,
c.      Hallucination –not seen with oral administration at therapeutic doses
d.      slurred speech,
e.       headache in elderly or /IV route

Long Term Use of Cimetidine at High Doses

Rare but chances of certain adrenergic side effects:

  1. decreases testosterone binding to the androgens receptors (infertility/impotency chances)
  2.  inhibits cytochrome that hydroxylates estradiol & inhibit degradation of estradiol –galactorrhea, gynecomastia
  3.  blood dyscrasias thrombocytopenia
  4. hypotension/ bradycardia I/V esp. in patients having cardiac problems

Drug Interactions

Mainly with cimetidine, Inhibit CYP1A2, CYP2C9 CYP2D6

  •  Tolerance to acid suppressing effect, may develop within 3 days –one reason why not commonly used
  •  Secondary hyper gastrin emipa

Rebound increase in acid secretion even after the drug is stopped (also by systemic antacids)

Therapeutic Uses

  1.   To promote healing of gastric/duodenal ulcers
  2.   To treat uncomplicated GERD
  3.   To prevent occurrence of stress ulcer
  4.   Cases of GERD in pregnancy with ranitidine

Anti muscarinic drugs

Although decrease basal secretion, do not increase pH to sufficient levels, although H2 blockers are used, which reduce secretions already.

Adverse effects include:

Abdominal discomfort, spasms, pain

Parenzepine and Olenzapine are M1 drugs helpful in some patients.

Because of M2 blockage, atropine is NOT USED, may cause tachycardia, dry mouth and urinary retention.

May promote secretion of mucous bicarbonates having limited role

Proton Pump Inhibitors

  • All are substituted benzimidazoles
  • Prodrugs, lipophilic weak bases
  • Racemic mixtures R and S isomers,
  • Inhibit the final common step in gastric acid secretion
  • All types available as oral formulations, enteric coated
  • Esmoprazole, pantoprazole also as I/V formulations

Lanosprazole is given orally, can disintegrate in mouth, is water soluble given in ITC. Can be given dissolved in water as well, or enteral route or by oral syringe. When enteric coated tablets are given, at alkaline pH, disintegrate and drug is released, all stimuli of gastric acid secretion are inhibited. Very effective as H K ATPase is the final step, if inhibited secretion becomes zero.

Mechanism of Action

  • at acidic pH it secretes into a reactive thiophilic sulfphenamide cation.
  • reacts covalently with SH GP of the HK+ – ATPase enzyme,i nactivates it irreversibly
  • Gets concentrated in the acidic pH of the parietal cell canaliculi
  • HCl secretion resumes only when new HK+ ATPase molecules are synthesized

Pharmacokinetics

  • Administered empty stomach 01 hr before break fast.
  •   Short serum half life 1.5 hrs, but acid inhibition last for 24 hours
  •   Rapid first pass hepatic metabolism
  •   I/V prep are preferred as continuous infusion to provide max. inhibition initially.

Clinical Uses

  1. Non erosive & erosive reflux disease (GERD)
  2.   Symptomatic GERD -first line therapy
  3.  Duodenal ulcer 90% healed 4 wks, Gastric ulcer 6-8 wks 90% as mucosal damage occurs
  4. NSAIDS associated ulcers.
  5. Prevention of rebleeding from peptic ulcer.
  6. Prevention of stress related mucosal bleeding .

Omeprazole is  administered by nasogastric tube
FDA approved oral immediate release fluids are available.

Adverse Effects

Safe drugs,

1.  GIT

  • Diarrhea,
  • headache,
  • abdominal pain (1-5% patients)

2.  With prolonged therapy, vitamin B12 levels decreased
5.  Hospitalized patient may have an increased risk for clostridium difficile infection .
6. ECL hyperplasia in response to hypergastrinemia.

7.  May reduce Ca absorption or inhibit osteoclast function – risk factor for those with osteoporosis
8. Increase in gastric bacterial concentration, increase risk of community acquired respiratory infection & nosocomial pneumonia among patient taking proton pump inhibitors.

Drug Interactions

Ketoconazole, Digoxin and antivirals, because of decreased acid secretion. (Atonavir actions are impaired)

Omeprazole inhibits metabolism of Diazepam and warfarin, Diazepam action is prolonged.

Combination of drugs used for the treatment of peptic ulcers due to H. Pylori infections

3 regimens are in the guidelines, depending upon lesions and compliance of patient. Combination increases buffering time, overuse may lead to side effects:

  1. Omeprazole 20mg twice daily before meals or lansoprazole 30 mg twice daily + metronidazole 500 mg twice daily + clarithromycin 500 mg twice daily after meals.
  2.  20 mg Omperazole or 30 mg lansoprazole  twice daily before meals + 1 g of amoxycillin twice daily + 500 mg of clarithromycin  twice daily after meals
  3.  240 mg of bismuth chelate 4 time daily + tetracycline 500 mg 4 time daily + metronidazole 250 mg 4 time daily. Quite cumbersome because:
  • has to be taken four times daily. If not responding to first two drugs then given. It was used as detaches from intestine and cause lysis. Additionally having mucoprotective role causing increase in secretion of mucous.
  • Blackening of tongue
  • Patient compliance is poor

All the above regimens should be given for 10-14 days. After this a  further course of omeprazole 20 mg once daily for 2 weeks or Lansoprazole 15 mg once daily for 2 weeks should be used for cases With duodenal ulcer. In patients with gastric ulcer omeprazole 40 mg And lansoprazole 30 mg should be given for further 6 weeks. H2 antagonists or sucrlfate can be given instead of proton pump inhibitors after the completion of 10-14 days regimens for H-Pylori eradication.

Prostaglandins

Prostaglandins have cytoprotective role TGE2, TGI2 by:

  1. Inhibiting acid secretion
  2. Promote healing of damaged gastric mucosa
  3. Increases microcirculation
  4. Enhances tight junctions of mucosa so that back diffusion does not occur.

Have very short half life. A number of stable prostaglandins analogs are available.

Misoprostol is given in 800 mg dose, given 3-4 times daily, effective in duodenal ulcer treatment but in initial one week treatment, induce pain themselves. Patient compliance is poor, reserved for gastroduodenal ulcers or NSAIDs induced.

Misoprostol (Cytotec)

Drug Class: Prostaglandin analog (synthetic)

Mechanism of Action

A methyl analog of PGE1. It is believed to stimulate mucus & bicarbonate secretion & enhance mucosal blood flow, thereby helping protect the stomach by forming a protective barrier against acid. It also binds to prostaglandin receptors on parietal cells, reducing histamine-stimulated cAMP production & causing modest inhibition of acid secretion.

Not superior to PPH and H2 antagonists.

Indications

Prevention of NSAID (including aspirin)-induced gastric ulcers in patients at high risk of complications from gastric ulcer, e.g., the elderly and patients with concomitant debilitating disease, as well as patients at high risk of developing gastric ulceration, such as patients with history of ulcer.

Contraindications:

Contraindicated, because of its abortifacient property, in women who are pregnant. Women of childbearing potential should be told that they must not be pregnant when misoprostol therapy is initiated, and that they must use an effective contraception method while taking misoprostol.

Side Effects:

Diarrhea, increased uterine contractions

Mucosal Protective Agents

Drug: Sucralfate (generic, Carafate )

Drug Class: Mucosal Protective Agent

Mechanism of Action:

Sucralfate is a salt of sucrose complexed to sulfated aluminum hydroxide.

Sucrose octasulphate + polyalumonium hydroxide

  1. When administered, required acidic pH is below 4. At less than 4, since complex, polymerization and cross linking different polymers are converted into viscous, tenacious paste that binds selectively to ulcers or erosions for up to 6 hrs. It is believed that the negatively charged sucrose sulfate binds to positively charged proteins in the base of ulcers or erosions, forming a physical barrier that restricts further caustic damage.
  2. Local production of epidermal factors stimulated
  3. Does not gets absorbed having physical action

Have to be given in high doses 4 times a day. 1g before each meal and at sleeping time. Duration of treatment is 4-6 weeks.

Have to stop other treatments as activated at acidic pH so cannot be given with H2, PPH or antacids, otherwise cannot get activated.

But protective layer is short lived given temporarily.

Indications:

Treatment of duodenal ulcer.

Pharmacokinetics:

Less than 3% of intact drug gets absorbed into the body. The remainder gets excreted in the feces.

Side Effects:

Constipation, black stool

Major drug interactions:

Don’t take with H2 blockers or antacids, which reduce the acidic environment required for activation of sucralfate.

Drug: Bismuth subsalicylate (Pepto-Bismol, others)

Drug Class: Colloidal Bismuth Compound

Mechanism of Action:

Like sucralfate, bismuth coats ulcers and erosions, creating a protective layer against acid and pepsin. It may also stimulate prostaglandins, mucus & bicarbonate secretion. It also has direct antimicrobial effects (e.g. against H. pylori) and binds enterotoxins (useful in treating traveler’s diarrhea). It also reduces stool frequency and liquidity in acute infectious diarrhea, due to salicylate inhibition of intestinal prostaglandins & chloride secretion.

Indications:

  1. treatment of dyspepsia &
  2. acute diarrhea,
  3. prevention of traveler’s diarrhea

Implication For Dentistry

Whether a patient is on a regimen of H2 blockers or antacids or has a history of gastric or duodenal ulcer, is important information for the dentist. Since this can influence the choice of a therapeutic agent or time of drug administration.

  • The use of aspirin as an analgesic is contraindicated becauseof its irritating effect on gastric mucosa, esp in elderly patients.
  • All NSAIDs share the ulcerogenic property of the salicylates – acetaminophen used as alternative analgesics  as it produces minimal damage to gastric
  • Systemic steroids if used after oral surgical procedures are potentially ulcerogenic.
  • Even topical steroids used in the management of oral leisons should be avoided in the ulcer patients, because there absorption through the mucosa will occur.
  • The choice of a preoperative or postoperative sedative is important for the ulcer patient. Chloral hydrate has irritating GIT side effects nausea & vomiting can occur.
  • Diazepam is appropriate since in addition to producing sedation, it can suppress the nocturnal secretion of gastric acid.
  • Absorption of orally administered diazepam is increased by the use of Al(OH).Mgsalt retards it absorption.
  • For a patient being treated with cimetidine or omeprazole it is better to prescribe lorazepam or oxazepam, as antianxieity drugs, not depdendent on hepatic oxidative biotransformation. They are eliminated in the urine as glucuronide conjugates, the formation of which is not impaired by either cimetidine or omeprazole.
  • Just one day of pretreatment with cimetidine causes much higher plasma concentrations of diazepam and a more pronounced sedative effect and slow elimination.
  • Important in elderly patients, so diazepam if prescribed for a dental patient on cimetidine its dose should be reduced.