Parasympathetic Postganglionic Blocking Agents

- Antimuscarinic

Anticholinergic

Parasympatholytic

Cholinolytic

Antimusarinic- acts by competitive antagonism of Ach binding to muscarinicreceptorTherapeutic actions:3 predictable and clinically useful results from blocking the muscarinic effetcs of Ach:1. Mydriatic effect and CyclopegiaBeneficial in :•opthalmology•Principal use in refraction studies in fitting lenses•Used to treat inflammation of the cornea (keratitis)•Treat inflammed iris and ciliary organs2. Antispasmodic effect3. Antisecretory effectAnticholinergicTherapeutic actions:•Minor role in management of peptic ulcer•Treatment for parkinsonism by decreasing the activity of cholinergic neurons in basal ganglia.ParasympatholyticCholonolytic drugs

Solanaceous Alkaloids and AnalogsForerunners of the class of antimusarinic drugs:•(-)-hyoscyamine, atropine•Scopolamine (hyoscine)Found in :1. Henbane (Hyoscyamus niger)2. Deadly nightshdae (atropa belladona)3.Jimsun weed (Datura stramonium)

•used topically for analgesic effect on hemorrhoids, skin infectinon, various itching dermatoses.•Application of belladona and its alkaloids results in mydriasis.•causes dimution of secreation•Increase heart rate•Depress motility of GI tract•Acts as antispasmodic on various smooth muscles•Directly stimulates the respiratory center

Products of Solanaeous Alkaloids and Analogs :1. Atopine, USP

• Standard by which similar drug are measured.•Widely used antispasmodic. A depressant effect on parasympathetically innervated smooth muscles.•Blocks all muscarinic receptor subtypes•Tropine ester of racemic tropic acid and is optically inactive•Occurs naturally in various Solanacea•Obtain from conventional method of alkoloid isolation from plant material (crude mixture of atropine) then racemized to atropine by refluxing chloroform or treating with cold dilute alkali. •Optically inactive, white, odorless crystals possesing bitter taste.•Not very soluble in water but more soluble in alcohol•Soluble in glycerin, ether and chloroform.•Free base is useful when nonaqeus solutions are to be made (e.i ointment base)•Plasma half life about 2-3 hours•metabolized in liver to become tropic acid and tropine.

2. Atropine sulfate, USP. (Atropisol)

•prepared by neutralizing atropine acetone or ether solution w/ alcoholic solution of sulfuric acid with care , to prevent hyrdolysis.•Colorless crystals or white crystalline powder.•Efflorescent in dry air and should be prevented from light.•Free soluble in water and in glycerin•Aqeous solution are not very stable, although it can be sterilized at 120C in autoclave if pH is kept below 6.•Produces mydriatic effect ( used 0.5%-1% solutions or gelatin disk)•Administerd in small doses before anesthesia.•Atropine causes restlesness, prolonged pupillary dilation, loss of visual accomodation and give rise to arrythmias.•Used as anesthetic premedicant to reduce excesive salivary and airway secreations and prevent vagal reflexes.•Used in rhinitis tablets for relief of colds•In cathartic preparations,used as antispasmodic to lessen smooth muscle spasm•Increase heartrate by blocking Ach on the vagus therfore treating arrhythmias•Adjunt to anesthesia to protect against bradycardia, hypotension.•Specific antidote to prevent muscarinic effect of Ach accumulation.

3. Hyoscyamine, USP

•One of commercial sources is Egyptian henbane (Hyoscyamus muticus) •Prepared from crude drug in manner similar to atropine and is purified as the oxalate.•Free base is obtained easily from this salt.•Sparingly soluble in water, more soluble in ether or benzene, very soluble in chloroform. Freely soluble in alcohol•It is used as hydrobromide (popular because of its nondeliquescentnature.)•Tends to racemize to atropine sulphate rather easily in a solution, atropine becomes more stable of the two.•Treat disorders of the urinary tract than any other sntispasmodic.•Used to treat spasm of the bladder•Urinary stimulant•Antispasmodic in therapy of peptic ulcer

4. Hyosyamine sulfate, USP. ( Levsin sulphate)

•White, odorless, crystalline compound of a deliquescent nature also affected by light.•Soluble in water and alchohol, insoluble in ether.•Solution is acidic to litmus•Drug used as an anticholinergic in the same manner and for the same indication as atropine and hyoscyamine.

5. Scopolamine ( hyoscine)

•Isolated from the mother liquor remaining from the isolation of hyoscyamine.•Hyoscine is the older name of this alkaloid.•Levo component of racemic mixture known as atroscine.•racemized readily in the presence of dilute alkali.•Slightly soluble in water but very soluble in alcohol, chloroform or ether.•Forms crystalline salts with most acids, with hydrobromide being most stable and most accepted.•Prevent motion sickness( transdermal form)•Act as CNS depressant.

6. Scopolamine Hyrdobromide, USP (hyoscine hydrobromide)

•Occur as white or colorles crystal, granular powder.•Odourless and effloresce in dry air.•Freely soluble in water, soluble in alcohol, slightly soluble in chloroform and insoluble in ether.•Action is on thehigher nerve centers.•Readily cross blood-brain barrier•Causes confusion in ederly.•Cause to sink in restful dreamless sleep followed by period of approx. Same length in which the patient is semiconscious state.•Twilight sleep- term used for temporary amnesia with administration with morphine.

7. Hamotropine Hydrobromide, USP. (Homatrocel)

•Occur as white crystal or crystalline powder that is affected by light•Soluble in water and alcohol, less soluble in chloroform an insoluble in ether•Solutions are incompatible with alkaline substances, which precipitate free base•Used topically to paralyze the ciliary structure of eye and to effect mydriasis•Behaves like atropine but weaker and less toxic•Acts more rapidly but less persistent than atropine in the eye•15-20 minutes to dilate the pupil and subsides in about 24 hours

8. Hamatropine Methylbromide, USP.

• Bitter, white, odourless powder and affected by light•Readily soluble in water and alcohol but insoluble in ether•The ph of a 1% solution is 5.9 and a 10% solution is 4.5.•Transported poorly across blood-brain barrier because of quartenary ammonium group therefore has fewer stimulant properties than atropine.•It does have all characteristic peripheral parasymphateticdepressant properties of atropine and is used to reduce oversecreation and relieve GI spasm.

9. Ipratropium Bromide (Atrovent)

•Quarternary ammonium derivative of atropine•Freely soluble in water and ethanol but insoluble in chloroform and ether.•Salt is stable in neutral and acidic solutions but rapidly hydrolyzed in alkaline solutions.•Used in inhalation teraphy producing dilation of bronchial smooth muscle for acute sthma attacks.•Bronchodilation by competitive inhibiton of cholinergic receptors bound to smooth muscle of bronchioles.•Slow onset of action within5-15 mins after being administered ( should not be used for acute asthma attacks)•1-2 hours the peak therapeutic dose•6hours effect last•Half life is 3.5 hours

10. Tiotropium Bromide (Spiriva)

•Antimuscarinic used as inhalation device to deliver the drug into lungs.•For treatment of COPD. ,chronic bronchitis and emphysema•18mcg is the standard dose. Once daily.

Synthetic Cholinergic Blocking Agents

*Aminoalcohol Esters*

•Solanaceous alkaloids are agreed to be potent parasympatholytics , but have undesirable property of producing wide range of effects through their non specific blockade of autonomic function. Therefore, synthesis of compounds possessing specific cholinolytic ly action has been very desirable field of study.

•Early research was carried out in pre-and post world war 2 before muscarinic subtypes were known.

Products

1. Clinidium Bromide, USP. (Quarzan)

•White,almost odorless crystalline powder that is optically inactive•Soluble in water and alcohol and very slightly soluble in ether and benzene•Librax- combination of minor tranquilizers chlordiazepoxide•For treatment of GI complains•Suggested for peptic ulcer, hyperchlorhydria, ulcerative or spastic colon,nervousstomach and others.•Contraindicated in glaucoma and other conditions that may be aggravated by parasympatholytic action, such as prostatic hypertrophy in elderly men, which could lead to urinary retention.

2. Cyclopentolate Hydrochloride ,USP. (Cyclogyl)

•Crystalline ,white , odorless solid•Very soluble in water, easily soluble in alcohol and slightly soluble in ether.•1% solution has ph of 5.0 to 5.4•Used only for its effect on the eye acting as parasympatholytic•Mydriatic in the management of iritis, keratitis and choroiditis•Has one half of antispasmodic effect of atropine and non irritating when instilled repeatedly in the eye•Neutralize with 1%-2% pilocarpine nitrate solution, recovery in 6 hours.•Supplied in ready made ophthalmic solution in concentration of 0.5%-2%

3. Dicyclomine Hydrochloride, USP.(Bentyl)

•Binds more firmly to M1 and M3 receptors•1/8 of the neurotropic activity of atropine and twice the musculotropic activity of papaverine.•Used for various spasmolytic effect of various smooth muscle spasm, particularly those associated with GI tract.•Usefull in dysmenorrhea, pylorospasm and biliary dysfunction.

4. Eucatropine Hydrochloride USP

•1,2,2,6-tetramethyl-4-piperidyl mandelate hydrochloride•Odorless,white, granular powder•Neutral solution to litmus•Soluble in water, freely soluble in alcohol and chloroform, almost insoluble in ether.•Less potent than atropine,although action is almost parallel.•Used topicallyin 0.1 ml dose of mydriatic in 2% solution or in a form of small tablets•Dilation takes place in about 30 mins and eye return to normal in 2-3 hours.

5. Glycopyrrolate, USP.

•3-hydroxy-1,1dimethylpyrrolidinium bromide a-cyclopentylmandelate(Robinul)•White, crystalline powder•Soluble in water and alcohol. Insoluble in ether and chloroform•Posesses atropine-like effects at adequate dosage level•Side effects also similar to atropine•Potent antagonist of M1 receptor•Low incidence of tachycardia•Rarely causes CNS disturbance•Adjunt in the management of peptic ulcer and GI ailments associated with hyperacidity•Hypermotility and spasm

6. Mepenzolate Bromide

•3-hydroxy-1,1-dimethylpiperidinium bromide benzilate(Cantil)•Relieve pain,cramps and bloating and help curb diarrhea.

7. Methanteline Bromide, USP.

•Diethyl(2-hydroxyethyl) methylammonium bromide xanthenes-9-carboxylate (Banthine Bromide)•White, slightly hygroscopic crystalline salt•Soluble in water producing solution of ph 5•Aqueous solution are not stable and hydrolyze in few days•Bromide form is very hygroscopic chloride•Introduced in 1950 is potent anticholinergic agent acting on nicotinic cholinergic recptors of both sympathetic and parasympathetic system•Indicated in gastritis, intestinal hyoermotility, bladder irritability, cholinergic spasm,pancreatitis, hyperhidrosos and peptic ulcer•Contraindicated in glaucoma

8. Oxyphencyclimine HCL

•1,4,5,6-tetrahydro-1methy-2pyrimidinyl methy a-phenylcyclohexaneglycolate monohydrochloride (Daricon, Vistrax)•Introduce in 1958 promoted as pperipheral anticholinergic-antisecratory agent•Reduce both volume and acid content of gastric juices•Low toxicity in comparison with many available anticholinergics•Absorbed from GI tract and duration of action is up to 12 hours•Suggested for use in peptic ulcer, pylospasm and functional bowel syndrome.

9. Oxybutynin

•4-diethylaminobut-2-ynly2-cyclohexy-2-hydroxy-2-phenyl-ethanoate (Oxytrol)•One one the first agents developed to exploit the effects that cholinergic blocking agents have on bladder.•Result in less urinary incontinence, urgency and frequency.•Competitive antagonism on M1 M2 M3 receptors

10. Trospium Chloride

•3a-benziloy-loxynortropane-8-spiro-1-pyrrolidinium chloride ( Sanctura)•Also a competitive antagonist of muscarinic receptors and is use to manage over active bladder•11. Solifenacin Succinate•(Vesicare)•Competitive antagonist of muscarinic subtypes•Selectivity for bladder over other tissues such as salivary glands

Aminoalcohol Esthers

•Used as antiparkinsonian drugs rather than conventional anticholinergics.

Products

1. Benztropine Mesylate, USP

•3a-(diphenymethoxy)- a H,5Ah-tropane methanesulfonate ( Cogentin) •Anticholinergic, antihistaminic and local anesthetic properties .•Antiparkinsonian agent•About as potent agent as atropine and share some of its side effects•Does not produce central stimulation instead exert sedative effect of antihistamines•Caution is exercised in patients with glaucoma

2. Orphenadrine Citrate

•N,N-dimethyl-2-(o-methyl-a-phenylbenzyloxy)ethylamine citarate ( Norflex)•Introduced in 1957 and closely resembles diphenhydramine structurally but lower antihistaminic effect and higher anticholinergic action.•Lacks sedative effect of diphenhydramine•Best used as adjunct to other agents such as benztropine,procyclidine in the treatment of paralysis agitans.•Adjunct to other measures to relieve pain of local muscle spasm.

Aminoalcohols

•Development of aminoalcohol as parasympatholytics took place in 1940s. It was soon established that these antispasmodics were equally efficacious in parkinsonism.•Structural feature common on all aminoalcoholanticholinergics is the y-aminopropanololarrangement.

Products

1.Biperiden USP

•a-5 norbornen-2-yl-a-phenyl-1-piperidinepropanol (Akineton)•introduced in1959, has relatively week visceral anticholinergics but strong nicotinolyic action in term of its ability to block nicotine-induced convulsion.•Neurotropic action is low on intestinal musculature and blood vessel•Strong musculatropic action about equal to papaverine.•Mydriatic action in the eye but much lower than atropine.•Mininimizing side effects of Parkinson syndrome.

2. Procyclidine Hydrochloride, USP.

•a – cyclohexyl-a- phenyl-1-pyrrolidinepropanolol-hydrochloride ( Kemadrin)•intoruced in 1956•clinically useful for its ability to relieve voluntary muscle spasticity by its central action therefore, has been used for its success in the treatment of Parkinson’s.•Toxicity is low, but when dosage is high side effects is noticeable.

3. Tridihexethyl Chloride, USP.

•3-cyclohexyl-3-hydroxy-3-phenylpropyl)triethylammonium chloride ( Panthilon)•White, bitter, crystalline powder.•Freely soluble in water and alcohol, aqueous solution is neutral in reaction.•Peripheral atropine-like activity dominates.•Has antispasmodic and antisecretory activities•Valueless in treating Parkinson’s.•Useful for adjunctive therapy in wide variety of GI disease•More effective in gastric hypersecretion than in hypermotility and spasm.•Best administered IV

4. Trihexyphenidyl HCL, USP.

•a – cyclohexyl-a-phenyl-1-piperidinepropanol hydrochloride (Artane, Tremin , Pipanol)•introduced in 1949•half as active as atropine as an antispasmodic but has milder side effects•about as toxic as atropine•treatment of Parkinsonism and relieves mental depression associated with the condition.5. Tolterodine•2-[3-[bis(1-methyl-ethy)amino]-1-phenyl-propyl]-4-methyl-phenol•Acts on M2 and M3 subtype receptors•Reduction of smooth muscle tone allowing greater volume of urine to be stored in the bladder

Aminoamides•Same type of molecule as aminoalcohol group with the important exception that the polar amide group replaces the corresponding polar hydroxyl group.

1. Isopropamide Iodide, USP.

•3-carbamoyl-3,3-diphenylpropyl)diisopropylmethylammoniumiodide(Darbid)•The only drug of this class that is used.•Bitter,white to pale yellow crystalline powder•Sparingly soluble in chloroform and alcohol.•Introduced in 1959•Producing atropine-like effects peripherally.•Does not cause sympathetic blockade at the ganglionic level except at high dosage.•Has long duration of action as long as 12 hours.•Used as adjunctive therapy in the treatment of peptic ulcer and other GI conditions associated with hypermotility and hyperacidity.•Contraindicated in glaucoma,prostatic hypertrophy..etc.

Miscellaneous•Structural modification can be found in these drugs. Each has a typical bulky group characteristics of the usual anticholinergicmolecule.

1. Diphemanil Methylsulfate USP.

•4-(diphenylmethylene)-1,1-dimethylpiperidiniummethylsulfate (Prantal)•Acts as effective parasympatholytic by blocking the nerve impulses of parasympathetic ganglia.•Does not invoke sympathetic ganglionic blockade.•Highly specific in activating gastric secreation and GI motility•Useful in the treatment of peptic ulcer and hyperhydrosis in low doses(50 mh twice daily)•Administered between meals.

2. Ethopropazine HCL, USP.

•10-[2-(diethylamino0propyl]phenothiazinemonohydrochloride (Parsidol)•Introduced in 1954•Useful in the symptomatic treatment of parkinsonism•Drowsiness and dizziness is the most common side effect•Contraindicated to patients with glaucoma.

3.Papaverine HCL,USP.

•6,7-dimethoxy-1-veratrylisoquinolone hydrochloride•Isolated by Merck in 1848 from opium•Main effect is spasmolytic of the smooth muscle,actingas direct, nonspecific relaxant on vascular,cardiac and other smooth muscle.•Often called nonspecific antagonist.

Nondepolarizing Competitive Ganglionic Blocking Agents-these compounds posses the affinity to attach to a nicotinic receptor sites specific for ACh but lack intrinsic activity necessary for impulse transmission.-prolonged administration results in tolerance,

Drugs falling in this class :

•Tetraethylammonium salts•Hexamethonium•Trimethapahan

Neuromascular Blocking Agents

•These are agents that block the transmission of Acetylcholine at the motor end plate•Primary as adjuvants in surgical anesthesia to obtain relaxation of skeletal muscle.•Used in orthopaedic procedures such as alignment of fractures and correlation of dislocation•Curariform or having curarimimetic activity are the therapeutically useful compounds of this group. Which were obtained from curare.

Curare and Curare Alkaloids

•In 1935 a pure crystalline alkaloid ,d-tubocurarine chloride was isolated from a plant possessing paralyzing action of curare.•Chondodendron tomentosum ( Menispermaceae ) was the known botanic source of the drug isolated by Wintersteinerand Dutcher in 1943.•Intocostrin was a standardized and purified curare tradename. The solid content which is almost one half tubocurarine solids.

•1.Tubocurarine Chloride, USP

•Prepared from crude curare by purification and crystallization.•Occurs as a white to grayish white ,odorless crystalline powder soluble in water. Stable to heat sterilization on aqueous solution.•A nondepolarizing blocking agent used for its paralyzing action on voluntary muscles.•Its action is inhibited by AChE inhibitors such as neostigmine . and then necessitated in respiratory embarrassment caused by overdosage.•Drug is inactive orally•Paralysis last for 2 hours although binds only for 1ms.•Half-life is 89 minutes.

Synthetic Compounds with Curariform Activity

1.Atracurium Besylate

•(Tracrium)•2.5 times more potent than d-tubocurarine. Duration of action is much shorter.•AChE inhibitors antagonize its paralyzing effect.

•2. Doxacurium Chloride•(Nuromax)•A long acting nondepolarizing blocking agent .•Has no vagolytic activity.•Used as skeletal muscle relaxant in surgical procedures that last 90minutes.

3. Gallamine Triethiodide, USP (Mivacron)

•Has strong vagolytic effect and persistent decrease in neuromascular function after successive doses that cannot be overcome by cholinesterase inhibitors.•Contraindicated to patients with myasthenia gravis•Action is cumulative •Antidote is neostigmine.•4.Mivacurium Chloride•(Mivacron)•Short acting nondepolarizing agent used as adjunct to anesthesia to elaxskeletal muscle.•AChE can prolong rather than reverse the effects of the drugs.

5.Pancuronium Bromide

•(Pavulon)•Based on the alkaloid malouetine•Acts on nicotinic receptor and ion channels inhibiting normal ion fluxes•Marketed at concentrations 1 or 2 mg/ml IV •5x more potent than tubocurarine chloride•Action is increased by inhilations anesthetics such as ether and halothane.•6. Pipercurium Bromide•(Arduan)•Action similar to the latter

7. Succinylcholine Chloride,USP

•(Anectine, Sucostrin)•White odorless,crystalline substance freely soluble in water to give solutions with ph of about 4.•Stable in acidic solutions and unstable in alkali•Has very short duration of action and quick recovery •Muscular paralysis•Anticholinestresase does not antagonize the action of this drug instead prolongs it.•It is a a muscle relaxant •May be used either for short or long periods of relaxation •Suitable for continous IV drip administration•Should not be used with thiopental