Parasympatholytic drugs

Pharmacology Of Anticholinergic Drugs

1. Parasympatholytic drugs Prepared by- Shagufta Farooqui Department of Pharmacology Nanded Pharmacy College, Nanded

2. Introduction Drugs that block or inhibit the action of acetyl choline (Ach) in the parasympathomimetic nervous system. Also called cholinegic blocking agent or parasympatholytics Often referred to as anticholinergics or antimuscarinics

3. Atropine is obtained from Atropa belladonna, and Datura stramonium . Scopolamine is found in the shrub Hyoscyamus niger and Scopolia carniolica . Atropine consists of equal parts of d-and l- hyoscyamine , but the anitimuscarinic activity is almost wholly due to the l-isomer. The active ingredient in scopolamine is l- hyoscine . Atropine ( hyoscyamine ) is composed of tropic acid (active) and tropine ( tropanol -inactive).

4. Atropine Pharmacological action At low doses atropine produces slowing of heart rate High doses accelerate heart beat. Atropine like drugs antagonize the fall in B.P caused by choline esters The most prominent effect of atropine is tachycardia . It is due to blockade of M2 receptors on the SA node through which vagal tone decreases HR

5. Atropine blocks waterly salivary secretions induced by parasympathetic stimulation. The drug which decrease the salivary secretion is termed as anhidrotic ( Anhidrosis is the inability to sweat normally. When you don't sweat (perspire), your body can't cool itself, which can lead to overheating and sometimes to heatstroke a potentially fatal condition.  Anhidrosis  — sometimes called hypohidrosis . It causes dry mouth ( Xerostomia ) a characteristic state of anxiety and sudden fear. Salivary Secretions:

6. Atropine does not affect normal peristaltic movement. It relieves on hyper motility. Atropine can reduce the volume and total acidity of gastric secretion. Atropine blocks the secretions increased by parasympathomimetic drugs   GIT:

7. Atropine produces an antispasmodic action on biliary tract. Biliary secretion

8. Urinary bladder: (Urinary tract). Atropine of reduces the tone of urinary bladder and tends to produce urinary retention. Atropine has relaxant action on ureter and urinary bladder; urinary retention can occur in older males with prostatic hypertrophy. However, this relaxant action can be beneficial for increasing bladder capacity and controlling detrusor hyperreflexia in neurogenic bladder/enuresis.

9. Bronchi: Atropine relaxes smooth muscles of bronchi. It reduces the secretions so it is not recommended in the treatment of bronchial asthma. They dry up secretion in the respiratory tract, may lead to its inspissation and plugging of bronchioles resulting in alveolar collapse and predisposition to infection. The mucociliary clearance is also impaired.

10. Orally administered atropinic drugs are bronchodilators, but less effective than adrenergic drugs; not clinically used. Inhaled ipratropium bromide has been found to be specially effective in asthmatic bronchitis and COPD, though less so in bronchial asthma.

11. Eye: Atropine produces mydriasis by blocking the cholinergic supply. Atropine causes increase in focal length of the lens. Individual can see the objects at long distance, cannot constrict the pupil for seeing near objects or in response to bright light. Individual suffers from photophobia. The process is known as, "Paralysis of accommodation of the eye or cycloplegia. Atropine on local instillation produces both mydriasis and cycloplegia. Atropine cause increase in ocular tension.

12. Topical instillation of atropine causes mydriasis , abolition of light reflex and cycloplegia lasting 7–10 days. This results in photophobia and blurring of near vision. The ciliary muscles recover somewhat earlier than sphincter pupillae . The intraocular tension tends to rise, especially in narrow angle glaucoma.

13. Body temperature : Rise in body temperature occurs at higher doses. The rise in temperature occurs inspite of the coetaneous vasodilatation produced by the drug. It is due to both inhibition of sweating as well as stimulation of temperature regulating centre in the hypothalamus. Children are highly susceptible to atropine fever. This effect of atropine may be due to its anhidrotic action. In case of atropine poisoning the body temperature may rise to 104 to 105 degree F

14. CNS: Atropine has an overall CNS stimulant action. However, these effects are not appreciable at low doses which produce only peripheral effects because of restricted entry into the brain. Hyoscine produces central effects ( depressant ) even at low doses. • Atropine stimulates many medullary centres—vagal , respiratory, vasomotor. • It depresses vestibular excitation and has antimotion sickness property. • By blocking the relative cholinergic over activity in basal ganglia, it suppresses tremor and rigidity of parkinsonism.

15. Pharmacokinatics : Atropine i.e. belladonna alkaloids are well absorbed orally and parenteral administration. Atropine crosses the placental barrier and also is secreted in breast milk. It is partially metabolized in the liver and partly excreted unchanged by kidneys. Interaction: Absorption of most drugs is slowed because atropine delays gastric emptying. This results in slower absorption and greater peripheral degradation of levodopa —less of it reaches the brain. This does not occur when a peripheral decarboxylase inhibitor is combined. Antacids interfere with absorption of anticholinergics . Antihistaminics , tricyclic antidepressants, phenothiazines , disopyramide , pethidine have anticholinergic property—additive side effects occur with atropinic drugs

16. Contraindications: Atropine generally is contraindicated in patients with glaucoma, pyloric stenosis or prostatic hypertrophy, except in doses ordinarily used for preanesthetic medication. Atropine Sulfate Injection, should be used with caution in all individuals over 40 years of age.

17. Uses

18. Toxic effects of Atropine 1) Due to toxicity, there is difficulty in speech, swallowing and dry mouth 2) The skin becomes dry and there is an increase in the body temperature, 3) There is mydriasis and paralysis of accommodation (cycloplegia), 4) There is urinary urgency and difficulty in micturition. 5) The excitement, restlessness and there is motor incordination

19. SCOPOLAMINE: It is also known as Hyoscine . It is a belladonna alkaloid, is anticholinergic agent. Mechanism of action: It acts: i ) as a competitive inhibitor at postganglionic muscarinic receptor sites of the parasympathetic nervous system and is it act on smooth muscles that respond to acetylcholine but lack cholinergic innervation . It binds to muscarinic receptors This prevents acetylcholine from binding to and activating the receptors which would re in contraction of the smooth muscle. The inhibition of contraction reduces spasms and their related pain during abdominal cramping.

20. Pharmacological Action: It possesses the same pharmacologic properties as atropine, but in some cases to differing degrees. The vagolytic action of scopolamine is less than that of atropine, as is its effect in producing mydriasis . In addition, whereas atropine produces a stimulation of the CNS, scopolamine depresses the cerebral cortex. Scopolamine possesses a more intense drying effect than atropine.

21. Side effect: It has possible side effects are excitement, restlessness, disorientation, and delirium during the postoperative recovery period. This does not occur with atropine or glycopyrrolate . Emergence delirium, as it is known, is more likely to be observed in the very young or older adult patient.

22. Pharmacokinetics: It is well absorbed by transdermal patch. The oral bioavailability is 27% and 0.25% ophthalmic solution is rapidly absorbed after ocular administration. The distribution is not well characterized, but may be reversibly bound to plasma proteins and known to cross the placenta and blood-brain barrier. Time to peak concentration after transdermal administration is 24 hours. It is extensively metabolized and conjugated. The renal excretion is less than 10 %, and less than 5% is unchanged.

23. Uses: It is a medication used to treat motion sickness and postoperative nausea and It is also sometimes used before surgery to decrease saliva. It is used antimuscarinic , anticholinergic agent. It is used to treat pain and discomfort caused by abdominal cramps, vomiting.menstrual cramps, or other spasmodic activity in the digestive system. It is also effective at preventing bladder spasms

24. ATROPINE SUBSTITUTES Many semisynthetic derivatives of belladonna alkaloids and a large number of synthetic compounds have been introduced with the aim of producing more selective action on certain functions. Most of these differ only marginally from the natural alkaloids, but some recent ones appear promising. Quaternary compounds These have certain common features— • Incomplete oral absorption. • Poor penetration in brain and eye; central and ocular effects are not seen after parenteral / oral administration. • Elimination is generally slower; majority are longer acting than atropine. • Have higher nicotinic blocking property. Some ganglionic blockade may occur at clinical doses → postural hypotension, impotence are additional side effects. • At high doses some degree of neuromuscular blockade may also occur.

25. Ipratropium bromide: 40–80 μ g by inhalation; it acts selectively on bronchial muscle without altering volume or consistency of respiratory secretions. Another desirable feature is that in contrast to atropine, it does not depress mucociliary clearance by bronchial epithelium. It has a gradual onset and late peak (at 40–60 min) of bronchodilator effect in comparison to inhaled sympathomimetics . Thus, it is more suitable for regular prophylactic use rather than for rapid symptomatic relief during an attack. Action lasts 4–6 hours. It acts on receptors located mainly in the larger central airways (contrast sympathomimetics whose primary site of action is peripheral bronchioles

26. Tiotropium bromide: A newer congener of ipratropium bromide which binds very tightly to bronchial M1/M3 muscarinic receptors producing long lasting bronchodilatation . Binding to M2 receptors is less tight confering relative M1/M3 selectivity (less likely to enhance ACh release from vagal nerve endings in lungs due to M2 receptor blockade). Like ipratropium , it is not absorbed from respiratory and g.i . mucosa and has exhibited high bronchial selectivity of action.

27. Propantheline 15–30 mg oral; it was a popular anticholinergic drug used for peptic ulcer and gastritis. It has some ganglion blocking activity as well and is claimed to reduce gastric secretion at doses which produce only mild side effects. Gastric emptying is delayed and action lasts for 6–8 hours. Use has declined due to availability of H2 blockers and proton pump inhibitors.

28. Vasicoselective drugs Oxybutynin This newer antimuscarinic has high affinity for receptors in urinary bladder and salivary glands alongwith additional smooth muscle relaxant and local anaesthetic properties. It is relatively selective for M1/M3 subtypes with less action on the M2 subtype. Because of vasicoselective action, it is used for detrusor instability resulting in urinary frequency and urgeincontinence . Beneficial effects have been demonstrated in post-prostatectomy vasical spasm, neurogenic bladder, spina bifida and nocturnal enuresis. Anticholinergic side effects are common after oral dosing, but intravasical instillation increases bladder capacity with few side effects. Oxybutynin is metabolized by CYP3A4; its dose should be reduced in patients being treated with inhibitors of this isoenzyme

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