7-29 Intro to Cholinergic Agonists and Antagonists - slide 39+ Flashcards
What happens when you activate an nAChR? (membrane response and molecular response)
Membrane:
Excitation, prejunctional control of ACh release
Molecular:
Increased cation permeability - Na+ and K+
What happens when you activate mAChR M1, M3, or M5? (membrane and molecular response)
Membrane:
Excitatory Gq/11
Molecular:
Activation of PLC:
increases IP3, DAG, Ca++, and PKC
What happens when you stimulate mAChR 2 and 4?
Membrane:
Inhibitory - Gi/0
Molecular:
Inhibition of adenylyl cyclase => decreased cAMP
Why do drugs that stimulate nicotinic ACh receptors have such wide ranging effects?
N AChR are located throughout ANS
- all postganglionic PNS and SNS neurons have these receptors
- all preganglionic ANS neurons release ACh
Drugs that stimulate these receptors on postganglionic neurons will affect tissues innervated, obv.
What is the specific physiological effect of a cholinergic agonist on the eye?
Iris sphincter and ciliary mm contraction
Increased aqueous humor outflow into Canal of Schlemm (drains ant. chamber)
What is the clinical relevance of a cholinergic agonist on the eye?
Glaucoma (replaced by beta blockers, prostaglandins)
Accommodative eostropia - misalignment of the eyes cause by farsightedness/hypermetropic accommodative error
What is the general physiological effect of a cholinergic agonist on the heart? What receptor mediates these effects?
Receptor : M2 mAChR
Effects:
reduction in peripheral vascular resistance
changes in heart rate
What is the effect of a minimal dose of an cholinergic agonist on the heart?
Causes vasodilation, resulting in a reduction in blood pressure and often accompanied by a reflex increase in heart rate
(homeostatic/baroreceptor reflex)
What is the effect of a larger dose of an cholinergic agonist on the heart?
bradycardia
decrease AV node conduction velocity
hypotension
What is the effect of an cholinergic agonist on blood vessels? What kind of receptor does this work through?
receptor: mAChRs on endothelial cells
Causes production and release of EDRF/nitric oxide (NO)
In the GI system, what glands are more affected by cholinergic agonists?
Tends to affect salivary and gastric glands more than the pancreas or small intestinal glands
Stimulation of what type of receptor is required for direct activation of smooth muscle contraction in the GI/GU system?
M3 mAChR
Generally speaking, the SNS will cause relaxation of smooth muscle in the GI/GU systems. Stimulation of what receptor will overcome this?
Adrenergic stimulation of M2 mAChR will reduce cAMP formation and will reduce relaxation from the SNS, resulting in contraction
Activation of what 2 receptors will cause muscle contraction in the GI/GU system?
M3 mAChR - excitatory
M2 mAChR - inhibitory
What type of receptor causes sphincter relaxation in the GI/GU system?
Sphincter relaxation via NO signalling, mediated by mAChR
What cascade of events follows stimulation of M3 mAChRs that results in GI/GU smooth muscle contraction?
M3 stimulated => Gq/11 stimulation => increased PLC
Increased PLC => increased IP3 & DAG =>
increased Ca++
Increased Ca++ binds calmodulin
Calmodulin stimulates myosin light chain kinase, leads to contraction
What sequence of events follows M2 mAChR stimulation that results in GI/GU smooth muscle contraction?
M2 is an indirect action
stimulating M2 => stimulates Gi/0 ==> blocks adenylyl cyclase
(adenylyl cyclase normally produces cAMP, which in turn blocks actions of myosin light chain kinase)
Unblocked myosin light chain kinase = muscle contraction
How does stimulation of ß adrenergic receptors induce smooth muscle relaxation in the GI/GU systems?
Activates Gs protein => activates adenylyl cyclase => increases cAMP
cAMP blocks myosin light chain kinase, which does contraction
What is the relative abundance of mAChRs in the brain versus the spinal cord?
brain = more mAChRs
spinal cord = mostly nAChRs
What actions are associated with excitatory mAChRs in the brain?
increased cognitive function - learning and memory
seizure activity
What actions are associated with inhibitory mAChRs in the CNS?
tremors
hypothermia
analgesia
What are the consequences of activating nAChRs in the brain?
Dose dependent response to nicotine:
mild alertness < tremor, emesis < convulsions < fatal coma
What is the clinical relevance of m & nAChRs in the CNS?
Dementia associated with Alzheimer and Parkinson disease
What drugs are derived from the Atropa belladonna/deadly nightshade/Belladonna plant?
Belladonna alkaloids:
cholinergic antagonists including:
atropine
scopolamine
hyoscyamine
What is the mechanism of action of atropine? What kind of a drug is it, generally speaking?
Cholinergic antagonist/antimuscarinic compound
Reversible antagonist of all 5 mAChRs - not selective, like other antimuscarinics
Salivary, bronchial, and sweat glands most sensitive
Gastric parietal cell acid secretion least sensitive
What are the physiological effects of atropine? (note, CV effects in another question)
decreased salivation
decreased micturition speed
increased heart rate
decreased accommodation
What are the physiological effects of atropine on the cardiovascular system?
Low dose atropine = initial bradycardia
Moderate to high dose atropine = tachycardia, due to blocking of vagal/PNS slowing of heart rate
A drug that competitively blocks the action of ACh and similar agonists at nAChRs of both PNS and SNS autonomic ganglia is a…?
Ganglion-blocking drug, little clinical use
Which arm of the ANS do ganglion blockers enhance? Why?
PNS tone dominates ANS (except for vascular smooth muscle)
Ganglion blockers enhance sympathetic tone
With no autonomic outflow, what changes do you expect to see in the CNS?
sedation, tremor, choreiform movements, mental aberrations
With no autonomic outflow, what changes do you expect to see in the eye?
cyclopegia, moderate mydriasis
With no autonomic outflow, what changes do you expect to see in the CV system?
decreased arterioloar and venomotor tone
decreased BP
diminished contractility
moderate tachycardia
With no autonomic outflow, what changes do you expect to see in the GI tract?
reduced secretion
profoundly inhibited motility
With no autonomic outflow, what changes do you expect to see in the GU system?
urination hesitancy
possible urinary retention with prostate hyperplasia
impotence
