Difenoxin and atropine

Difenoxin and atropine Uses, Dosage, Side Effects, Food Interaction and all others data.

Atropine binds to and inhibit muscarinic acetylcholine receptors, producing a wide range of anticholinergic effects. Atropine is an anticholinergic agent which competitively blocks the muscarinic receptors in peripheral tissues such as the heart, intestines, bronchial muscles, iris and secretory glands. Some central stimulation may occur. Atropine abolishes bradycardia and reduces heart block due to vagal activity. Smooth muscles in the bronchi and gut are relaxed while glandular secretions are reduced. It also has mydriatic and cycloplegic effect.

Atropine, a naturally occurring belladonna alkaloid, is a racemic mixture of equal parts of d- and l-hyoscyamine, whose activity is due almost entirely to the levo isomer of the drug. Atropine is commonly classified as an anticholinergic or antiparasympathetic (parasympatholytic) drug. More precisely, however, it is termed an antimuscarinic agent since it antagonizes the muscarine-like actions of acetylcholine and other choline esters. Adequate doses of atropine abolish various types of reflex vagal cardiac slowing or asystole. The drug also prevents or abolishes bradycardia or asystole produced by injection of choline esters, anticholinesterase agents or other parasympathomimetic drugs, and cardiac arrest produced by stimulation of the vagus. Atropine may also lessen the degree of partial heart block when vagal activity is an etiologic factor. Atropine in clinical doses counteracts the peripheral dilatation and abrupt decrease in blood pressure produced by choline esters. However, when given by itself, atropine does not exert a striking or uniform effect on blood vessels or blood pressure.

Difenoxin is a 4-phenylpiperidine which is closely related to the opioid analgesic meperidine. Difenoxin alone is a USA Schedule I controlled drug, as it may be habit forming. However, it is listed as a Schedule IV controlled drug if combined with atropine, which is added to decrease deliberate misuse. Motofen(R) is a brand mixture which combines atropine sulfate and difenoxin hydrochloride. It is approved by the FDA to treat acute and chronic diarrhea.

Difenoxin is an active metabolite of the anti-diarrheal drug, diphenoxylate, which is also used in combination with atropine in the brand mixture Lomotil(R). It works mostly in the periphery and activates opioid receptors in the intestine rather than the central nervous system (CNS). [3] Difenoxin is also closely related to loperamide, but unlike loperamide it is still capable of crossing the blood brain barrier to produce weak sedative and analgesic effects. However, the antidiarrheal potency of difenoxin is much greater than its CNS effects, which makes it an attractive alternative to other opioids.

Difenoxin acts as a potent antidiarrheal by slowing the movement of the intestines. It also crosses the blood brain barrier to a slight degree to exert weak sedative and analgesic effects.

Difenoxin and atropine
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Difenoxin and atropine
Generic	Atropine + difenoxin
Type	Oral
Therapeutic Class
Manufacturer
Available Country	United States
Last Updated:	September 19, 2023 at 7:00 am

Uses

Atropine is used for Non ulcer dyspepsia, Irritable bowel syndrome, Diverticular disease, Bradycardia, Organophosphorus poisoning, Premedication in anesthesia, Poisoning or overdosage with compound having muscarinic actions, Ophthalmic Inflammatory eye disorders, Eye refraction.

Difenoxin is an antidiarrheal agent used as an adjunct for the management of acute nonspecific diarrhea and acute exacerbations of chronic functional diarrhea.

Motofen(R) is a combination of atropine, an anticholinergic drug, and difenoxin, an antidiarrheal drug. It has been used in many countries for many years as a second line opioid-agonist antidiarrheal, which exists an intermediate between loperamide and paragoric. [2]

Diarrhea which is a result of cyclic or diarrhea predominant Inflammatory Bowel Syndrome may not be treated effectively with difenoxin, diphenoxylate, or loperamide. As such, diarrhea and cramping which does not respond to non-centrally acting derivatives or belladonna derivatives such as atropine are often treated with conservative doses of codeine. In patients with acute ulcerative colitis, as induction of toxic megacolon is possible, and thus use of Motofen(R) is cautioned.

Motofen(R) has been assigned pregnancy category C by the FDA, and is to be used only when the potential benefits outweigh the potential risk to the fetus. The safety of use during lactation is unknown and thus not recommended.

Difenoxin and atropine is also used to associated treatment for these conditions: Amblyopia, Atrioventricular Heart Block, Bradycardia, Bronchospasm, Crying, Detrusor Hyperreflexia, Excessive bronchial secretion, Hypertonic uterine contraction, Hypertonicity of the small intestine, Ocular Inflammation, Parkinsonism, Peptic Ulcer, Poisoning by parasympathomimetics (cholinergics), Poisoning caused by mushrooms, Poisoning caused by organophosphate anticholinesterase nerve agents, Poisoning caused by organophosphorus pesticides, Pylorospasm, Rhinorrhoea, Sinus Bradycardia, Spasms, Toxic effect of organophosphate and carbamate, Hypermobility of the colon, Laughing, Muscarinic side effectsDiarrhoea, Acute exacerbations of functional diarrhea

How Difenoxin and atropine works

Atropine binds to and inhibit muscarinic acetylcholine receptors, producing a wide range of anticholinergic effects.

Difenoxin acts as an antidiarrheal by activating peripheral opioid receptors in the small intestine and thereby inhibiting peristalsis. However, research has suggested that non-opioid receptor pathways exist. This would explain the potent antidiarrheal effects of difenoxin despite only limited opioid action [1].

Dosage

Difenoxin and atropine dosage

Adult:

IV: Bradycardia: 500 mcg every 3-5 mins. Total: 3 mg.
IV/IM: Organophosphorus poisoning: 2 mg every 10-30 mins until muscarinic effects disappear or atropine toxicity appears.
IM/SC: Premedication in anesthesia: 300-600 mcg 30-60 mins before anesthesia.
IV/IM/SC: Poisoning or overdosage with compound having muscarinic actions: 0.6-1 mg, repeat 2 hrly.
Ophthalmic: Inflammatory eye disorders: As 0.5-1% solution: 1-2 drops 4 times/day.
Ophthalmic: refraction: 1% solution 1 drop twice daily for 1-2 days before procedure.
Oral: Non ulcer dyspepsia, Irritable bowel syndrome, Diverticular disease: 0.6-1.2 mg as a single dose at bedtime.

Usual Pediatric Dose for Anesthesia:

7 to 16 pounds: 0.1 mg, IV, IM, or subcutaneously
17 to 24 pounds: 0.15 mg, IV, IM, or subcutaneously
24 to 40 pounds: 0.2 mg, IV, IM, or subcutaneously
40 to 65 pounds: 0.3 mg, IV, IM, or subcutaneously
65 to 90 pounds: 0.4 mg, IV, IM, or subcutaneously
Over 90 pounds: 0.4 to 0.6 mg, IV, IM, or subcutaneously

Side Effects

Injection: Dry mouth, dysphagia, constipation, flushing and dryness of skin, tachycardia, palpitations, arrhythmias, mydriasis, photophobia, cycloplegia, raised intraocular pressure. Toxic doses cause tachycardia, hyperpyrexia, restlessness, confusion, excitement, hallucinations, delirium and may progress to circulatory failure and resp depression.

Eye drops or ointment: Systemic toxicity esp in children, on prolonged use may lead to irritation, hyperaemia, oedema and conjunctivitis. Increased intraocular pressure.

Toxicity

Oral, mouse: LD₅₀ = 75 mg/kg. Symptoms of overdose includes widespread paralysis of parasympathetically innervated organs. Dry mucous membranes, widely dilated and nonresponsive pupils, tachycardia, fever and cutaneous flush are especially prominent, as are mental and neurological symptoms. In instances of severe intoxication, respiratory depression, coma, circulatory collapse and death may occur.

Precaution

Reflux oesophagitis; elderly; infants and children; Pregnancy.

Interaction

Additive anticholinergic effects with quinidine, antidepressants and some antihistamines.

Elimination Route

Atropine is rapidly and well absorbed after intramuscular administration. Atropine disappears rapidly from the blood and is distributed throughout the various body tissues and fluids.

A high percentage of Motofen(R) is absorbed, and absorption occurs rapidly. Peak plasma concentrations are achieved within 40-60 minutes. [Lexicomp, 2013]

Half Life

3.0 ± 0.9 hours in adults. The half-life of atropine is slightly shorter (approximately 20 minutes) in females than males.

The elimination half life was calculated to be 7.24 hours. The appearance half life was calculated to be 0.82h. [3]

Elimination Route

Much of the drug is destroyed by enzymatic hydrolysis, particularly in the liver; from 13 to 50% is excreted unchanged in the urine.

Both the drug and its metabolites are excreted, mainly as conjugates, in urine and feces. [Lexicomp, 2012]

Pregnancy & Breastfeeding use

Pregnancy Category C. Animal reproduction studies have not been conducted with atropine. It also is not known whether atropine can cause fetal harm when given to a pregnant woman or can affect reproduction capacity. Atropine should be given to a pregnant woman only if clearly needed.

Contraindication

Glaucoma, chronic respiratory disease, sick sinus syndrome, thyrotoxicosis, cardiac failure, pyloric stenosis, prostatic hypertrophy.

Acute Overdose

May cause hyperthermia, hypertension, increased respiratory rate, nausea and vomiting. May also lead to CNS stimulation. Severe intoxication may lead to CNS depression, coma, respiratory failure and death.