Homatropine Hydro bromide
Atropine occurs in the form of optically inactive, white, odorless crystals possessing a bitter taste. It is not very soluble in water (1:460, 1:90 at 80°C) but is more soluble in alcohol (1:2, 1:1.2 at 60°C). It is soluble in glycerin (1:27), in chloroform (1:1), and in ether (1:25). Saturated aqueous solutions are alkaline in reaction (pH —9.5). The free base is useful when nonaqueous solutions are to be made, such as in oily vehicles and ointment bases. Atropine has a plasma half-life of about 2 to 3 hours. It is metabolized in the liver to several products, including tropic acid and tropine.
Atropine Sulfate, USP. Atropine sulfate (Atropisol) is prepared by neutralizing atropine in acetone or ether solution with an alcoholic solution of sulfuric acid, with care used to prevent hydrolysis. The salt occurs as colorless crystals or as a white, crystalline powder. It is efflorescent in dry air and should be protected from light to prevent decomposition.
Atropine sulfate is freely soluble in water (1:0.5), in alcohol (1:5, 1:2.5 at boiling point), and in glycerin (1:2.5). Aqueous solutions are not very stable, although solutions may be sterilized at 120°C (15 lb pressure) in an autoclave if the pH is kept below 6. Sterilization probably is best effected by the use of aseptic techniques and a bacteriological filter. It has been suggested that no more than a 30-day supply of an aqueous solution should be made and that for small quantities the best procedure is to use hypodermic tablets and sterile distilled water.73 Kondritzer and Zvirblis74 have studied the kinetics of alkaline and proton-catalyzed hydrolyses of atropine in aqueous solution. The region of maximal stability lies between pH 3 and approximately 5. They have also proposed an equation to predict the half-life of atropine undergoing hydrolysis at constant pH and temperature.
The action of atropine or its salts is the same. It produces a mydriatic effect by paralyzing the iris and the ciliary muscles and, for this reason, is used by the oculist in iritis and corneal inflammations and lesions. Its use is rational in these conditions because one of the first rules in the treatment of inflammation is rest, which, of course, is accomplished by the paralysis of muscular motion. Its use in the eye (0.5%-1% solutions or gelatin disks) for fitting glasses is widespread. Atropine is administered in small doses before general anesthesia to lessen oral and air passage secretions and, when administered with morphine, to lessen the respiratory depression induced by morphine.
Atropine causes restlessness, prolonged pupillary dilation, and loss of visual accommodation and, furthermore, gives rise to arrhythmias such as atrioventricular dissociation, ventricular extrasystoles, and even ventricular fibrillation. Even though ether has been gradually replaced by other anesthetics, thereby eliminating problems with respiratory secretions caused by ether and thus requiring atropine, surgeons and anesthesiologists today continue to use it as an anesthetic premedicant to reduce excessive salivary and airway secretions and to prevent vagal reflexes.
Its ability to dry secretions has also been used in the so-called rhinitis tablets for symptomatic relief in colds. In cathartic preparations, atropine or belladonna has been used as an antispasmodic to lessen the smooth muscle spasm (griping) often associated with catharsis.
Atropine may be used to treat some types of arrhythmias. It increases the heart rate by blocking the effects of ACh on the vagus. In this context, it is used to treat certain reversible brad-yarrhythmias that may accompany acute myocardial infarction. It is also used as an adjunct to anesthesia to protect against bradycardia, hypotension, and even cardiac arrest induced by the skeletal muscle relaxant succinylcholine chloride.
Another use for atropine sulfate emerged following the development of the organophosphates, which are potent inhibitors of AChE. Atropine is a specific antidote to prevent the muscarinic effects of ACh accumulation, such as vomiting, abdominal cramps, diarrhea, salivation, sweating, bron-choconstriction, and excessive bronchial secretions. It is used intravenously but does not protect against respiratory failure caused by depression of the respiratory center and the muscles of respiration.
Hyoscyamine, USP. Hyoscyamine is a levorotatory alkaloid obtained from various solanaceous species. One of the commercial sources is Egyptian henbane (Hyoscyamus muticus), in which it occurs to the extent of about 0.5%. Usually, it is prepared from the crude drug in a manner similar to that used for atropine and is purified as the oxalate. The free base is obtained easily from this salt.
It occurs as white needles that are sparingly soluble in water (1:281), more soluble in ether (1:69) or benzene (1:150), very soluble in chloroform (1:1), and freely soluble in alcohol. It is used as the sulfate and hydrobromide. The principal reason for the popularity of the hydrobromide has been its nondeliquescent nature. The salts have the advantage over the free base in being quite water soluble.
Hyoscyamine is the levo form of the racemic mixture known as atropine. The dextro form does not exist naturally but has been synthesized. Cushny75 compared the activities of (-)-hyoscyamine, (+)-hyoscyamine, and the racemate (atropine) in 1904 and found greater peripheral potency for the (-) isomer and twice the potency of the racemate. All later studies have essentially confirmed that the (+) isomer is only weakly active and that the (—) isomer is, in effect, the active portion of atropine. Inspection of the relative doses of atropine sulfate and hyoscyamine sulfate illustrates the differences very nicely. The principal criticism offered against the use of hyoscyamine sulfate exclusively is that it tends to racemize to atropine sulfate rather easily in solution, so that atropine sulfate then becomes the more stable of the two. All of the isomers behave very much the same in the CNS.
Hyoscyamine is used to treat disorders of the urinary tract more so than any other antispasmodic, although there is no evidence that it has any advantages over the other belladonna preparations and the synthetic anticholinergics. It is used to treat spasms of the bladder and, in this manner, serves as a urinary stimulant. It is used together with a narcotic to counteract the spasm produced by the narcotic when the latter is used to relieve the pain of urethral colic. Hyoscyamine preparations are also used as antispasmodics in the therapy of peptic ulcers.
Hyoscyamine Sulfate, USP. Hyoscyamine sulfate (Levsin sulfate) is a white, odorless, crystalline compound of a deliquescent nature that also is affected by light. It is soluble in water (1:0.5) and alcohol (1:5) but almost insoluble in ether. Solutions of hyoscyamine sulfate are acidic to litmus.
This drug is used as an anticholinergic in the same manner and for the same indications as atropine and hyoscyamine, but it possesses the disadvantage of being deliquescent.
Scopolamine. Scopolamine (hyoscine) is found in various members of the Solanaceae (e.g., H. niger, Duboisia my-oporoides, Scopolia spp., and Datura metel). Scopolamine usually is isolated from the mother liquor remaining from the isolation of hyoscyamine.
Hyoscine is the older name for this alkaloid, although scopolamine is the accepted name in the United States. Scopolamine is the levo component of the racemic mixture that is known as atroscine. The alkaloid is racemized readily in the presence of dilute alkali.
The alkaloid occurs in the form of a levorotatory, viscous liquid that is only slightly soluble in water but very soluble in alcohol, chloroform, or ether. It forms crystalline salts with most acids, with the hydrobromide being the most stable and the most popularly accepted. An aqueous solution of the hydrobromide containing 10% mannitol is said to be less prone to decomposition than unprotected solutions. The commercially available transdermal system of scopolamine comprises an outer layer of polymer film and a drug reservoir containing scopolamine, polyisobutylene, and mineral oil, which is interfaced with a microporous membrane to control diffusion of the drug. In this dosage form, scopolamine is effective in preventing motion sickness. The action is believed to be on the cortex or the vestibular apparatus. Whereas atropine stimulates the CNS, causing restlessness and talkativeness, scopolamine usually acts as a CNS depressant.
Scopolamine Hydrobromide, USP. Scopolamine hy-drobromide (hyoscine hydrobromide) occurs as white or colorless crystals or as a white, granular powder. It is odorless and tends to effloresce in dry air. It is freely soluble in water (1:1.5), soluble in alcohol (1:20), only slightly soluble in chloroform, and insoluble in ether.
Scopolamine is a competitive blocking agent of the parasympathetic nervous system as is atropine, but it differs markedly from atropine in its action on the higher nerve centers. Both drugs readily cross the blood-brain barrier and, even at therapeutic doses, cause confusion, particularly in the elderly.
A sufficiently large dose of scopolamine will cause an individual to sink into a restful, dreamless sleep for about 8 hours, followed by a period of approximately the same length in which the patient is in a semiconscious state. During this time, the patient does not remember events that take place. When scopolamine is administered with morphine, this temporary amnesia is termed twilight sleep.
Homatropine Hydrobromide, USP. Homatropine hydrobromide, 1ah,5ah-tropan-3a-ol mandelate (ester) hydrobromide (Homatrocel), occurs as white crystals or as a white, crystalline powder that is affected by light. It is soluble in water (1:6) and alcohol (1:40), less soluble in chloroform (1:420), and insoluble in ether.
Solutions are incompatible with alkaline substances, which precipitate the free base, and with the common reagents that precipitate alkaloids. As with atropine, solutions are sterilized best by filtration through a bacteriological filter.
Homatropine hydrobromide is used topically to paralyze the ciliary structure of the eye (cycloplegia) and to effect mydriasis. It behaves very much like atropine but is weaker and less toxic. In the eye, it acts more rapidly but less persistently than atropine. Dilation of the pupil takes place in about 15 to 20 minutes, and the action subsides in about 24 hours. By using a miotic, such as physostigmine, it is possible to restore the pupil to normality in a few hours.
Homatropine Methylbromide, USP. Homatropine methylbromide, 3a-hydroxy-8-methyl-1ah,5ah-tropanium bromide mandelate (Novatropine, Mesopin), occurs as a bitter, white, odorless powder and is affected by light. The compound is readily soluble in water and alcohol but insoluble in ether. The pH of a 1% solution is 5.9 and that of a 10% solution is 4.5. Although a solution of the compound yields a precipitate with alkaloidal reagents, such as mercuric potassium iodide test solution, addition of alkali hydroxides or carbonates does not cause the precipitate that occurs with nonquater-nary nitrogen salts (e.g., atropine, homatropine).
Homatropine methylbromide is transported poorly across the blood-brain barrier because of its quaternary ammonium group and, therefore, has far fewer stimulant properties than atropine. It does have all the characteristic peripheral parasympathetic depressant properties of atropine and is used to reduce oversecretion and to relieve GI spasms.
Ipratropium Bromide. Ipratropium bromide, 3-(3-hy-droxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3.2.1]octane bromide (Atrovent), is a quaternary ammonium derivative of atropine. It is freely soluble in water and ethanol but insoluble in chloroform and ether. The salt is stable in neutral and acidic solutions but rapidly hy-drolyzed in alkaline solutions.
Tropic Acid Tropine
Ipratropium bromide is used in inhalation therapy to produce dilation of bronchial smooth muscle for acute asthmatic attacks. The drug produces bronchodilation by competitive inhibition of cholinergic receptors bound to smooth
muscle of the bronchioles. Ipratropium may also act on the surface of mast cells to inhibit ACh-enhanced release of chemical mediators. The drug has a slow onset of action, within 5 to 15 minutes after being administered by inhalation, and should not be used alone for acute asthmatic attacks. The peak therapeutic effect from one dose is observed between 1 and 2 hours. The effects of the drug last for about 6 hours. It has a half-life of 3.5 hours.
Tiotropium Bromide. Tiotropium bromide, (1a,2fi, 4j8,7jS)-7-[(hydroxidi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane, (Spiriva) is an antimuscarinic agent that is used in an inhalation device to deliver the drug into the lungs. It is indicated in the treatment of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. The standard once-daily dose is 18 fig of tiotropium.
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