Belladonna/Phenobarbital

Belladonna/Phenobarbital 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.

Hyoscyamine is a tropane alkaloid and the levo-isomer of atropine. It is commonly extracted from plants in the Solanaceae or nightshade family. Research into the action of hyoscyamine in published literature dates back to 1826. Hyoscyamine is used for a wide variety of treatments and therapeutics due to its antimuscarinic properties.

Although hyoscyamine is marketed in the United States, it is not FDA approved.

Hyoscyamine is not FDA approved, and so it has not official indications. However, it is used as an antimuscarinic agent in a number of treatments and therapies. Hyoscyamine has a short duration of action as it may need to be given multiple times per day. Patients should be counselled regarding the risks and signs of anticholinergic toxicity.

Phenobarbital is a long-acting barbiturate. It depresses the sensory cortex, reduces motor activity, changes cerebellar function and produces drowsiness, sedation and hypnosis. Its anticonvulsant property is exhibited at high doses.

Phenobarbital acts on GABAA receptors, increasing synaptic inhibition. This has the effect of elevating seizure threshold and reducing the spread of seizure activity from a seizure focus. Phenobarbital may also inhibit calcium channels, resulting in a decrease in excitatory transmitter release. The sedative-hypnotic effects of phenobarbital are likely the result of its effect on the polysynaptic midbrain reticular formation, which controls CNS arousal.

Phenobarbital, the longest-acting barbiturate, is used for its anticonvulsant and sedative-hypnotic properties in the management of all seizure disorders except absence (petit mal).

Scopolamine is a tropane alkaloid isolated from members of the Solanaceae family of plants, similar to atropine and hyoscyamine, all of which structurally mimic the natural neurotransmitter acetylcholine. Scopolamine was first synthesized in 1959, but to date, synthesis remains less efficient than extracting scopolamine from plants. As an acetylcholine analogue, scopolamine can antagonize muscarinic acetylcholine receptors (mAChRs) in the central nervous system and throughout the body, inducing several therapeutic and adverse effects related to alteration of parasympathetic nervous system and cholinergic signalling. Due to its dose-dependent adverse effects, scopolamine was the first drug to be offered commercially as a transdermal delivery system, Scopoderm TTS®, in 1981. As a result of its anticholinergic effects, scopolamine is being investigated for diverse therapeutic applications; currently, it is approved for the prevention of nausea and vomiting associated with motion sickness and surgical procedures.

Scopolamine was first approved by the FDA on December 31, 1979, and is currently available as both oral tablets and a transdermal delivery system.

Scopolamine is an anticholinergic belladonna alkaloid that, through competitive inhibition of muscarinic receptors, affects parasympathetic nervous system function and acts on smooth muscles that respond to acetylcholine but lack cholinergic innervation. Formulated as a patch, scopolamine is released continuously over three days and remains detectable in urine over a period of 108 hours. Scopolamine is contraindicated in angle-closure glaucoma and should be used with caution in patients with open-angle glaucoma due to scopolamine's ability to increase intraocular pressure. Also, scopolamine exhibits several neuropsychiatric effects: exacerbated psychosis, seizures, seizure-like, and other psychiatric reactions, and cognitive impairment; scopolamine may impair the ability of patients to operate machinery or motor vehicles, play underwater sports, or perform any other potentially hazardous activity. Women with severe preeclampsia should avoid scopolamine. Patients with gastrointestinal or urinary disorders should be monitored frequently for impairments, and scopolamine should be discontinued if these develop. Scopolamine can cause blurred vision if applied directly to the eye, and the transdermal patch should be removed before an MRI procedure to avoid skin burns. Due to its gastrointestinal effects, scopolamine can interfere with gastric secretion testing and should be discontinued at least 10 days before performing the test. Finally, scopolamine may induce dependence and resulting withdrawal symptoms, such as nausea, dizziness, vomiting, gastrointestinal disturbances, sweating, headaches, bradycardia, hypotension, and various neuropsychiatric manifestations following treatment discontinuation; severe symptoms may require medical attention.

Belladonna/Phenobarbital
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	Belladonna/Phenobarbital
Generic	Atropine + hyoscyamine + phenobarbital + scopolamine
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.

Hyoscyamine is an anticholinergic indicated to treat functional gastrointestinal disorders, biliary and renal colic, and acute rhinitis.

As a drug that is not FDA approved, hyscyamine has no official indications. Intravenous hysocyamine has been used to reduce gastric motility, reduce pancreatic pain and secretions, to facilitate imaging of the gastrointestinal tract, treat anticholinesterase toxicity, treat certain cases of partial heart block, improve visualization of the kidneys, and for symptomatic relief of biliary and renal colic. Intravenous hyoscyamine is also used pre-operatively to reduce secretions of the mouth and respiratory tract to facilitate intubation. Oral hyoscyamine is used to treat functional intestinal disorders, for symptomatic relief of biliary and renal colic, and symptomatic relief of acute rhinitis.

Phenobarbital is used as-

Sedative and hence it relieves anxiety, tension and fear
Hypnotic and hence it is used for short term insomnia
Pre-anaesthetics
Anti-epileptic in epilepsy with Partial seizure or Generalized Tonic-clonic seizure, status epilepticus
Certain acute convulsive episodes

Scopolamine is a belladonna alkaloid with anticholinergic effects indicated for the treatment of nausea and vomiting associated with motion sickness and postoperative nausea and vomiting (PONV).

Scopolamine is indicated in adult patients for the prevention of nausea and vomiting associated with motion sickness and for the prevention of postoperative nausea and vomiting (PONV) associated with anesthesia or opiate analgesia.

Belladonna/Phenobarbital 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 effectsBiliary Colic, Colic, Cystitis, Diverticulitis, Heart Block, Irritable Bowel Syndrome (IBS), Neurogenic Bladder Dysfunction, Neurogenic Bowel Dysfunction, Pancreatitis, Parkinsonism, Peptic Ulcer, Poisoning caused by anticholinesterases, Pylorospasm, Renal Colic, Spastic bladder, Tracheo-bronchial secretion excess, Acute Enterocolitis, Acute Rhinitis, Gastric secretions, Mild Dysentery, Pharyngeal secretions, Salivary secretions, Spastic colitisAlcohol Withdrawal Syndrome, Anxiety, Febrile Convulsions, Hyperbilirubinemia, Insomnia, Menopausal Symptoms, Partial-Onset Seizures, Withdrawal Symptoms, Generalized seizure, SedationMotion Sickness, Post Operative Nausea and Vomiting (PONV), Preanesthetic medication therapy

How Belladonna/Phenobarbital works

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

Hyoscyamine competitively and non-selectively antagonises muscarinic receptors in the smooth muscle, cardiac muscle, sino-atrial node, atrioventricular node, exocrine nodes, gastrointestinal tract, and respiratory tract. Antagonism of muscarinic M1, M4, and M5 receptors in the central nervous system lead to cognitive impairment; antagonism of M2 in the sinoatrial and atrioventricular nodes leads to bradycardia and lowers contractility; and antagonism of M3 in smooth muscle results in reduced peristalsis, bladder contraction, salivary secretions, gastric secretions, bronchial secretions, sweating, increased bronchodilation, mydriasis, and cycloplegia.

Acetylcholine (ACh) is a neurotransmitter that can signal through ligand-gated cation channels (nicotinic receptors) and G-protein-coupled muscarinic receptors (mAChRs). ACh signalling via mAChRs located in the central nervous system (CNS) and periphery can regulate smooth muscle contraction, glandular secretions, heart rate, and various neurological phenomena such as learning and memory. mAChRs can be divided into five subtypes, M1-M5, expressed at various levels throughout the brain. Also, M2 receptors are found in the heart and M3 receptors in smooth muscles, mediating effects apart from the direct modulation of the parasympathetic nervous system. While M1, M3, and M5 mAChRs primarily couple to G_q proteins to activate phospholipase C, M2 and M4 mainly couple to G_i/o proteins to inhibit adenylyl cyclase and modulate cellular ion flow. This system, in part, helps to control physiological responses such as nausea and vomiting.

Scopolamine acts as a non-selective competitive inhibitor of M1-M5 mAChRs, albeit with weaker M5 inhibition; as such, scopolamine is an anticholinergic with various dose-dependent therapeutic and adverse effects. The exact mechanism(s) of action of scopolamine remains poorly understood. Recent evidence suggests that M1 (and possibly M2) mAChR antagonism at interneurons acts through inhibition of downstream neurotransmitter release and subsequent pyramidal neuron activation to mediate neurological responses associated with stress and depression. Similar antagonism of M4 and M5 receptors is associated with potential therapeutic benefits in neurological conditions such as schizophrenia and substance abuse disorders. The significance of these observations to scopolamine's current therapeutic indications of preventing nausea and vomiting is unclear but is linked to its anticholinergic effect and ability to alter signalling through the CNS associated with vomiting.

Dosage

Belladonna/Phenobarbital 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

Adults:

Hypnosis: 100 to 320 mg
Sedation: 30 to 120 mg/day in 2 to 3 divided doses
Epilepsy: 60 to 250 mg/day
Convulsion: 50 to 100 mg/day in 2 to 3 divided doses
Status epilepticus: IV 10-20 mg/Kg, repeat if needed

Children:

Preoperative: 1-3 mg/Kg body weight
Convulsion: 4-6 mg/Kg/day
Status epilepticus: IV 15-20 mg/Kg over 10-15 minutes

Dilute with most IV infusion soln (e.g. NaCl 0.45% or 0.9%, lactated Ringer's, dextrose 5%, Ringer's).

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.

Drowsiness is the most common side effect. Less common side effects are CNS depression, nervousness, agitation, psychiatric disturbance, lethargy, mental depression, ataxia, nightmares, bradycardia, apnea, nausea, vomiting, constipation, restlessness and confusion in the elderly and hyperkinesia in children.

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.

Patients experiencing an overdose may present with headache, nausea, vomiting, dizziness, dry mouth, difficulty in swallowing, dilated pupils, blurred vision, urinary retention, hot dry and flushed skin, tachycardia, hypertension, hypotension, respiratory depression, CNS stimulation, fever, ataxia, excitation, lethargy, stupor, coma, and paralysis. Patients should be treated with symptomatic and supportive therapy which may include emesis, gastric lavage, activated charcoal, artificial respiration, or intravenous physostigmine. Dialysis is expected to remove hyoscyamine sulfate from circulation.

CNS and respiratory depression which may progress to Cheyne-Stokes respiration, areflexia, constriction of the pupils to a slight degree (though in severe poisoning they may wshow paralytic dilation), oliguria, tachycardia, hypotension, lowered body temperature, and coma. Typical shock syndrome (apnea, circulatory collapse, respiratory arrest, and death) may occur.

Scopolamine overdose may manifest as lethargy, somnolence, coma, confusion, agitation, hallucinations, convulsion, visual disturbance, dry flushed skin, dry mouth, decreased bowel sounds, urinary retention, tachycardia, hypertension, and supraventricular arrhythmias. In some cases, overdose symptoms may appear similar to those associated with withdrawal following discontinuation. However, withdrawal symptoms such as bradycardia, headache, nausea, abdominal cramps, and sweating can help to distinguish between these possibilities. Overdose management primarily involves the removal of all transdermal patch systems combined with symptomatic and supportive care. Ensuring an adequate airway, supplemental oxygen, establishing intravenous access, and continuous monitoring are recommended. In cases where patients have swallowed one or more patch systems, it may be necessary to remove them or administer activated charcoal.

Animal studies revealed an oral LD₅₀ of 1880 mg/kg in mice and 1270 mg/kg in rats, and a subcutaneous LD₅₀ of 1650 mg/kg in mice and 296 mg/kg in rats.

Precaution

Reflux oesophagitis; elderly; infants and children; Pregnancy.

Phenobarbital is potentially habit forming if taken over an extended period of time. When being prescribed to overcome insomnia, the drug should not be used for a period longer than two weeks. Caution should be taken in patients who are mentally depressed, have hepatic damage, suicidal tendencies or a history of drug abuse.

Interaction

Additive anticholinergic effects with quinidine, antidepressants and some antihistamines.

Phenobarbital can interact with a number of prescription and nonprescription medications including acetaminophen, anticoagulants such as warfarin, chloramphenicol, monoamine oxidase inhibitors (MAOIs), antidepressants, asthma medicine, cold medicine, anti-allergy medicine, sedatives, steroids, tranquilizers, and vitamins. Interactions with these medications can increase the drowsiness caused by phenobarbital.

Volume of Distribution

The volume of distribution of scopolamine is not well characterized. IV infusion of 0.5 mg scopolamine over 15 minutes resulted in a volume of distribution of 141.3 ± 1.6 L.

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.

Hyoscyamine is completely absorbed by sublingual and oral routes, though exact data regarding the C_max, T_max, and AUC are not readily available.

Absorbed in varying degrees following oral, rectal or parenteral administration. The salts are more rapidly absorbed than are the acids. The rate of absorption is increased if the sodium salt is ingested as a dilute solution or taken on an empty stomach.

The pharmacokinetics of scopolamine differ substantially between different dosage routes. Oral administration of 0.5 mg scopolamine in healthy volunteers produced a C_max of 0.54 ± 0.1 ng/mL, a t_max of 23.5 ± 8.2 min, and an AUC of 50.8 ± 1.76 ng*min/mL; the absolute bioavailability is low at 13 ± 1%, presumably because of first-pass metabolism. By comparison, IV infusion of 0.5 mg scopolamine over 15 minutes resulted in a C_max of 5.00 ± 0.43 ng/mL, a t_max of 5.0 min, and an AUC of 369.4 ± 2.2 ng*min/mL.

Other dose forms have also been tested. Subcutaneous administration of 0.4 mg scopolamine resulted in a C_max of 3.27 ng/mL, a t_max of 14.6 min, and an AUC of 158.2 ng*min/mL. Intramuscular administration of 0.5 scopolamine resulted in a C_max of 0.96 ± 0.17 ng/mL, a t_max of 18.5 ± 4.7 min, and an AUC of 81.3 ± 11.2 ng*min/mL. Absorption following intranasal administration was found to be rapid, whereby 0.4 mg of scopolamine resulted in a C_max of 1.68 ± 0.23 ng/mL, a t_max of 2.2 ± 3 min, and an AUC of 167 ± 20 ng*min/mL; intranasal scopolamine also had a higher bioavailability than that of oral scopolamine at 83 ± 10%.

Due to dose-dependent adverse effects, the transdermal patch was developed to obtain therapeutic plasma concentrations over a longer period of time. Following patch application, scopolamine becomes detectable within four hours and reaches a peak concentration (t_max) within 24 hours. The average plasma concentration is 87 pg/mL, and the total levels of free and conjugated scopolamine reach 354 pg/mL.

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 half life of hyoscyamine is 3.5 hours.

53 to 118 hours (mean 79 hours)

The half-life of scopolamine differs depending on the route. Intravenous, oral, and intramuscular administration have similar half-lives of 68.7 ± 1.0, 63.7 ± 1.3, and 69.1 ±8/0 min, respectively. The half-life is greater with subcutaneous administration at 213 min. Following removal of the transdermal patch system, scopolamine plasma concentrations decrease in a log-linear fashion with a half-life of 9.5 hours.

Clearance

IV infusion of 0.5 mg scopolamine resulted in a clearance of 81.2 ± 1.55 L/h, while subcutaneous administration resulted in a lower clearance of 0.14-0.17 L/h.

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.

The majority of hyoscyamine is eliminated in the urine as the unmetabolized parent compound.

Following oral administration, approximately 2.6% of unchanged scopolamine is recovered in urine. Compared to this, using the transdermal patch system, less than 10% of the total dose, both as unchanged scopolamine and metabolites, is recovered in urine over 108 hours. Less than 5% of the total dose is recovered unchanged.

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.

Pregnancy Category D. Phenobarbital can cause potential fetal damage. Their use in pregnancy alone, or in combination with other anticonvulsants, can cause coagulation defects in the newborn infant which may be preventable by the prophylactic administration of Vitamin K to the mother prior to delivery. Phenobarbital is excreted through human milk; so caution should be taken during lactation period.

Contraindication

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

Phenobarbital is contraindicated in patients with acute intermittent porphyria and who have a natural or idiosyncrasy to barbiturates

Special Warning

Debilitated patient: Reduce dose

Renal Impairment: Reduce dose. Severe: Contraindicated

Hepatic Impairment: Reduce dose. Severe: Contraindicated

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.

Phenobarbital should not be used more than the dosage guide line. 1 gm Phenobarbital oral dose may cause serious poisoning and 2 gm may cause even death. Over dosage produces severe, persistent depression. Treatment includes artificial respiration, maintenance of fluid balance and antibiotics to prevent pneumonia. Alkalinisation of the urine and forced diuresis or haemodialysis have been used in cases of severe poisoning.