PHAR 736 Exam 3 Flashcards
Effects of muscarinic receptor agonists (SLUDS)
Salivation, Lacrimation, Urination, Defecation, Sweating
Effect of muscarinic receptor agonist on eye
Miosis through contraction of iris sphincter may help dislodge an adherent iris in acute (closed angle) glaucoma
Nearsightedness: contraction of ciliary muscle may improve aqueous humor flow in chronic glaucoma
Effect of muscarinic agonist on GI tract
Contraction of longitudinal muscles and relaxation of sphincters for increased motility
Effect of muscarinic agonist on urinary tract
Contraction of detrusor muscle and relaxation of sphincter for increased urinary output
Effect of muscarinic agonist on heart
Decrease heart rate at sino-atrial node, and conductivity through AV node
Effect of mucarinic agonist on lungs
Bronchoconstriction
Effect of muscarinic agonist on glands
Increased salivation, lacrimation and sweating
Describe ACh synthesis
Choline acetyltransferase synthesizes ACh from choline and acetate
Inhibition of ACh release
Inhibited by M2 muscarinic receptors on presynaptic neurons (AKA acetylcholine autoreceptors)
Nicotinic receptors
Ligand-gated ion channels
Muscarinic receptors
Located on parasympathetically innervated organs
G-protein coupled receptors; 2 pharmacologic sub-classes (M1 and M2) from five gene products (m1, m2, m3, m4, m5)
*few agonists are capable of distinguishing among the receptor sub-types
Describe M1 type
Consists of m1, m3, and m5 gene products
Coupled to Gq/11 family of G proteins and activate phospholipase C-beta enzymes | increases IP3, DAG, intracellular Ca2+ levels | protein kinase C activation
M1 locations and effects at parasympathetically innervated organs
*predominately m3 receptors
Glands (pulmonary, GI, sweat, lacrimal, nasopharyngeal) increasing secretions
Longitudinal GI smooth muscle, increasing motility and tone
Bladder smooth muscle, increasing tone and emptying
Bronchiol smooth muscle, increasing bronchoconstriction
Iris sphincter, producing miosis
Ciliary muscle, accommodating for near-sightedness
M1 locations and effects at locations outside of parasympathetic nervous system
Brain
Blood vessels (vascular endothelium): M1 type (m3) stimulate release of NO | m3 receptors activate PLC-beta to cause NO (endothelium-derived relaxing factor) release | NO stimulates increases in cAMP in smooth muscle which is relaxing
What is the catch with m3 receptors?
There are no PNS nerves and no ACh at vascular endothelium so these m3 receptors are not ever naturally activated
Only exogenous substances can activate them
Describe M2 type
Consist of m2 and m4 gene products
Coupled to Gi/o family of G proteins | Inhibit adenyly cyclase | inhibit Ca2+ channel opening
Couple to release of G-beta-Y proteins | activate K+ channels causing cell hyperpolarization | hyperpolarization inhibits neurotransmitter release
Locations of M2 receptors
Heart (decreasing rate and force of contraction)
Preganglionic cholinergic nerve terminals (inhibiting ACh release)
Brain
Presynaptic on SNS adrenergic neurons
Describe cAMP and its effects on heart
Increases cAMP leads to increased rate and contractility (opposite of smooth muscle)
Decrease in cAMP leads to hyperpolarization by opening K+ channels, and inhibition of Ca2+ channels and other effects leading to decreased heart rate and contractility
Describe M2 receptor function on presynaptic SNS adrenergic neurons
Heteroreceptors on presynaptic sympathetic neurons, causing inhibition of neurotransmitter release
Further decrease in HR by inhibiting NE release
Further bronchoconstriction by inhibiting NE release onto pulmonary smooth muscle
Relax GI and bladder sphincters by inhibiting NE release (parasympathetic nerves only synapse on sympathetic nerve)
Promote vasorelaxation by inhibiting NE release onto vascular smooth muscle (no parasympathetic nerves)
Muscarinic agonists and BPH
Not indicated in BPH and be careful when using post trauma (e.g. postpartum) | painful swelling and pressure may ensue if urinary retention is due to blockage of urethra or ureter
Muscarinic agonists and Sjogren’s syndrome
Anti-m3 muscarinic receptor antibodies are produced and destroy the receptors, leading to eventual destruction of secretory glands
Primary symptoms are dry eyes, severely dry mouth, and anhidrosis
May also include bladder irritability, constipation, fluctuating blood pressure, dilated pupils, and blurred vision.
ACh analogue muscarinic agonists
Acetylcholine, Methacholine, Carbachol, Bethanechol
Duration of action limited by acetylcholinesterase | usefulness limited by poor selectivity for muscarinic versus nicotinic receptors
Acetylcholine
Endogenous neurotransmitter for muscarinic receptors
Rapidly hydrolyzed by AChE (acetylcholinesterase)
Also activates nicotinic receptors which is problematic
Used in the eye to induce miosis, short-term
Bethanechol
Long duration of action, NOT a substrate for AChE
Reduced activity at nicotinic receptors
Poor absorption from GI
Used to increase GI motility and bladder emptying
Plant alkaloids and synthetic muscarinic agonists
NOT substrates for AChE, this long duration of action
Muscarine-poison, Pilocarpine, Cevimeline
Muscarine-poison
Prototype muscarinic agonist derived from poisonous mushrooms
High selectivity for muscarinic receptors over nicotinic receptors
Problematic muscarinic side effects (MUST LIST)
Pilocarpine
High selectivity for muscarinic over nicotinic receptors
Used topically to treat glaucoma
Used as a sialogogue to treat dry mouth
Associated with excessive diaphoresis (sweating)
Cevimeline
M1-selective muscarinic agonist
Approved for Sjogren’s syndrome
No M2 activation so less cardiac effects than other drugs.
Muscarinic antagonists indications/contraindications or problems for eye
Retinal exam requiring mydriasis | rare use in acute glaucoma, alternating with a miotic, to break adhesion between iris and lens
Glaucoma | photophobia | Dry eyes | Blurred vision
Muscarinic antagonists indications/contraindications or problems for Heart
Cardiac stimulation, concurrent with epinephrine in cardiac failure | reflex sinus bradycardia or atrial fibrillation that may follow cardiac catheterization
Tachycardia by blocking parasympathetic basal cardiac tone
Muscarinic antagonists indications/contraindications or problems for Bladder
Incontinence, reduced bladder capacity, and irritable bladder syndrome by reducing bladder contractility
Urinary retention | BPH
Muscarinic antagonists indications/contraindications or problems for glands
Control drooling in children | pre-anesthetic to decrease salivation
Xerostomia | anhidrosis and consequent over-heating
Muscarinic antagonists indications/contraindications or problems for lungs
Chronic obstructive airway diseases (emphysema), chemically-irritated airway constriction and asthma
Increased susceptibility to infection due to decreased respiratory secretions
Muscarinic antagonists indications/contraindications or problems for stomach
Peptic ulcer by blocking stomach acid secretions
Nausea, delayed stomach emptying
Muscarinic antagonists indications/contraindications or problems for GI tract
GI spasms and irritable bowel syndrome by slowing motility
Constipation
Muscarinic antagonists indications/contraindications or problems for Blood vessels
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Muscarinic antagonists indications/contraindications or problems for CNS
Motion sickness by acting on vestibular apparatus | tremors associated with Parkinson’s disease and side effects of anti-psychotics
Hallucinations and drowsiness
Efficacy of muscarinic receptor antagonists
Antagonists have zero efficacy on their own; they only have an effect when blocking an agonist such as an endogenous neurotransmitter
All are competitive antagonists at the muscarinic receptors
Few distinguish among the five muscarinic receptor subtypes
Atropine
Historic uses as a cosmetic and poison (Catherine de Medici’s ring)
Hierarchical effects of atropine based on dose
Used as cardiac stimulant | useful in treating mushroom poisoning | combined with an opioid for diarrhea | useful for treating nerve gas poisoning | long duration of action (will dilate pupil for 7-10 days)
Atropine Hierarchical dosing
- 5 mg (dry mouth, dry skin)
- 0 mg (increased heart rate, thirst)
2 mg (pupillary dilation, blurred vision, tachycardia)
5 mg (reduced peristalsis, urinary retention, hot dry skin, fatigue, flushing)
10 mg (rapid and weak pulse, ataxia, hallucinations, delirium, coma)
Hyoscyamine
Natural product | old drug | marketed before FDA approval was required
Used for irritable bowel syndrome, incontinence, hyperhidrosis, peptic ulcers
Sedating | side effects similar to scopolamine
Scopolamine
Natural derivative of atropine from Datura stramonium “Jimson weed”
Easily crosses BBB
Used for treating motion sickness
Amnesia, sedation, stupor and hallucinations | criminally abused to render victims compliant
Muscarinic antagonists used for obstructive pulmonary disease
Tiotropium, Ipratopium, Aclidinium bromide, Umeclidinium
Poor systemic penetrance - few side effects when inhaled | fewer effects on pulmonary secretions | Tiotropium and umeclidinium have longest duration of action
Dosed once daily
Aclidinium has widest therapeutic index (bronchorelaxation relative to tachycardia) due to rapid hydrolysis in plasma | dosed bid
Muscarinic antagonists for urinary incontinence, urgency and bladder hyper-irritability
Fesoterodine, Tolterodine, Oxybutynin, Trospium, Solifenacin succinate, Darifenacin
Primary side effects are xerostomia, dry eyes and constipation
Tropicamide
Muscarinic receptor antagonist for eye exams
Shorter duration of action than atropine (6 hours)
Useful in eye exams for pupillary dilation and treatment of iritis
Glycopyrrolate
Muscarinic antagonist for decreased salivation
Old drug with no CNS effects
Used as pre-anesthetic agent to control salivation during intubation | recently approved for severe drooling in children associated with neurologic disorders such as cerebral palsy
Fewer effects on heart rate to which children are particularly susceptible
Recently renamed “Glycopyrronium bromide” in an NDA to the FDA as a long acting muscarinic agonist for bronchodilation
Benztropine, Biperiden
Muscarinic antagonist
Used as anti-parkinson’s agent | lots of CNS penetrance
