Y2S1B1 - Pharm - Cholinergic Drugs

Front 1

What are the 3 categories of cholinergic agonists?

Back 1

Choline esters
New M3 specific agonists
Natural alkaloids

Front 2

What is an example of a choline ester?

Back 2

Bethanechol

Front 3

What is an example of an M3 specific agonist?

Back 3

Cevimeline

Front 4

What is an example of a natural alkaloid?

Back 4

Pilocarpine

Front 5

Why isn't Ach used clinically?

Back 5

As soon as you ingest it, it gets broken down?

Front 6

What is the main difference between Ach and metacholine?

Back 6

Metacholine has more muscarinic effects than nicotinic effects. (also a little less hydrolyzed by acetylcholinesterase)

Front 7

Carbachol is used in treatment of what, seldomly?

Back 7

Glaucoma

Front 8

Bethanechol is used in treatment of what?

Back 8

Bladder and GI hypotonia

Front 9

Pilocarpine is used in treatment of what?

Back 9

Glaucoma

Front 10

Cevimeline is used in treatment of what?

Back 10

dry mouth in patients with Sjogren's Syndrome

Front 11

Bethanechol

1. Clinical Uses
2. MOA

Back 11

1. Clinical Uses:
Disorders associated with decreased parasympathetic tone
- Postoperative (d/t anesthetics) & postpartum urinary retention and/or inadequate emptying of the bladder
- Postoperative abdominal distension or GI tract atony or paresis

2. MOA:
Acts at the muscarinic receptors
- To contract detrusor muscle of urinary bladder, usually enough to initiate micturition
- To increase GI motility

Front 12

Pilocarpine

1. Clinical Uses
2. MOA

Back 12

1. Clinical Uses:

Clinical Uses:
Topical formulations are used
- To reduce intraocular pressure (IOP) in certain types of Glaucoma (Better tolerated than AChE inhibitors)
- To treat dry mouth (xerostomia)
- To reverse the effects of atropine, which is commonly used for dilation of the pupil during eye exams

MOA:
- Reduces IOP by improving drainage. Contracts the sphincter pupillae (M3 receptors) and reduces angle block (mydriasis can cause angle block)
*Warning! It is a tertiary amine and can cross the conjunctiva leading to systemic effects*
- Xerostomia: Acts at the M3 receptors on the salivary gland to increase secretion

Front 13

Cevimeline

1. Clinical Uses
2. MOA

Back 13

Cevimeline

1. Clinical Uses:
- Treatment of Xerostomia following head & neck irradiation
- Xerostomia associated with Sjogren’s syndrome
- Enhances lacrimal secretions in Sjogren’s syndrome

*Sjogren's syndrome destroys lacrimal and salivary glands

2. MOA:
- Newer M3 receptor specific agonist
- More selective, potent action at the salivary glands & lacrimal glands

*Fewer side effects than pilocarpine

Front 14

What are some side effects of muscarinic agonists (aka cholinergic agonists)?

Back 14

- Diarrhea
- Diaphoresis
- Miosis
- Nausea
- Salivation
- Urinary urgency

*With drugs that cross the BBB (ex: pilocarpine) you may see CNS disturbances

Front 15

Why is asthma a contraindication for muscarinic agonists?

Back 15

Muscarinic agonists can cause bronchoconstriction and increase mucous secretion

Front 16

Why is heart disease a contraindication for muscarinic agonists?

Back 16

Slowing conduction of cardiac action potential through AV node may precipitate arrhythmias.
IV drugs can also cause hypotension & reduce coronary blood flow. The hypotension can then trigger reflex increase in sympathetic activity to the heart leading to arrhythmia.

decrease HR, decrease SV, decrease CO, decrease BP

Front 17

What inhibits transport of choline in the neuron?

Back 17

Hemicholinium

Front 18

What toxin blocks release of Ach from the neuron?

Back 18

Botulinum Toxin

Front 19

What toxin CAUSES release of Ach from the neuron?

Back 19

Spider venom

Front 20

What are 2 examples of pseudo cholinesterases?

Back 20

Plasma cholinesterase
Butyryl cholinesterase

Front 21

What are potential sites of action for Ach esterase inhibitors?

Back 21

- At all effector organs innervated by parasympathetic system such Eye, GI, urinary bladder
- Neuromuscular junction (NMJ)
- All autonomic ganglia

Front 22

What is a short (~10 min), reversible AChE inhibitor?

Back 22

Edrophonium

Front 23

What are some intermediate, reversible AChE inhibitors?

Back 23

- Physostigmine
- Neostigmine
- Pyridostigmine
- Rivastigmine
- Galantamine
- Ambenonium
- Donepezil
- Tacrine

Front 24

What are some synthetic organophosphate, irreversible (long) AChE inhibitors?

Back 24

- Ecothiophate
- Isofluorophate

Front 25

What are some nerve gas, irreversible (long) AChE inhibitors?

Back 25

- Sarin
- Soman

Front 26

What AChE inhibitors are used for myasthenia gravis?

Back 26

- Edrophonium (diagnostic test only)
- Neostigmine
- Pyridostigmine
- Ambenonium

Front 27

What AChE inhibitor is used for hypotonia of bladder and GI?

Back 27

Physostigmine

Front 28

What AChE inhibitors are used for Glaucoma?

Back 28

- Physostigmine
- Ecothiophate

Front 29

What AChE inhibitors are used for Alzheimers?

Back 29

- Donepezil
- Rivastigmine
- Tacrine
- Galantamine

*All these drugs cross the BBB to increase cholinergic effects in the brain!

Front 30

Neostigmine

1. Clinical Uses
2. MOA
3. Adverse effects

Back 30

1. Clinical Uses:
- Effect at NMJ is greater than that of physostigmine, hence used in myasthenia gravis

2. Synthetic compound that cannot enter the brain

3. Adverse effects:
- Effects of generalized cholinergic stimulation and drop in blood pressure (usually not a problem)
- Overdose can cause cholinergic crisis & muscle paralysis (too much ACh, desensitizes it -> flaccid paralysis)

Front 31

Physostigmine

1. Clinical Uses
2. MOA
3. Adverse effects

Back 31

1. Clinical Uses:
- Antidote for overdoses of atropine & other anticholinergic drugs. Especially useful in reversing the CNS side effects
- Reduces intraocular pressure in Glaucoma. Similar mechanism as pilocarpine

2. MOA:
- Plant alkaloid & tertiary amine that CAN cross the BBB
- Potentiates Ach effects at Muscarinic & Nicotinic receptors of the ANS and also nicotinic receptors at the NMJ

3. Adverse effects:

- Diarrhea, nausea, sweating, miosis, urinary urgency
- At high doses physostigmine can cause convulsions , bradycardia & hypotension

Front 32

a) How might someone get organophosphate poisoning?

b) What symptoms does it cause?

c) MOA?

Back 32

a) Many insecticides and pesticides contain cmpds that are long acting AChE inhibitors. Accidental or intentional poisoning gives rise to a slew of symptoms that involve activation of muscarinic & nicotinic receptors. Also from nerve gases!

b) First 4 symptoms:
S: SALIVATION
L: LACRIMATION
U:URINATION
D: DEFECATION
*Also increased are GI motility, emesis/vomiting, miosis

c) These compounds phosphorylate AchE thereby inactivating the enzyme.
The organophosphate- enzyme complex undergoes an “aging” process which inactivates AChE permanently. Depending on the agent it can take 2 min or hrs.

Front 33

How is organophosphate poisoning treated prophylactically?

Back 33

Pyridostigmine (during chemical warfare)

Front 34

How is organophosphate poisoning treated post-exposure?

Back 34

High doses of muscarinic antagonist atropine or Scopolamine followed by an injection of Pralidoxime can reverse the effects of poisoning

*Pralidoxime reactivates acetylcholinesterase. However, pralidoxime therapy is ineffective once “aging” has occurred

Front 35

What are 2 subcategories of muscarinic receptor antagonists?

Back 35

Belladona Alkaloids
Synthetic & Semi-synthetic Derivatives

Front 36

What are examples of Belladona alkaloids?

Back 36

Atropine
Scopolamine

Front 37

What are some commonly used examples of synthetic and semi-synthetic derivatives (muscarinic receptor antagonists)?

Back 37

Ipratropium
TiotropiumI
Tolterodine

Front 38

Atropine

1. Clinical Uses.
2. MOA
3. Side Effects

Back 38

1. Clinical Uses:
- Reversal of severe bradycardia
- To produce mydriasis and cycloplegia ( loss of accomodation) for examination of the eye
- Antispasmodic
- To suppress respiratory secretions prior to surgery
- To treat organophosphate (AChE inhibitors) insecticide poisoning
- To treat mushroom poisoning

2. MOA:
- Belladonna alkaloid, it is a tertiary amine & can cross the BBB ( but not at therapeutic doses)
- Non selective muscarinic antagonist
- Eye- Blocks all parasympathetic effects on the eye & causes mydriasis (dilation of pupil), Cycloplegia (loss of accomodation)
- GI- Reduces GI motility
- Reduces salivary, sweat & lacrimal secretions

3. Side Effects:
- Dry mouth
- Constipation
- Dilated pupils (Mydriasis)
- Blurred vision due to cycloplegia
- Hot, dry flushed skin
- Tachycardia
- Fever
- CNS disturbances

Front 39

Scopolamine

1. Clinical Uses
2. MOA
3. Side Effects

Back 39

1. Clinical Uses
- Prophylactic for motion sickness (~ 4 hrs before travel)
- Adjunct drug in anesthesia to produce sedation & amnesia
- Opthalmic use

2. MOA:
- Scopolamine crosses BBB much more than atropine at clinical doses

3. Side effects:
Similar to side effects seen with Atropine except that CNS effects are more prominent Eg: Drowsiness, amnesia, fatigue, loss of REM sleep

Front 40

Ipratropium Bromide

1. Clinical Uses
2. MOA
3. Side Effects

Back 40

1. Clinical Uses:
- Used in asthma & Chronic obstructive pulmonary disorder (COPD) to cause bronchodilation as an adjunct to albuterol
- It is also be used alone as an alternative to albuterol in patients who are unable to take adrenergic agonists

2. MOA:
- Blocks muscarinic receptors and reduces bronchoconstriction mediated by parasympathetic activity
- Minimal inhibitory effect on mucociliary clearance when compared to atropine

3. Side Effects:
- Less CNS effects

Front 41

At very low doses, what is unique about atropine?

Back 41

It causes slight cardiac slowing, because every nerve terminal regulates its own release. The M2 presynaptic reduces release of ACh.
(M1 increases, M2 decreases ACh release)

Front 42

Tiotropium Bromide

Back 42

- Clinical uses: COPD and Asthma
- Much more selective action at the bronchioles
- Greater affinity for M3 vs M2

Front 43

Tolterodine

1. Clinical Uses
2. MOA

Back 43

1. Clinical Uses:
Treatment of overactive bladder
- Reduce the number of incontinent episodes
- Increase the amount of urine, the bladder can hold
- Reduce frequency of urination
- Decrease urgency

2. MOA:
- Blocks M3 receptors on detrusor muscle reducing parasympathetic mediated contraction of the bladder & helps diminish urge incontinence during the initial stages of filling
- Also blocks parasympathetic tone to the sphincter and prevents leaks

Front 44

What is a contraindication to M3 antagonists?

Back 44

Slows Voiding: Not appropriate in individuals with urinary retention (eg Benign prostatic Hyperplasia (BPH)

Front 45

What makes tolterodine different from the other M3 antagonists (Fesoterodine,
Solifenacin,
Darifenacin, Oxybutynin)?

Back 45

The others don't favor M3 much more than M2

Front 46

What are some contraindications to muscarinic antagonists?

Back 46

- Glaucoma (b/c of mydriasis)
- Benign prostatic Hyperplasia (BPH) or any urinary condition , or kidney condition with urination problems
- Myasthenia Gravis (don't want to block ACh effects!)
- Excessive constipation

Front 47

T/F

Very few ganglionic blockers are used clinically.

Back 47

True!

Hexamethonium bromide and Trimethopham are examples.

Front 48

What are some non-depolarizing NMJ blockers?

Back 48

Atracurium*
Cistracurium
Vecuronium
Rocuronium
Pancuronium
Tubocurarine

curiums and curoniums

Front 49

What is an example of a depolarizing NMJ blocker?

Back 49

Succinyl choline

Front 50

What is the MOA of non-depolarizing NMJ blockers?

Back 50

They block the nicotinic receptor at the NMJ & prevent the actions of acetylcholine.

aka: Surmountable or Competitive blockers:
Blocking effect CAN be overcome by increasing the amount of Ach available in the synaptic cleft
For example, with a AchE inhibitor

Front 51

What is the molecular structure of succinylcholine?

Back 51

2 ACh molecules linked end to end

*It is metabolized by plasma cholinesterase (pseudo cholinesterase, butyryl cholinesterase), but NOT by AChE.
So it has to diffuse out of the tissues to get broken down.

THEREFORE:
Rapid onset, short duration of action (minutes for a single dose). Duration may be prolonged in patient with genetic variants of pseudocholinesterase

Front 52

What is the MOA for succinyl choline? (Both phase 1 and phase 2)

Back 52

PHASE 1:
- Succinylcholine is an agonist at nicotinic receptors & initially depolarizes the muscle membrane, releases Ca2+ & causes fasiculations
- The Ca2+ is removed from the cytosol back into sarcoplasmic reticulum , muscle relaxes, and the patient is paralyzed (Flaccid paralysis)
*AchE inhibitors will worsen Phase 1 (b/c you activate more receptors)

PHASE 2:
Upon continued exposure to succinylcholine, the phase I block changes to phase II block
- i.e the membrane is repolarized but the muscle is resistant to further activation by ACh being released at the NMJ

In more detail...

Unlike the acetylcholine, succinylcholine is not subject to hydrolysis by acetylcholinesterase and therefore remains in the junction longer. Soon after administration of the drug, some receptors are desensitized and, although occupied by an agonist, they do not open to allow current to flow to depolarize the area.  
If succinylcholine is applied in high concentration and allowed to remain at the neuromuscular junction for a long time, other effects occur, including entry of the drug into the channel to obstruct it or to pass through it into the cytoplasm. Succinylcholine also has effects on prejunctional structures, and the combination of prejunctional and postjunctional effects plus secondary ones on muscle and nerve homeostasis results in the complicated phenomenon known as phase II blockade

Front 53

What are side effects of succinyl choline?

Back 53

- Muscle pain postoperatively (damaged muscle due to fasciculations (?))
- Hyperkalemia (from prolonged use, K+ is kicked out of cells into the ECF)
- At high doses can also block ganglionic nicotinic receptors
- Decreased heart rate
- Increased IOP

Serious side effects: MAKE SURE they don't have genetic variant!
- Malignant hyperthermia (ryanodine receptor, increase in Ca2+ release from SR, can happen suddenly)
---> Treat with Dantrolene