Farmacología Ex 3.pdf

Nicotinic Acetylcholine Receptors (nAChRs) • Mediate neurotransmission at: ✓Neuromuscular junction. • Controls skeletal muscle contraction. ✓Autonomic ganglia & in the CNS • Controls release of neurotransmitters. • Both nicotine and ACh stimulate them. • Distinct subtypes of nAChRs exist: ✓Muscle...

Nicotinic Acetylcholine Receptors (nAChRs) • Mediate neurotransmission at: ✓Neuromuscular junction. • Controls skeletal muscle contraction. ✓Autonomic ganglia & in the CNS • Controls release of neurotransmitters. • Both nicotine and ACh stimulate them. • Distinct subtypes of nAChRs exist: ✓Muscle nAChR (neuromuscular junction). ✓Neuronal nAChR (Ganglia and CNS). Ganglionic nAChRs Nicotinic receptor activation causes depolarization of the nerve cell. • There are multiple nicotinic receptor subunits in ganglia, with α3 and b2 being most abundant. • Ganglionic action potential is generated when EPSP threshold is reached at the postganglionic neuron. ✓Requires multiple synapses to be activated before transmission is effective. ✓Discrete end plate activation with focal localization. Nicotine Actions in the ANS • Autonomic ganglia are important sites of nicotinic synaptic action. ✓Nicotinic agents cause activation of both para- and sympathetic ganglia. ✓Ganglionic nAChRs, like all nAChR are subject to both depolarizing and nondepolarizing blockade. • Nicotinic agents display a biphasic action (the effects of nicotine are going to depend on the dose). Ganglionic stimulating drugs Nicotine Nicotine administration results in complex and unpredictable effects due to its ability to stimulate and block receptors. • Small doses of nicotine stimulate the ganglion cells directly and may facilitate impulse transmission. • Larger doses, the initial stimulation is followed very quickly by a blockade of transmission. • This biphasic action also applies to the adrenal medulla: ✓Small doses ↑ discharge of catecholamines. ✓Larger doses prevent their release. Depolarizing Blockade • Prolonged agonist occupancy of the nAChR abolishes the effector response. ✓Postganglionic neuron stops firing. ✓Skeletal muscle cell relaxes. • Depolarizing blockade (phase I): continued presence of the agonist prevents electrical recovery of the post-junctional membrane. ✓Occurs initially during persistent occupancy of the receptor. agonist Depolarizing Blockade • Depolarizing blockade: continued presence of the agonist prevents electrical recovery of the postjunctional membrane. Desensitization • Desensitization: Continued agonist occupancy is associated with return of membrane voltage to the resting level. ✓The receptor becomes desensitized to agonist. • This state is refractory to reversal by other agonists. Depolarizing vs Desensitization blockade Effects of Nicotine Nicotine action is the same on both parasympathetic and sympathetic ganglia. The initial response is simultaneous discharge of both systems. • Cardiovascular System: The effects are sympathomimetic. ✓Dramatic hypertension is produced, tachycardia may alternate with a bradycardia mediated by vagal discharge. ✓Nicotine elicits a discharge of epinephrine from the adrenal medulla, which accelerates heart rate and raises blood pressure. • Gastrointestinal and Urinary tracts: the effects are largely parasympathomimetic. ✓Nausea, vomiting, diarrhea, and urination. Effects of Nicotine • CNS: mark stimulation. ✓Low doses analgesia. produce weak ✓Higher doses, tremors leading to convulsions. • Stimulation of the CNS with large doses is followed by Depression; death results from failure of respiration owing to both central paralysis and peripheral blockade of the diaphragm and intercostal muscles that facilitate respiration. Effects of Nicotine • Neuromuscular Junction: effects of high doses are those of the ganglia. • The stimulant phase is obscured largely by the rapidly developing paralysis. ✓Neuromuscular blockade by depolarization and desensitization. Nicotine in Cigarettes “Cigarette smoking is clearly the largest single preventable cause of illness and premature death in the United States.” • The health costs of tobacco smoking to the smoker and its socioeconomic costs to the public are still incompletely understood. The 1979 Surgeon General’s Report on Health Promotion and Disease Prevention stated that “cigarette smoking is clearly the largest single preventable cause of illness and premature death in the United States.” • The average cigarette contains 6-11 mg nicotine and delivers ~1-3 mg nicotine systemically to the smoker; bioavailability can ↑ as much as 3-fold with the intensity of puffing and technique of the smoker. Basis of Nicotine Addiction The addictive power of cigarettes is directly related to their nicotine content. • At lower concentrations nicotine's effects reflect its higher affinity for a neuronal nicotinic receptor (a4b2) than for the neuromuscular junction receptor (α1β1γδ). • Chronic exposure to nicotine has a dual effect at nicotinic receptors: ✓Activation: ↑ release of dopamine in the mesolimbic system. • Mild alerting action and addictive properties. ✓Desensitization: ↓ release of dopamine. Nicotine • The fatal dose of nicotine is ≈ 60 mg (20-60 cigarettes); or 1 cartridge of the pure liquid (e-cigarettes). ✓Fortunately, most of the nicotine in cigarettes is destroyed by burning or escapes via the “sidestream” smoke. • Toxic effects of a large dose of nicotine are: 1. Central stimulant actions, cause convulsions, may progress to coma and respiratory arrest. 2. Skeletal muscle end plate depolarization, which may lead to depolarization blockade and respiratory paralysis. 3. Hypertension and cardiac arrhythmias. CDC study finds dramatic increase in ecigarette-related calls to poison centers • More than half (51.1%) of the calls involved young children under age 5, and about 42% of the poison calls involved people > 20. • The most common adverse effects mentioned were vomiting, nausea and eye irritation. Nicotine • Treatment of acute nicotine poisoning is: ✓Muscarinic excess resulting from parasympathetic stimulation can be controlled with atropine. • Central stimulation is anticonvulsants (diazepam). treated with ganglion parenteral • Neuromuscular blockade is not responsive to pharmacologic treatment and may require mechanical ventilation. ✓Fortunately, nicotine is metabolized and excreted relatively rapidly. Patients who survive the first 4 hours usually recover completely if hypoxia has not resulted in brain damage. Smoking Cessation Medications Smoking cessation Medications reduce the craving for nicotine and/or inhibit the reinforcing effects of nicotine. • Approaches to help patients stop smoking: ✓Replacement therapy • Nicotine in the form of gum, transdermal patch, nasal spray, or inhaler. ✓Varenicline (CHANTIX): a partial agonist at CNS nicotinic receptors (antagonist properties, long half-life and high affinity). • Prevents the stimulant effect of nicotine at α4β2 receptors that causes release of dopamine (weak activity toward α3β2 receptors most prevalent in ganglia). ✓Bupropion: efficacy in smoking cessation therapy stems from its non-competitive antagonism of nicotinic receptors where it displays some selectivity among neuronal subtypes. Ganglionic blocking agents Ganglionic receptors, like those of the skeletal muscle, are subject to both depolarizing and non-depolarizing blockade. • Nicotine and acetylcholine (if amplified with a cholinesterase inhibitor) can produce depolarizing ganglionic block. • Ganglion blockers are used rarely because more selective autonomic blocking agents are available. ✓First effective therapy for the treatment of hypertension (extensively used during the 1950s and 1960s). ✓Numerous undesirable side effects due to effects on both sympathetic and parasympathetic neurotransmission. Effects of Ganglionic blocking drugs SITE The physiological effects can be anticipated by knowing which division of the autonomic nervous system exercises dominant control of various organs. PREDOMINANT TONE EFFECTS OF GANGLIONIC BLOCKADE Arterioles Sympathetic (adrenergic) Vasodilation; ↑ peripheral blood flow; hypotension Veins Sympathetic (adrenergic) Vasodilation; pooling of blood; ↓ venous return; ↓ cardiac output Heart Parasympathetic (cholinergic) Tachycardia Iris Parasympathetic (cholinergic) Mydriasis (pupil dilation) Ciliary muscle Parasympathetic (cholinergic) Cycloplegia (focused to far vision) Gastrointestinal tract Parasympathetic (cholinergic) ↓ Tone and motility; constipation; ↓ secretions Urinary bladder Parasympathetic (cholinergic) Urinary retention Salivary glands Parasympathetic (cholinergic) Xerostomia (dry mouth) Sweat glands Sympathetic (cholinergic) ↓ Diaphoresis (sweating) Ganglionic blocking Drugs • Mecamylamine: improve absorption from the GI tract. ✓Non-selective and non-competitive antagonist of nAChRs. ✓Crosses the blood-brain barrier and readily enters the CNS. • Sedation, tremor, choreiform movements, and mental aberrations. ✓FDA approved as an Orphan drug for Tourette's syndrome. Neuromuscular blocking agents 1. Competitive agents: ✓Long acting: d-Tubocurarine, Pancuronium. ✓Intermediate acting: Atracurium, Cisatracurium, Vecuronium, Rocuronium. ✓Short acting: Mivacurium. 2. Depolarizing agents: ✓Succinylcholine. 3. Inhibition of ACh degradation (AChE Inhibitors): ✓Results in depolarizing blockade (endogenous ACh). 4. Inhibition of ACh release: ✓Botulinum toxin. Neuromuscular Junction • Small, rapidly moving muscles relax before bigger slow moving. ✓ Eyes, jaw, and larynx relax before the limbs and trunk. ✓ Lastly, the intercostal muscles and finally the diaphragm are paralyzed (respiration ceases). • Recovery occurs in the reverse order. Neuromuscular blocking agents Therapeutic Applications • Muscle relaxation: adjuvant in surgical anesthesia. ✓↓ the level of anesthetics needed. ✓Shortens post-anesthetic recovery. • Short duration used to facilitate endotracheal intubation, laryngoscopy, bronchoscopy, and esophagoscopy in combination with a general anesthetic agent. • Control of muscular spasms, strabism, hemifacial spasms, oromandibular and cervical dystonia, spasms of the lower esophageal sphincter. Neuromuscular blocking agents Adverse Effects • Prolonged apnea. • Cardiovascular collapse. • ↑Histamine release. ✓Tubocurarine, Mivacurium, Atracurium and Succinylcholine. • Malignant Hyperthermia. • Respiratory Paralysis. • The depolarizing agents can release K+ rapidly from intracellular sites. Neuromuscular blocking agents Adverse Effects Treatment • Competitive blockade can be treated with AChE inhibitors ✓Reverse and ↓ the duration of blockade. ✓Use atropine concomitantly to prevent stimulation of muscarinic receptors and thereby to avoid slowing of the heart rate. AChE inhibitors will not reverse depolarizing neuromuscular blockade. Neuromuscular blocking agents Drug-Drug Interactions • Halogenated anesthetics: ↑ neuromuscular blockade. ✓Sensitize the NMJ to the effects of neuromuscular blockers. • Aminoglycoside antibiotics: gentamicin and tobramycin. Inhibit ACh release by competing with calcium ions. ✓Synergize with competitive blockers, enhancing the blockade. • Calcium channel blockers: ↑ neuromuscular blockade of competitive blockers. • Cholinesterase inhibitors: can overcome the action of nondepolarizing neuromuscular blockers. Curare Curare: plant extract from Chondrodendron tomentosum and Strychnos toxifera. • Used by South America tribes as arrow poison for game hunting. ✓The animals got paralyzed, if not killed by the arrow. • Muscle paralyzing active compounds are alkaloids, tubocurarine, toxiferine. Curare • Neuromuscular blocking agents are very poorly absorbed from the GI tract, cannot cross the BBB (virtually devoid of central effects following ordinary clinical doses). • Tubocurarine produces histamine release. ✓Bronchospasm, hypotension, excessive bronchial and salivary secretion. Strychnos toxifera • At high doses, partial blockade is produced both at autonomic ganglia and at the adrenal medulla (↓BP &HR). Competitive blocking agents Long acting: 1. d-Tubocurarine (6 min onset, 80 min duration). 1. Pancuronium (3-4 min onset, 85 min duration). Has a vagolytic action (↑HR). Intermediate acting: 1. Atracurium (3 min onset, 45 min duration): for patients with hepatic or renal insufficiency, hydrolyze by plasma Esterases. 2. Cisatracurium (2-8 min onset, 45 min duration): atracurium isomer with 3x its potency (hepatic or renal insufficiency) and no histamine release. • Atracurium > cisatracurium metabolism result in production of laudanosine. ✓Has been shown to be epileptogenic. ✓Accumulates in patients with renal insufficiency. Plasma laudanosine concentrations are lower in patients receiving cisatracurium compared with patients receiving clinically equivalent doses of atracurium. Competitive blocking agents 3. Vecuronium (2-3 min onset, 40-45 min duration) • No adverse cardiovascular effects. 4. Rocuronium (1-2 min onset, 36-73 min duration): rapid onset and lower potency. • Alternative to succinylcholine in rapid-induction anesthesia and in relaxing the laryngeal and jaw muscles to facilitate tracheal intubation. Short acting: 1. Mivacurium (2-3 min onset, 15-21 min duration). • Sensitive to catalysis by cholinesterase, causes histamine release. Competitive blocking agents Interventional Strategies for Toxic Effects • Neostigmine: effectively antagonizes only the skeletal muscular blocking action of the competitive blocking agents. ✓↑ side effects as hypotension & bronchospasm. • Atropine or glycopyrrolate: counteract muscarinic stimulation. Reversal of Effects by Chelation Therapy •Sugammadex: a modified γ-cyclodextrin, is a chelating agent specific for rocuronium and vecuronium. Competitive vs Depolarizing block Competitive blockers: compete with ACh released from motor nerve endings (NM-receptors). ✓Reversed by administration of anti-cholinesterase agents. Depolarizing blockers: Open the channels (initially produce twitching and fasciculations). Neuro-muscular blockade can be divided into two phases: ✓Phase I block: rapid in onset, results from persistent depolarization of muscular end-plate. ✓Phase II block: Slow in onset, results from desensitization of the NMreceptor. • Not reversed by administration of anti-cholinesterase agents. Succinylcholine Succinylcholine (1-2 min onset, 6-11 min duration): at doses producing muscular relaxation rarely causes effects attributable to ganglionic blockade. • Persist for longer durations at the neuromuscular junction because of their resistance to AChE. • The extremely brief duration of action of succinylcholine is due largely to its rapid hydrolysis by butyrylcholinesterase. Succinylcholine Adverse Events: rarely causes effects attributable to ganglionic blockade. ✓Cardiovascular effects are sometimes observed due to successive: • Stimulation of vagal ganglia (manifested by bradycardia). • Stimulation of sympathetic ganglia (resulting in hypertension and tachycardia). • Life-threatening hyperkalemia (cardiac arrest). • Malignant Hyperthermia (Rhabdomyolysis). • Muscle soreness. ✓Small prior doses of competitive blocking agents have been employed to minimize fasciculations and muscle pain. Succinylcholine Fastest onset and shortest duration of action of all muscle relaxants. • Major role in the context of trauma care. ✓Where endotracheal intubation may need to be completed very quickly. • Not indicated for children ≤ 8 years of age unless emergency intubation or securing an airway is necessary. • Does not produce unconsciousness or anesthesia. ✓Cause considerable psychological distress while simultaneously making it impossible for a patient to communicate. Botox Blocks ACh release at neuromuscular junctions. • Botulinum toxin produced by the bacterium C. botulinum. ✓One of the most powerful known toxins: about one microgram is lethal to humans when inhaled. • Botulism causes respiratory failure by paralyzing the muscles of the chest; can progress to respiratory arrest. • When injected in small amounts, it can effectively weaken a muscle for a period of 3-4 months. Botox Therapeutic Applications • Approved for the treatment of: ✓Ocular conditions (strabismus and blepharospasm). ✓Spasms (hemifacial, torticollis and lower esophageal sphincter). ✓Dystonias (oromandibular and cervical). • Off-label use in children with cerebral palsy. • Dermatological uses include treatment of hyperhidrosis of the palms and axillae that is resistant to topical remedies; and removal of facial lines associated with excessive nerve stimulation and muscle activity. ✓The reduction of wrinkles is temporary the effect of Botox can be renewed by re-administration. • The FDA has issued a safety alert, warning of respiratory paralysis from unexpected spread of the toxin from the site of injection.