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.
A flexible molecule with two or more electronegative groups that form stable coordinate bonds with a cationic metal atom.
Metals having Physiological Importance
Clinically Important Metals
Positively charged metal ion binds with functional groups (OH-SH-NH) of enzymes, proteins, co-enzymes and membranes, inactivate the enzymes.
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
Source Streptomyces pilosus
Affinity Fe++, Ca++, Al+++
Chelate Fe in hemosiderin & ferritin
But Fe in hemoproteins, cytochromes and microsomes is resistant
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
Severe hypotension on rapid I/V infusion, so given slowly
Adverse drug reactions on prolonged administration include neurotoxicity
Acute respiratory distress syndrome
Not given in patients suffering from renal insufficiency and anuria.
Acute toxicity (oral?)
Chronic Poisoning 1g I/V repeat after 2-4 hours maximum 6g
Management of Thalassemia
Repeated blood transfusions cause accumulation of iron, treated by:
Admit the Patient
30/40mg/kg S/C abdominal wall
DRC (Doses/Urinary excretion)
Add ascorbic acid in low doses
Repeat for 5 days
Local reaction at the site of injection
Neurotoxicity 30% children
Loss of hearing
Tridentate ligand binds Fe >> Zn, Cu
Bioavailability is 70%
Protein binding is 99%
Chronic transfusional iron over load
Dose 10-20 mg/kg daily
Iron excretion is predominant fecal
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
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.
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
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.
Tetany (Slow infusion)
Renal toxicity, degeneration of renal tubular cells, reversible. urgency, frequency
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.
Anti Muscarinics (M1 Selective) (control acid secretion)
a. Physicochemically acting
b. Chemically acting
Ca carbonate (non ulcer dyspepsia)
Drugs that Increase Mucosal Resistance
Sulfated Sucrose Derivative Sucralfate
Colloidal bismuth compounds
dicitrato tripotassium bismuthate,
Drugs used for the Eradication of Helicobacter Pylori (Antibiotics)
Proton Pump Inhibitors
Mucosal Surface Protectors
Bismuth salts (better options are available)
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:
Milk alkali syndrome
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
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.
5 times potent
Undergoes 1st pass metabolism
Does not undergo (only 10%)
Action mainly GIT
I/V within 4-5 hours effect
6-8 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.
Well tolerated by most patients, occur in less than 3%
a. Diarrhea, abdominal pain b. constipation c. head ache, d. Drowsiness, e. Fatigue, f. Muscular pain,
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:
decreases testosterone binding to the androgens receptors (infertility/impotency chances)
inhibits cytochrome that hydroxylates estradiol & inhibit degradation of estradiol –galactorrhea, gynecomastia
blood dyscrasias thrombocytopenia
hypotension/ bradycardia I/V esp. in patients having cardiac problems
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)
To promote healing of gastric/duodenal ulcers
To treat uncomplicated GERD
To prevent occurrence of stress ulcer
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 H+ K+ – ATPase enzyme,i nactivates it irreversibly
Gets concentrated in the acidic pH of the parietal cell canaliculi
HCl secretion resumes only when new H+ K+ ATPase molecules are synthesized
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.
Omeprazole is administered by nasogastric tube FDA approved oral immediate release fluids are available.
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.
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:
Omeprazole 20mg twice daily before meals or lansoprazole 30 mg twice daily + metronidazole 500 mg twice daily + clarithromycin 500 mg twice daily after meals.
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
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 have cytoprotective role TGE2, TGI2 by:
Inhibiting acid secretion
Promote healing of damaged gastric mucosa
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.
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.
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.
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.
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
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.
Local production of epidermal factors stimulated
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.
Treatment of duodenal ulcer.
Less than 3% of intact drug gets absorbed into the body.The remainder gets excreted in the feces.
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.
treatment of dyspepsia &
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)., Mg+ salt 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.