Pharm 2013.09.05 Cholinergic 2

Question 1

What is the difference between muscarinic and nicotinic receptors in terms of overstimulation?

Answer 1

• Muscarinic overstimulation leads to more effect

* Nicotinic overstimulation leads to reduced effect

Question 2

What are the ACh NON-SPECIFIC drugs?

Answer 2

ACh

Carbachol

Question 3

What are the Muscarinic agonists?

Answer 3

Methacoline
Bethanechol
Pilocarpine

Question 4

What are the Nicotinic agonists?

Answer 4

Nicotine

Varenicline (Chantix)

Question 5

What are the categories of Indirect cholinergics?

Answer 5

Cholinesterase inhibitors (short, medium, and long acting)
Presynaptic release stimulator of ACh (metoclopramide)

Question 6

What are the short acting Cholinergics?

Answer 6

Edrophonium

Question 7

What are the intermediate acting cholinergics?

Answer 7

Neostigmine

Physostigmine

Question 8

What are the long acting cholinergics?

Answer 8

Echothiophate
Parathion
Malathion
Sarin
Soman

Question 9

What is the presynaptic ACh releasing drug?

Answer 9

Metoclopramide

Question 10

Where are the muscarinic receptors?

Where are the nicotinic recptors?

Answer 10

Musc: Brain, CNS, all of para effector sites ie post ganglionic targets (visceral), sweat glands (sympa), endothelium (non-innervated tissue)

Nicotinic: Brain, CNS, all sympa ganglia, adrenal medulla, skeletal muscles

Question 11

What would happen if we gave I.V. ACh?

Answer 11

1) CNS, but actually penetrates the blood-brain-barrier (BBB) poorly
2) Skeletal muscle mediated at the MNJ
3) Parasympathetic nervous system from two sites:
* Parasympathetic ganglia
* Postganglionic termini
4) Sympathetic nervous system from two sites:
* Sympathetic ganglia including the adrenal gland
* Postganglionic sympathetic-cholinergic fibers
5) Vascular endothelial cells (noninnervated receptors)

Question 12

What is the hierarchy of accessibility from blood of I.V. ACh?

Answer 12

The hierarchy of accessibility from blood:
Endothelial cell 
Para & sympathetic effector tissues
NMJ
Ganglia
(CNS)  

Note: ACh is rapidly cleared from blood
Plasma psuedocholinesterase
Further limits access to less perfused site, so really just the first two need to be considered.

Question 13

What is Cholinergic Sydrome?

What are the two mneumonics?

Answer 13

1) DUMBBELSS

2) SLUDGE

Question 14

What is SLUDGE in cholinergic syndrome?

Note: this is a combination of muscarinic and nicotinic activation.

Answer 14

Salivation, Lacrimation, Urination, Defication, GI upset, Emesis

Lacrimation is detrusor muscle
Defication is anal sphincter

Question 15

What is DUMBBELSS in Cholinergic Syndrome?

Note: this is due to muscarinic activation.

Answer 15

Diarrhea (increased gut motility)
Urination (contraction of the detrusor muscle)
Miosis (contraction of sphincter muscle of the iris)
Bronchorrhea (increased secretions) Bronchoconstriction (wheezing)
Bradycardia (as above)
Emesis (increased and uncoordinated stomach and GI tone)
Lacrimation (tearing)
Salivation
Sweating (sympathetic-cholinergic)

Question 16

What causes hypotension of endothelial cells from muscarinic stimulation?

Answer 16

• Activation of noninnervated M3/M5 on endothelial cells
• Rapid activation of endothelial nitric oxide (NO) synthase (eNOS) (arginine → citrulline and NO)
• NO diffuses into vascular smooth muscle cells (vSMCs)
• NO stimulates guanylate cyclase (GTP → cGMP)
• cGMP binds to myosin light chains to relax vSMCs → vasodilation → reduced BP
• Clinical note: nitroglycerin releases NO to reduce vascular resistance
• Clinical note: sildenafil (Viagra™) blocks cGMP degradation, potentates NO vasodilation
• Nomenclature note: NO previously referred to as endothelial derived relaxing factor (EDRF)

Question 17

What are the HR effects of muscarinic stimulation?

Answer 17

Eventhough there is hypotension, there is bradycardia due to the muscarinic receptors on the SA node

Question 18

Why are Muscarine and ACh not good therapeutic agents?

Answer 18

Side effects
Don’t arrive at effectors in organized fashion
AChEsterase

Question 19

What are the three types of AChE?

Answer 19

True AChE at the cholinergic junctions
Pseudo ACheE in the blood plasma
RBC AChE

Note: there are rare genetic disorders without pseudo AChE

Question 20

What are the modified Muscarine ACh Agonists?

Answer 20

Methacholine
Bethanechol
Pilocarpine

Question 21

What is Methacholine?

What is it used for?

Answer 21

Poorly absorbed, but used in the Dx of Bronchial Hyperreactivity (asthma)
Hyperreactive airways always respond with bronchoconstriction to lower concentrations of Methacholine

Question 22

What is Bethanechol?

What is it used for?

Answer 22

Relieves GI dysmotility syndromes, such as postsurgical ileus

Question 23

What has replaced Bethanechol?

What receptors does this replacment stimulate?

Answer 23

Largely replaced by metoclopramide which stimulates presynaptic D2 receptors that trigger the release of ACh

Question 24

What is Pilocarpine?

Answer 24

Used in Glaucoma
See the additional “Self-Study” lecture
Note: this is a plant alkaloid

Question 25

What are the two basic flavors of Nicotinic receptors?

Answer 25

Nn for nerves | Nm for muscles at NMJ

Question 26

Where are Nn Nicotinic receptors found?

Answer 26

Post synaptic, on efferents to soma of postganglionic neurons Also in the CNS

Question 27

What is the receptor mechanism of Nicotinic receptors?

Answer 27

Ligand gated Na+/K+ channels When pore is open, Na+ goes into cell, K+ comes out More Na+ goes in than K+ comes out, net +ve charge in → membrane depolarizes Depolarization triggers action potential

Question 28

What is the mechanism of Nicotine addiction?

Answer 28

Nicotinic receptors in NUCLEUS ACCUMBENS and PREFRONTAL CORTEX Stimulation of these receptors elevates MESOLIMBIC DOPAMINE When dopamine falls cravings develop

Question 29

Note: toddlers can overdose on nicotine gum and patches

Answer 29

…

Question 30

What are the effects of Nicotine receptor overactivation?

Answer 30

1) ACh interaction with nicotinic receptors is very different from competitive-reversible actions on muscarinic receptors 2) Initial activation → subsequent deactivation 3) Initial depolarization leads to muscle fasciculations 4) Prolonged receptor occupancy with ACh leads to receptor phosphorylation and inactivation (termed: depolarization-desensitization blockade) 5) Result is a paradoxical flaccid paralysis which cannot be practically reversed; have to wait until agonist is cleared 6) Most critical concern is skeletal muscle/diagphram

Question 31

What are the initial mechanisms of nicotine poisoning?

Answer 31

Initially, stimulation of parasympathetic/sympathetic ganglia and adrenals, then depolarization-desensitization blockade

Question 32

What are the major signs of nicotine poisoning?

Answer 32

``` tachycardial hypertension nausea/vomitting/diarrhea/salivation urinary incontinence cold sweat syncopy, collapse, unconsciousness flaccid paralysis (may need respiratory support) ```

Question 33

``` Varenicline (Chantix) The whole shabang Drug Class? Pharmacodynamics? Pharmacokinetics? Toxicity? Interactions? Special Considerations? Indications and Dose/route? Monitor? ```

Answer 33

Drug class: Very selective and potent competative partial agonist of a2-b4 nicotinic receptors, for smoking cessation Pharmacodynamics: CNS mesolimbic dopamine, partial a4-b2 stimulation prevents low dopamine and cravings; also prevents nicotine from creating dopamine surges, No chemical reward Pharmacokinetics: well absorbed; peak 4 h, t1/2 = 24 h; excreted primarily in urine as unchanged drug Toxicity: N/A Interactions: No direct interactions identified Special considerations: Reports of suicidal thoughts and aggressive and erratic behavior → patients and caregivers should be instructed about the importance of monitoring for neuropsychiatric symptoms, and to communicate immediately with the prescriber the emergence of agitation, depression, unusual changes in behavior, or suicidality. Psychiatric patients – use extreme caution. Contraindicated in pregnancy/lactation. Causes drowsiness, caution operating machinery Indications and dose/route: 1 mg PO BID for healthy adults, 0.5 mg PO BID for renal impairment CrCl < 50 ml/min Monitor: neuropsychiatric symptoms

Question 34

Varenicline | What is the drug class?

Answer 34

Very selective and potent competative partial agonist of a2-b4 nicotinic receptors, for smoking cessation

Question 35

Varenicline | What are the pharmacodynamics?

Answer 35

CNS mesolimbic dopamine, partial a4-b2 stimulation prevents low dopamine and cravings; also prevents nicotine from creating dopamine surges, No chemical reward

Question 36

``` Varenicline Pharmacokinetics How absorbable? What is peak time? What is half life? How is the drug removed from the body? ```

Answer 36

well absorbed peak 4 h t1/2 = 24 h excreted primarily in urine as unchanged drug

Question 37

Varenicline What is the toxicity? What are the interactions with other drugs?

Answer 37

Toxicity: N/A Interactions: No direct interactions identified

Question 38

Varenicline What are special considerations? What are side effects?

Answer 38

Reports of suicidal thoughts and aggressive and erratic behavior Psychiatric patients – use extreme caution. Contraindicated in pregnancy/lactation. Causes drowsiness, caution operating machinery

Question 39

Varenicline | What are indications and dose/route?

Answer 39

1 mg PO BID for healthy adults | 0.5 mg PO BID for renal impairment CrCl < 50 ml/min

Question 40

Varenicline | What needs to be monitored?

Answer 40

neuropsychiatric symptoms | DO NOT GIVE TO A PATIENT LIVING ALONE

Question 41

What are the general considerations of AChE inhibitors?

Answer 41

Short, Intermediate, and Long acting Affect both muscarinic and nicotinic Only affect synapses when ACh is released Effects True (synaptic) AChE, Plasma AChE, and RBC AChE

Question 42

What is the hierarchy of effects of the three types of AChE?

Answer 42

Plasma AChE is affected first and neutralizes some of the inhibitors in order to protect neural AChE Note: can test for plasma and RBC AChE levels if suspecting an AChE Inhibitor poisoning

Question 43

What are the effects of AChE inhibitor poisoning?

Answer 43

Major hazard is respiratory inundation * Paralysis of intercostal muscles & diaphragm (nicotinic depolarization desensitization blockade) * increased bronchial secretions & bronchoconstriction (muscarinic) * Central respiratory arrest * Respiratory support is essential

Question 44

What is the AChE mechanism?

Answer 44

1) Anionic site binds quaternary ammonium cation 2) Esteric site is catalytic, hydrolyzes ACh ester bond * * Ester Bonding to acetyl group → liberate choline * * Rapid hydrolysis releases acetate 3) Enzyme ready for next ACh

Question 45

What are the short acting Cholinergics?

Answer 45

Edrophonium

Question 46

``` Edrophonium What is it? What is mechanism? Does it cross the BBB? What is the dose? How long are the effects? What is it used for in Dx? ```

Answer 46

1) Short acting AChE are competitive inhibitors, do NOT form ester bond to AChE (temporarily blocks ACh from AChE) 2) Highly charged, does not cross BBB 3) Given I.V. (onset 1 min) or I.M. (onset 2 – 10 min) 4) Extremely short lived effects (5-10 min IV; 5-30 min IM) 5) Dx of myasthenia gravis (90-95% accuracy)

Question 47

What is Myasthenia Gravis?

Answer 47

1) Autoimmune disease 2) Antibodies against a thymocyte epitope cross react with NMJ 3) Attack and distruction of motor end plates, over months/years, causing impairment of neurotransmission 4) Patients complain of muscle weakness and rapid muscle fatigue 5) By transiently inhibiting ChE, edrophonium makes more ACh available in the synapse to restore transmission 6) Patients note rapid increase in muscle strength

Question 48

What are the intermediate acting cholinergics aka Carbamates?

Answer 48

Neostigmine | Physostigmine

Question 49

What is the mechanism of the Carbamates?

Answer 49

1) Bind anionic and esteric sites 2) AChE forms an ester bond to the carbamoyl group 3) This bond hydrolyzes slowly, over hours 4) Effects last much longer than those of edrophonium

Question 50

What are the Carbamates used for?

Answer 50

Insecticide Tx for Myasthenia gravis Tx to Reverse the paralytic effects of nondepolarizing blockers of the NMJ (Nicotinic antagonists – NOT nicotinic agonists) (See Lecture C-5)

Question 51

Physostigmine Does it cross the BBB? Is it used to Tx Myasthenia gravis? What is it used for?

Answer 51

1) Uncharged and lipid soluble so it DOES cross the BBB * * Note: ChE inhibitors in the CNS have dangerous effects 2) Not useful in myastenia gravis (strictly a peripheral disease) 3) Occasionally used to treat CNS signs of muscarinic blockers (See Lecture C-5)

Question 52

``` Neostigmine Does it cross the BBB? Is it used to Tx Myasthenia gravis? What is the delicate nature of Tx? What other drug can monitor Tx? ```

Answer 52

1) Designed with quaternary ammonium group to keep it out of the CNS 2) Just peripheral effects so useful for myasthenia gravis 3) Treatment is an exercise in brinksmanship * * Too little drug is inadequate to restore transmission → myasthenic crisis (respiratory paralysis, flacid paralysis) * * Too much results in depolarization-desensitization blockade → cholinergic crisis (respiratory paralysis, flacid paralysis) 4) IV edrophonium can distinguish between the two states

Question 53

Compare Physostigmine and Neostigmine in terms of the BBB and Myasthenia gravis.

Answer 53

Physostigmine DOES cross the BBB and DOES NOT treat Myasthenia gravis Neostigmine DOES NOT cross the BBB and DOES treat Myasthenia gravis

Question 54

What are the long acting cholinergics aka Organophosphates?

Answer 54

``` Echothiophate Parathion Malathion Sarin Soman ```

Question 55

What are the general mechanisms of the long acting cholinergics aka organophosphates?

Answer 55

1) Over 50,000 organophoshpate AChE inhibitors 2) Covalently bond the esteric site → phosphorylated enzyme 3) Bond may require hundreds of hours to hydrolyze 4) Some of the agents split off an alkyl group at which point the phosphorylation is essentially irreversible (aging)

Question 56

1) Drugs, Echothiophate * * Once used to treat narrow angle glaucoma * * Largely replaced by other types of agents 2) Insecticides: * * A frequent source of poisoning * * Parathion, extremely toxic insecticide, poorly metabolized * * Malathion, “mammal friendly” insecticide 3) Nerve gas, weapons of mass destruction * * Sarin * * Soman

Answer 56

…

Question 57

What is the antidote to organophosphate poisoning?

Answer 57

Pralidoxime 2-PAM

Question 58

What does Pralidoximne 2-PAM do? When is it effective? When is it contraindicated?

Answer 58

1) Can reactivate phosphorylated enzymes if given soon enough (within a few h) 2) Most effective if “aging” has not occurred 3) Rescues muscular function 4) Contraindicated in poisoning by carbamate ChE inhibitors (makes worse due to competitive inhibition of AChE)

Question 59

What are other Tx for organophosphate poisoning?

Answer 59

Manage DUMBBELSS/SLUDGE with muscurinic blockers (e.g. atropine) Aggressive respiratory support

Question 60

.

Answer 60

Receptor Nonspecific ACh (topical for glaucoma) Carbachol (topical for glaucoma) Muscarinic agonists (DUMBBELSS) Methacholine (Inhalation for Dx of asthma, clinical research) Bethanechol (Oral for neurogenic illeus) Pilocarpine (topical for glaucoma) Nicotinic agonists Nicotine (oral/patch for smoking cessation) But can lead to depolarization desensitization blockade Varenicline (Chantix™) (oral for smoking cessation)

Question 61

.

Answer 61

Cholinesterase inhibitors Short acting (Competitive inhibitors) Edrophonium (IV/IM for Dx of myasthenia gravis) Intermediate acting (Carbamates) Physostigmine (IV, Rx for CNS side effects of muscurinic antagonist) Neostigmine (PO, Rx for myasthenia gravis) Long acting (Organophosphates) Echothiophate (topical for glaucoma) Parathion, extremely toxic insecticide Malathion, “mammal friendly” insecticide Sarin – nerve gas (hopefully not common) Soman – nerve gas (hopefully not common) Presynaptic Metoclopramide (PO/IV/IM, Rx neurogenic illeus, nausea) Binds presynaptic D2 receptors to stimulate ACh release Has largely replaced bethanecol