Exam 4 - Lecture 35, Cholinergic Agonists and Cholinesterase Inhibitors

Question 1

Direct Acting drugs

Answer 1

Agonist at muscarinic receptors (M type GPCRs)

Agonist at nicotinic receptors (nAChR ion channels)

Question 2

Indirect acting drugs

Answer 2

Inhibitors of cholinesterase = increase ACh

Question 3

M1, M3,M5

Answer 3

Gaq

Mechanism: IP3, DAG cascade

Question 4

M2 or Cardiac M2

Answer 4

Gai/o

Mechanism: Inhibition of cAMP production, activation of K+ channels

Question 5

M4

Answer 5

Gai/o

Mechanism: Inhibition of cAMP production

Question 6

Nm and Nn ion channels

Answer 6

Mechanism: Na, K depolarizing ion channel

Question 7

Nicotinic acetylcholine receptors

Answer 7

Pentameric channel, conducting Na,K,CA2+

Activation of receptor depolarizes membrane potential, initiating action potentials in neurons and contraction of muscle

Binding 1 ACh molecule results in modest increase in open probability; simultaneous binding gives significant increase in Po

Question 8

Single nAChR channels

Answer 8

Fetal (immature) channels

Mature channels

Question 9

Fetal (immature) channel

Answer 9

consists of 2 X a1 subunits and one each of beta, delta, and gamma-subunits. This channel has low amplitude currents with long open time

Question 10

Mature channels

Answer 10

Gamma subunits are replaced with E-subunits.

Open time decreases but current amplitude increases

Question 11

Whole-cell nAChR channels

Answer 11

some isoforms are pentamer of a7-subunits

activations results in fast, rapidly decaying currents

Question 12

In response to continued activation, nAChR channels will….

Answer 12

Desensitize

Increase in Ca2+ will cause an increase in PKC (phosphorylates proteins that facilitate Desensitization of channels)

Active -> Desensitization -> resting state

Question 13

Example action of activated nAChRs

Answer 13

Ach will bind to receptor, activate channel and they will pass Na and depolarize membrane…leads to EPSP (if large enough) and it will cause action potential and contraction

Question 14

M1, M3, M5 detailed pathway

Answer 14

1. Activates PLCB
2. PLCB metabolizes PIP2 to DAG and IP3
3. DAG activates PKC
4. IP3 activates IP3 receptors on ER
5. NOTE: decrease of PIP2 also has cellular effect (inhibition of M-current

Question 15

M2 and M4 detailed pathway

Answer 15

1. Gai inhibits Adenylate Cyclase -> decrease cAMP
2. Gbg activates GIRK channels, made of Kir3-subunits, increase K+ flux and decrease excitability
3. Gbg inhibits activity of specific Cav channels; decrease Ca2+ flux and decreasing excitability

Question 16

Organophosphates

Answer 16

Irreversible , covalent inhibitors of AChE

most common type of chemical pesticide

Ex. DDT, banned by most countries in 70s and 80s and superseded by parathion

Question 17

Toxicity of direct & indirect cholinomimetic drugs

Answer 17

DUMBBELSS

D- diarrhea, defacation (muscarinic)
U- Urination (M)
M - Miosis (M)
B - Bronchospasm (M)
B - Bradycardia (M)
E - Excitation (N...followed by block)
L - Lacrimation (M)
S - Salivation (M)
S - Sweating (M)

Question 18

Medical use of cholinomimetic agents

Answer 18

Glaucoma
Ileus or Urinary retention
Myasthenia Gravis

Question 19

Glaucoma

Answer 19

often caused by high ocular pressure

Drugs constriction pupil and ciliary muscle, increasing outflow of humor form eye and reducing ocular pressure

Question 20

ILeus (Loss of peristaltic activity) or Urinary Retention

Answer 20

can occur after surgery or neurological injury

Question 21

Myasthenia Gravis

Answer 21

Autoimmune degradation of SM nAChRs, causing weakness treated with cholinesterase inhibitors

Short acting (15 min, used to diagnose)
Long-acting for treatment (4hr, neostigmine...8hr, pyridostigmine)

Question 22

Neostigmine

Answer 22

Used in treatment of Myasthenia graves

Used to treat Ogilvile syndrome

Used to treat envenomation from snake bite, particularly kraits

Question 23

Physostigmine

Answer 23

Reversible cholinesterase inhibitor

Used to treat glaucoma and delayed gastric emptying, mydiasis

Crosses BBB so can be used as antidote for OD with anticholinergics such as Atropine and Belladonna

Can cause death by respiratory arrest and paralysis of cardiac muscle

Question 24

Acetylcholinesterase enzymes

Answer 24

Found in high conc at chemical synapses and neuromuscular junctions

Required to terminate action of ACh

Inhibitors augment the action of ACh so are cholinomimics

Some AChE-inhibitors have medial utility, some are dangerous toxins

Question 25

Action of nicotinic cholinomimetics

Answer 25

Autonomic ganglia:
Both sympathetic and parasympathetic ganglia are activated; downstream action on innervated organs is unpredictable

SM neuromuscular junctions:
Depolarization due to opening of nAChR channels, causes muscle contraction. Maintained stimulation desensitizes nAChRs, leading to paralysis

Question 26

Action of muscarinic cholinomimetics on eye

Answer 26

contract pupillary constrictor and ciliary muscle; the pupil is biotic and focus is on near vision

Question 27

Action of muscarinic cholinomimetics on airway

Answer 27

contracts smooth muscle of airway, causing wheeing

Question 28

Action of muscarinic cholinomimetics on blood vessels

Answer 28

smooth muscle in most vessels has few cholinoreceptors; endothelium has M-receptors

if activated, endothelial cells produce NO, it diffuses into adjoining smooth muscle causing relaxation, BP falls and baroreceptors maybe evoked

Question 29

Action of muscarinic cholinomimetics on heart

Answer 29

Activation of vagal nerve causes bradycardia and slowed A-V conduction

Indirect cholinomimetics amplify effects of endogenous ACh

Direct cholinomimetics cause sufficient hypotension to evoke tachycardia

Question 30

Action of muscarinic cholinomimetics on exocrine gland

Answer 30

Lacrimal, salivary and thermoregulatory (eccrine) sweat glands stimulated

Question 31

Action of muscarinic cholinomimetics on GI and GU tract

Answer 31

smooth muscle contracts and motility increases, sphincters relaxed

Question 32

Recycling of GPCRs

Answer 32

Continued activation of GPCR can lead to B arresting binding which causes desensitization or internalization. It can be recycled back into membrane or it can be degraded

Question 33

Vagal regulation of the sinoatrial node

Answer 33

M2 receptors, coupled to Gai are activated when ACh is released by vagus nerve (parasympathetic)

Gbg is released and activates Kir3.1/3.4 (GIRK1/4) channels, hyper polarizing the membrane potential

Inhibition of adenylate cyclase reduces generation of cAMP -> decrease PKA -< decrease voltage gated Ca2+ current -> contraction

Decreased activation of HCN channels (funny current channels)

** Note: Activation of B-receptors -> Gas increases AC activity -> increase cAMP

Question 34

Gai and Gas often in complex together

Answer 34

Adenylate cyclase is in complex, trying to make cAMP with it being up and down regulated by Gai and Gas

Cholinergic (sympathetic)
M2 and M4 receptors are Gai coupled

Adrenergic (parasympathetic)
a2 adrenoceptors are Gai coupled
B1-3 adrenoceptors are Gas coupled

** M1, M3, M5, and a1 not couple to either Gai or Gas but to are coupled to Gaq **