7-29 Intro to Cholinergic Agonists and Antagonists - slide 39+

Question 1

What happens when you activate an nAChR? (membrane response and molecular response)

Answer 1

Membrane:

Excitation, prejunctional control of ACh release

Molecular:

Increased cation permeability - Na+ and K+

Question 2

What happens when you activate mAChR M1, M3, or M5? (membrane and molecular response)

Answer 2

Membrane:

Excitatory Gq/11

Molecular:

Activation of PLC:

increases IP3, DAG, Ca++, and PKC

Question 3

What happens when you stimulate mAChR 2 and 4?

Answer 3

Membrane:

Inhibitory - Gi/0

Molecular:

Inhibition of adenylyl cyclase => decreased cAMP

Question 4

Why do drugs that stimulate nicotinic ACh receptors have such wide ranging effects?

Answer 4

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.

Question 5

What is the specific physiological effect of a cholinergic agonist on the eye?

Answer 5

Iris sphincter and ciliary mm contraction

Increased aqueous humor outflow into Canal of Schlemm (drains ant. chamber)

Question 6

What is the clinical relevance of a cholinergic agonist on the eye?

Answer 6

Glaucoma (replaced by beta blockers, prostaglandins)

Accommodative eostropia - misalignment of the eyes cause by farsightedness/hypermetropic accommodative error

Question 7

What is the general physiological effect of a cholinergic agonist on the heart? What receptor mediates these effects?

Answer 7

Receptor : M2 mAChR

Effects:

reduction in peripheral vascular resistance

changes in heart rate

Question 8

What is the effect of a minimal dose of an cholinergic agonist on the heart?

Answer 8

Causes vasodilation, resulting in a reduction in blood pressure and often accompanied by a reflex increase in heart rate

(homeostatic/baroreceptor reflex)

Question 9

What is the effect of a larger dose of an cholinergic agonist on the heart?

Answer 9

bradycardia

decrease AV node conduction velocity

hypotension

Question 10

What is the effect of an cholinergic agonist on blood vessels? What kind of receptor does this work through?

Answer 10

receptor: mAChRs on endothelial cells

Causes production and release of EDRF/nitric oxide (NO)

Question 11

In the GI system, what glands are more affected by cholinergic agonists?

Answer 11

Tends to affect salivary and gastric glands more than the pancreas or small intestinal glands

Question 12

Stimulation of what type of receptor is required for direct activation of smooth muscle contraction in the GI/GU system?

Answer 12

M3 mAChR

Question 13

Generally speaking, the SNS will cause relaxation of smooth muscle in the GI/GU systems. Stimulation of what receptor will overcome this?

Answer 13

Adrenergic stimulation of M2 mAChR will reduce cAMP formation and will reduce relaxation from the SNS, resulting in contraction

Question 14

Activation of what 2 receptors will cause muscle contraction in the GI/GU system?

Answer 14

M3 mAChR - excitatory

M2 mAChR - inhibitory

Question 15

What type of receptor causes sphincter relaxation in the GI/GU system?

Answer 15

Sphincter relaxation via NO signalling, mediated by mAChR

Question 16

What cascade of events follows stimulation of M3 mAChRs that results in GI/GU smooth muscle contraction?

Answer 16

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

Question 17

What sequence of events follows M2 mAChR stimulation that results in GI/GU smooth muscle contraction?

Answer 17

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

Question 18

How does stimulation of ß adrenergic receptors induce smooth muscle relaxation in the GI/GU systems?

Answer 18

Activates Gs protein => activates adenylyl cyclase => increases cAMP

cAMP blocks myosin light chain kinase, which does contraction

Question 19

What is the relative abundance of mAChRs in the brain versus the spinal cord?

Answer 19

brain = more mAChRs

spinal cord = mostly nAChRs

Question 20

What actions are associated with excitatory mAChRs in the brain?

Answer 20

increased cognitive function - learning and memory

seizure activity

Question 21

What actions are associated with inhibitory mAChRs in the CNS?

Answer 21

tremors

hypothermia

analgesia

Question 22

What are the consequences of activating nAChRs in the brain?

Answer 22

Dose dependent response to nicotine:

mild alertness < tremor, emesis < convulsions < fatal coma

Question 23

What is the clinical relevance of m & nAChRs in the CNS?

Answer 23

Dementia associated with Alzheimer and Parkinson disease

Question 24

What drugs are derived from the Atropa belladonna/deadly nightshade/Belladonna plant?

Answer 24

Belladonna alkaloids:

cholinergic antagonists including:

atropine

scopolamine

hyoscyamine

Question 25

What is the mechanism of action of atropine? What kind of a drug is it, generally speaking?

Answer 25

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

Question 26

What are the physiological effects of atropine? (note, CV effects in another question)

Answer 26

decreased salivation decreased micturition speed increased heart rate decreased accommodation

Question 27

What are the physiological effects of atropine on the cardiovascular system?

Answer 27

Low dose atropine = initial bradycardia Moderate to high dose atropine = tachycardia, due to blocking of vagal/PNS slowing of heart rate

Question 28

A drug that competitively blocks the action of ACh and similar agonists at nAChRs of both PNS and SNS autonomic ganglia is a...?

Answer 28

Ganglion-blocking drug, little clinical use

Question 29

Which arm of the ANS do ganglion blockers enhance? Why?

Answer 29

PNS tone dominates ANS (except for vascular smooth muscle) Ganglion blockers enhance sympathetic tone

Question 30

With no autonomic outflow, what changes do you expect to see in the CNS?

Answer 30

sedation, tremor, choreiform movements, mental aberrations

Question 31

With no autonomic outflow, what changes do you expect to see in the eye?

Answer 31

cyclopegia, moderate mydriasis

Question 32

With no autonomic outflow, what changes do you expect to see in the CV system?

Answer 32

decreased arterioloar and venomotor tone decreased BP diminished contractility moderate tachycardia

Question 33

With no autonomic outflow, what changes do you expect to see in the GI tract?

Answer 33

reduced secretion profoundly inhibited motility

Question 34

With no autonomic outflow, what changes do you expect to see in the GU system?

Answer 34

urination hesitancy possible urinary retention with prostate hyperplasia impotence