Muscarinic Antagonists 2023.pdf

CHOLINERGIC SYSTEM MUSCARINIC ANTAGONISTS José O. Colón Sáez PhD. FARM-7225 OBJECTIVES ▪ Understand the actions of Anticholinergic drugs in different organ systems. ▪ Understand the different uses of specific anticholinergic drugs. ✓ Ophthalmologic ✓ Asthma and COPD ✓ Urinary Incontinence ✓ Ga...

CHOLINERGIC SYSTEM MUSCARINIC ANTAGONISTS José O. Colón Sáez PhD. FARM-7225 OBJECTIVES ▪ Understand the actions of Anticholinergic drugs in different organ systems. ▪ Understand the different uses of specific anticholinergic drugs. ✓ Ophthalmologic ✓ Asthma and COPD ✓ Urinary Incontinence ✓ Gastric ✓ Parkinson’s ✓ Motion Sickness 2 ANTICHOLINERGIC Plants containing Atropine, hyoscyamine and Scopolamine. ▪ Atropa Belladona ✓ Used (eye-drops) by women to dilate the pupils of the eyes to make them appear seductive. ▪ Datura Stramonium ✓ Used in indian medicine for asthma symptoms. ▪ Hyoscyamus niger ✓ Used in combination with other plants, such as mandrake, deadly nightshade, and datura as an anesthetic potion, as well as for its psychoactive properties. 3 MUSCARINIC ANTAGONISTS Many antihistaminic, antipsychotic, and antidepressant drugs have similar structures and significant antimuscarinic effects. ▪ The muscarinic receptor antagonists include: 1. The naturally occurring alkaloids: ATROPINE ✓ Atropine prototypical antagonist. ✓ Scopolamine better CNS penetration even at low doses displays CNS effects. 2. Semisynthetic derivatives: SCOPOLAMINE ✓ Which primarily differ from the parent compounds in their disposition in the body or their duration of action. 3. Synthetic derivatives: ✓ Show selectivity for subtypes of muscarinic receptors. 4 ATROPINE Highly selective for muscarinic receptors. ▪ Well, absorbed membranes. from the gut and conjunctival ✓ Significant levels are achieved in the CNS within 30 minutes to 1 hour (limit the dose tolerated). ▪ Partially metabolized in the liver. ✓ About 50% of the dose is excreted unchanged in the urine. ▪ The drug’s effect on parasympathetic function declines rapidly in all organs except the eye. ✓ Duration of action ≈ 4 hrs. ✓ Effects on the iris and ciliary muscle persist for ≥ 72 hrs. 5 ATROPINE ▪ No selectivity among muscarinic receptors. (M1 ≈ M2 ≈ M3) ▪ Other antimuscarinic drugs are moderately selective for one or another of these subgroups. ▪ Most synthetic antimuscarinic drugs are considerably less selective than atropine in interactions with non-muscarinic receptors. Atropine commonly used to block vagal reflexes and ↓ secretions induced by surgical manipulation of visceral organs. 6 DOSE EFFECT 0.5 mg Slight cardiac slowing; some dryness of mouth; inhibition of sweating (blocking presynaptic receptors → ↑ ACh release) 1 mg Definite dryness of mouth; thirst; acceleration of heart, sometimes preceded by slowing; mild dilation of pupils 2 mg Rapid heart rate; palpitation; marked dryness of mouth; dilated pupils; some blurring of near vision 5 mg All the above symptoms marked; difficulty in speaking and swallowing; restlessness and fatigue; headache; dry, hot skin; reduced intestinal peristalsis 10 mg and more Above symptoms more marked; pulse rapid and weak; iris practically obliterated; vision very blurred; skin flushed, hot, dry, and scarlet; ataxia, restlessness, and excitement; hallucinations and delirium; Dra. I Oquendo Copyright 2008 coma 7 ATROPINE Pharmacological Effects ▪ Secretions: ✓ ↓ Salivary glands (Xerostomia). ✓ ↓ Lacrimal glands (Sandy eyes). ✓ ↓ Sweat Glands (Temperature). • Innervated by sympathetic cholinergic fibers. • Sweating may be depressed enough to ↑ body temperature. ▪ Eye: Effects last 5-6 days. ✓ Mydriasis. • Unopposed sympathetic activity. ✓ Cycloplegia. M3 • Loss of the ability to accommodate (cannot focus for near vision). a1-AR 8 ATROPINE Pharmacological Effects ▪ Lungs: cause some bronchodilation and ↓ secretion. ✓ More significant in respiratory disease. patients with ▪ Heart: effects depend on dose ✓ Low dose → ↓HR (presynaptic M4). ✓ As the dose ↑ it causes a progressive tachycardia (inhibition of cardiac M2). Produces cardiac arrhythmias, without significant cardiovascular symptoms. 9 ATROPINE Pharmacological Effects ▪ Urinary tract: relaxes smooth muscle of the ureters and bladder wall and slows voiding. ▪ GI tract: Gastrointestinal smooth muscle motility is affected from the stomach to the colon. ✓ ↓ the tone and propulsive movements, the walls of the viscera are relaxed. 10 ATROPINE Pharmacological Effects ▪ Central Nervous therapeutic doses. System: minimal effects at ▪ Toxic doses, result in central excitation leading to: ✓Restlessness, irritability, disorientation, hallucinations, or delirium. ▪ Scopolamine has prominent central effects at low therapeutic doses. 11 ATROPINE Therapeutic Applications ▪ Considered the initial treatment of patients with acute myocardial infarction cause by excessive vagal tone. ▪ Commonly given to block responses to vagal reflexes induced by surgical manipulation of visceral organs. ▪ Anticholinesterase Poisoning. ✓ Used to antagonize the parasympathomimetic effects of pyridostigmine or other anticholinesterases administered in the treatment of myasthenia gravis. 12 THERAPEUTIC APPLICATIONS Ophthalmology ▪ Mydriasis is necessary for thorough examination of the retina and optic disc. ✓ Semisynthetic derivative, preferred because of their shorter duration of action: • Tropicamide (MYDRIACYL) 15-60 min. • Cyclopentolate (CYCLOGYL) 2-6 hrs. • Homatropine (ISOPTO HOMATROPINE) 12-24 hrs. 13 14 THERAPEUTIC APPLICATIONS COPD and Asthma ▪ Anticholinergics in COPD and Asthma (M3 selective): ✓ Ipratropium (ATROVENT) • Last 4-6 hrs. • FDA-approved for rhinorrhea. ➢ Common cold, allergic nonallergic rhinitis. or ✓ Tiotropium (SPIRIVA) • Last 24 hrs. ✓ Umeclidinium • Duration of action 24 hrs. ✓ Aclidinium • Duration of action 12 hrs. 15 16 THERAPEUTIC APPLICATIONS COPD and Asthma 17 18 THERAPEUTIC APPLICATIONS Urinary tract ▪ Overactive urinary bladder and urinary incontinence: ✓ ↓ vesicular pressure → ↑ capacity → ↓ frequency of contractions. • Antagonizing parasympathetic control of the bladder. ✓ Alter bladder sensation during filling. • Receptors for acetylcholine on the urothelium (the epithelial lining of the urinary tract) and on afferent nerves. ▪ Used to treat enuresis in children. ▪ ↓ urinary frequency and ↑ bladder capacity in spastic paraplegia. 19 THERAPEUTIC APPLICATIONS Urinary tract ▪ Oxybutynin (t1/2 2-5 hrs): High incidence of side effects, particularly xerostomia. ✓Lower for transdermal patch (OXYTROL) or topical gel (GELNIQUE) formulations. 20 THERAPEUTIC APPLICATIONS Urinary tract ▪ Tolterodine (t1/2 2-10hrs): selectivity for the urinary bladder → greater patient acceptance. ▪ Fesoterodine (t1/2≈ 7 hrs): pro-drug, rapidly hydrolyzed to desfesoterodine (5hydroxymethyltolerodine/active metabolite). ▪ Trospium kidneys. primarily eliminated by the ▪ Darifenacin (t1/2 13-18hrs) ▪ Solifenacin (t1/2 55hrs) High selectivity for M3 receptors. 21 FESOTERODINE: INDIVIDUALZED TREATMENT OF URGENCY URINARY INCONTINENCE ACROSS PATIENT GROUPS https://www.sciencedirect.com/science/article/abs/pii/S1569905611000042 22 23 THERAPEUTIC APPLICATIONS GI tract ▪ Pirenzepine and Telenzepine (M1 selective): inhibits gastric acid secretion. ✓ Muscarinic receptor antagonists ↓ gastric motility and the secretion of gastric acid. • At antisecretory doses produce side effects. ▪ Dicyclomine weak antagonist, has spasmolytic effects. Used for diarrhea predominant irritable bowel syndrome. 24 THERAPEUTIC APPLICATIONS Motion Sickness ▪ Scopolamine: Crosses the BBB, used prophylactically to prevent, or even reverse vestibular disturbances especially motion sickness. ▪ CNS: can produce significant amnesia and sedation for the events associated with surgery and obstetric delivery, an adverse effect that was considered desirable. ▪ Exacerbates urinary retention and intestinal hypomotility following surgery antimuscarinic actions. 25 THERAPEUTIC APPLICATIONS Parkinson’s disease ▪ Tremors and rigidity result from a relative excess of cholinergic activity due to a deficiency of dopaminergic activity in the basal ganglia striatum system. ✓ The tremor of Parkinson’s disease is ↓ by centrally acting antimuscarinic drugs. ▪ The combination of an antimuscarinic agent with a dopamine precursor drug (levodopa) provides 26 more effective therapy than either drug alone. THERAPEUTIC APPLICATIONS ▪ Parkinson’s disease has a mean age of onset of 57 years and a prevalence of 1% to 2% among adults ≥60 years. ▪ Manifested by bradykinesia, rigidity, resting tremor, postural instability, frozen gait disorder, and flexed posture. ▪ The disease begins as a movement disorder, but with advancing age is complicated by dementia (≈80%). 27 THERAPEUTIC APPLICATIONS Parkinson’s disease ▪ Cells of the substantia nigra send neurons back to the neostriatum, secreting dopamine (inhibitory). ✓ Mutual inhibitory pathway maintains a degree of inhibition of both areas. ▪ Destruction of Dopaminergic neurons (substantia nigra) results in ↓ dopamine secretion in the neostriatum. ✓ Results in overproduction of acetylcholine. • Abnormal signaling causes a loss of the control of muscle movements. 28 THERAPEUTIC APPLICATIONS Parkinson’s disease ▪ Antimuscarinic agents: benztropine, trihexyphenidyl and procyclidine. biperiden, ▪ Less efficacious than levodopa and play only an adjuvant role in antiparkinsonism therapy. ▪ ↓Cholinergic transmission produces effects similar to ↑dopaminergic transmission. ✓ Corrects the imbalance in dopamine/acetylcholine ratio. 29 THERAPEUTIC APPLICATIONS Parkinson’s disease ▪ Glycopyrrolate (oral solution) used to ↓ drooling (Parkinson disease and cerebral palsy). ✓ Does not cross BBB. ✓ Duration of anti-salivary action 8 hrs. ✓ Undergoes little metabolism (80% excreted unchanged). Potential medications commonly used for treating drooling in Parkinson's disease. 30 THERAPEUTIC APPLICATIONS Cholinergic Poisoning ▪ Atropine effective at reversing the muscarinic effects (CNS as well as peripheral effects). ▪ Large doses (1–2 mg IV every 5–15 minutes) are needed to oppose the muscarinic effects of potent agents (parathion and nerve gases). ▪ Has to be given many times (acute effects of the cholinesterase inhibitor last >24–48 hours. As much as 1 g/day may be required for as long as 1 month for full control of muscarinic excess. 31 Toxicity of muscarinic antagonists ✓ Blind as a bat (dilated pupils/mydriasis) ✓ Red as a beet (vasodilation/flushing) ✓ Hot as a hare (hyperthermia) ✓ Dry as a bone (dry skin) ✓ Mad as a hatter (hallucinations) ✓ Bloated as a Toad (ileus, urinary retention) ✓ And the heart runs alone (tachycardia) ▪ Substances that may cause this toxidrome include the four "anti"s: ✓ antihistamines, antipsychotics, antidepressants, and antiparkinsonian. 32 CONTRAINDICATIONS ▪ Important contraindications to the use of muscarinic antagonists include: ✓ Urinary tract obstruction. ✓ GI obstruction. ✓ Uncontrolled (or susceptibility to) glaucoma. ✓ Benign prostatic hyperplasia. Adverse effects and contraindications are reduced with administration through inhalation or topical use. 33 CONTRAINDICATIONS ▪ Infants and young children are especially susceptible to the toxic effects of muscarinic antagonists. ✓ Intoxication can result from ophthalmic application. ✓ Transdermal preparations of scopolamine used for motion sickness can cause toxic psychoses, in children and elders. ▪ Atropine poisoning syndrome may last > 48 hours. ✓ Depression and circulatory collapse (evident in severe intoxication); the blood pressure declines, convulsions may ensue, respiration becomes inadequate, and death due to respiratory failure may follow a period of paralysis and coma. • Physostigmine rapidly abolishes the delirium and coma caused by large doses of atropine. 34 Questions??? 35