Cholinergic Agonists

Front 1

Direct Acting Drugs?

Back 1

Acetylcholine, Bethanechol, Carbachol,

Cevimeline, Pilocarpine, Muscarine,

Methacholine, Nicotine, Varenicline,

Succinylcholine

Front 2

Indirect Acting Drugs?

Back 2

Ambenonium, Demecarium, Donepezil,

Edrophonium, Neostigmine, Parathion,

Malathion, Sarin, Physostigmine,

Pyridostigmine, Rivastigmine, Galantamine,

Tacrine

Front 3

What Are the 6 Fates of Acetylcholine?

Back 3

1. Synthesis (Transport of Choline Inhibited by Hemicholinium)

2. Uptake into Storage Vesicles (Prevents Degradation)

3. Release (Caused by Spider Venom, Inhibited by BoTox)

4. Binding to Postsynaptic Receptor (Activate)

5. Degradation by AchE in Synaptic Cleft

Front 4

General MOA for Cholinergic Agonists?

Back 4

Direct:

• Bind to cholinoceptors
  
• Longer duration of action than Ach
• Limited Clinical Use (Muscarinic preference increases)

Indirect: Inhibit AchE

Front 5

What Are Some Choline Esters?

Back 5

Acetylcholine, Bethanechol, Carbachol,

Methacholine

Front 6

What Are Some Natural Alkaloids?

Back 6

Muscarine, Pilocarpine, Cevimeline

Front 7

In the Sympathetic Innervation of the Adrenal Medulla, The____Neurons release the NT___, which binds to the____receptors on the Adrenal Medulla, release the NTs____and____into the blood and they bind to____receptors in the effector organs.

Back 7

Preganglionic

Ach

Nicotinic

NP and EP

Adrenergic

Front 8

In the Sympathetic Pathway, The____Neurons release the NT___, which binds to the____receptors, activate___Neurons that releases the NT____, which binds to the____receptors in the effector organs.

Back 8

Preganglionic

Ach

Nictotinic

Postganglionic

NP

Adrenergic

Front 9

In the Parasympathetic Pathway, The____Neurons release the NT___, which binds to the____receptors, activate___Neurons that releases the NT____, which binds to the____receptors in the effector organs.

Back 9

Preganglionic

Ach

Nicotinic

Postganglionic

Ach

Muscarinic

Front 10

In the Somatic Pathway, there are___ganglia. Instead___is directly released into the blood and binds to the___receptors in the___of Skeletal Muscle.

Back 10

No

Ach

Nicotinic

NMJ

Front 11

What Are the Most Common Effects of Cholinergic Agonists?

Back 11

Diarrhea

Miosis

Urinary Urgency

Diaphoresis

Nausea

Front 12

Besides Nicotine, What is the Other Drug Specific for Only the Nicotinic Receptor?

Which Receptor Do the Other Drugs Bind?

Back 12

Succinylcholine

Muscarinic

Front 13

What Are the General Uses and Contradictions of Muscarinic Agonists?

Back 13

• Ophthalmic: exam,glaucoma
  
• Gastro-Urinary
  
• Xerostomia
  

Antidote for antimuscarinic poisoning Supraventricular tachycardia

Contraindications: asthma, ulcer, GI/urinary obstruction,Parkinson's, some CV diseases (AV block, bradycardia), surgery, seizures

Front 14

Describe Acetylcholine, be sure to include MOA and Physiological Effects.

Back 14

NT that binds to Nicotinic and Muscarinic Rec.

Pharmacological Effects:

Cardiac:
-Decrease in heart rate and cardiac output -Decrease in blood pressure

Muscle:

-Excitatory neurotransmitter

CNS:

-Arousal,reward, neuromodulatory actions -Damage to cholinergic neurons in CNS is associated with Alzheimer's disease

Gastro-intestinal:

Stimulates intestinal secretions and motility

Front 15

What Are the Theraputic Uses and Adverse Effects of Acetylcholine?

Back 15

It's rapidly degraded by cholinesterases and so has no real therapuetic uses other than Intraocular use during cataract surgey for rapid Miosis.

It has no significant Clinical Adverse Effects.

Front 16

Describe Muscarine, be sure to include MOA and Physiological Effects.

Back 16

Has no medical uses due to high toxicity.

Pharmacological Effects: Salivation, Miosis,

Urination/defecation, Sweating, Bronchial

constriction/ secretion, Bradycardia, Nausea/

vomiting, Headache, Hypotension, Shock

Front 17

What Are the Systemic and Localized Adverse Effects of Muscarinic Cholinoceptor Stimulation?

Back 17

Systemic: Sweating, Salivation, Flushing, Decreased blood pressure, Nausea, Abdominal pain, Diarrhea, Bronchospasm

Localized: Visual difficulty on far vision or in dim light, Reddening, stinging and burning of the conjunctiva, Postoperative iritis, Cataract (8-10% of patients, with long-term use), Retinal detachment (with long-term use)

Front 18

Describe Metacholine and it's MOA, PK and Clinical Use.

Back 18

MOA:

• Relatively selective for cardiovascular muscarinic cholinoceptors
  

-Magnitude of response is unpredictable

PK:

• Highly resistant to Acetylcholinesterase
  

Clinical use:

• Only use is in diagnosis of asthma
  

-Bronchial reactivity testing

Front 19

What Are the Adverse Effects and Contradictions of Methacholine?

Back 19

Adverse effects:

• Light headedness
• Headache
• Throat irritation
• Dyspnea (shortness of breath)
  

Contraindications:

• Vagomimetic so contraindicated when:
  

-Recent heart attack

-Stroke

-Aortic aneurysm

-Uncontrolled hypertension

Front 20

Describe Bethanechol including its MOA, PK, PE and TE.

Back 20

MOA:

• Cholinoceptor agonist- muscarinic preference

-Almost no nicotinic activity

PK:

• Duration of action up to2 h
  
• Poor substrate for acetylcholinesterase
  

-Expulsion of Urine

Pharmacological effects:

• Increased motility and tone in GI tract
• Stimulates detrusor muscles of bladder
  

TE:

• Useful in postpartum or postoperative nonobstructive urinary retention
  

Front 21

Describe Carbachol including it's MOA, PK and Systemic Effects.

Back 21

MOA:

• Muscarinic receptor agonist

PK:

• Poor substrate for acetylcholinesterase
• Duration of action ~1 h

Systemic effects:

• CV and GI stimulation followed by depression
• Not useful therapeutically in systemic administration
• Some Nicotinic action

-Causes epinephrine release from adrenal medulla

Front 22

Describe Carbachol and it's PE, TE and AE.

Back 22

Pharmacological effects:

• Causes pupillary contraction and decreased intraocular pressure
  

TE:

• Localized use in the eye to treat glaucoma
• Adverse effects:
  
• Corneal clouding
• Persistent bullous keratopathy
• Retinal detachment
• Postoperative iritis following cataract extraction

Front 23

Describe Pilocarpine and it's MOA and PK.

Back 23

MOA:

• M3 agonist
  

-Less potent than acetylcholine

PK:

• Tertiary amine so hydrolyzed by acetylcholinesterase
• Unchargedand can penetrate CNS
  

-Stimulates profuse sweating and salivation

• Duration of action up to 2 h
  

Front 24

What's the Theraputic Use of Pilocarpine?

Back 24

Therapeutic Uses:

• Used topically in ophthalmology
  

-Rapid miosis and contraction of cilliary muscle

-Drug of choice for immediate drop in intraocular pressure

• Promotes salivation in patients with xerostomia resulting from irradiation of head and neck
  
• Can also be used to help diagnose cystic fibrosis
  

-“sweat test”-Chloride & sodium levels

Front 25

Describe Cervimeline and It's Key Theraputic Use.

Back 25

Selective Muscarinic (M1 & M3) agonist

• Used to treat xerostomia in Sjögrens syndrome

-Systemic autoimmune disease where exocrine glands that produce tears and saliva are attacked

-Sometimes in combination with pilocarpine

Front 26

Describe Nicotine and it's Adverse Effects.

Back 26

Has no therapeutic indications except for smoking cessation

• Stimulates all ganglia and Neuromuscular Junction
  
• Very toxic
  

-dose dependent,can be fatal

• Chronic exposure
  

-tolerance develops to many effects

-Cardio vascular abnormalities (1/3 of CV fatalities related to nicotine)

• Ulcers
  

Front 27

Describe Succinylcholine including MOA, PK and Clinical Use.

Back 27

MOA:

• Choline ester with high affinity for nicotinic cholinoceptors
  

PK:

• More resistant to AChE than ACh
  

Clinical uses:

• Induce paralysis during surgery through depolarizing blockade
  

-Brief excitement> widespread fasciculations> flaccid paralysis

• Some what short duration so good for intubation, but not long term muscle paralysis
  

Front 28

What Are the AE of Succinylcholine?

Back 28

Adverse effects:

• Muscle rigidity & myalgia
  
• Raised intraocular pressure
  
• Cardiac arrest
  
• Malignant hyperthermia
  

-Overcome with Dantrolene

• Respiratory depression
  

Front 29

Describe Varenicline (Chantix) and It's MOA, PK, Clinical Uses and AE.

Back 29

MOA:

• Partial agonist at nicotinic receptors
  

PK:

• Duration of action ~12 h
  

Clinicaluses:

• Smoking cessation
  

Adverse effects:

• Hypertension,sweating, diarrhea, sensory disturbances, menstrual irregularities
  

Front 30

What is the Principle Difference Between Direct and Indirect Acting Cholinergic Drugs?

Back 30

The direct acting will always cause and effect where the indirect will only have an effect if there is a background parasympathetic tone of target.

Front 31

Describe Cholinergic Crisis, It's Common Symptoms and the Best Treatment.

Back 31

Acetylcholinesterase inhibitors increase circulating Ach, which can lead to cholinergic crisis.

Symptoms:

• Early: increased sweating,salivation, bronchial secretions, miosis.
  
• If nothing is done: flaccid paralysis, respiratory failure, coma, death

Atropine is the drug of choice for combating cholinergic crisis.

Front 32

Describe Physostigmine and it's MOA, PK, PE and AE.

Back 32

MOA:

• Wide effects at muscarinic and nicotinic receptors in ANS and also nicotinic receptors of neuromuscular junction
  

PK:

• Duration of action ~2-4 h
  

-Intermediate-acting

Pharmacological effect:

• Increases intestinal and bladder motility
  
• Produces miosis and spasm of accommodation in eye
  
• Lowers intraocular pressure
  
• Used to treat overdoses of anticholinergic drugs & TCAs
  
• Adverse effects- rare at therapeutic doses: High doses:
  

-Convulsions,bradycardia, decrease cardiac output

-Accumulation of ACh in NMJ leads to skeletal muscle paralysis

Front 33

Describe Neostigmine and it's MOA, PK, TE and AE.

Back 33

MOA:

• Greater effect on skeletal muscles than physostigmine
  
• Stimulates contractility before paralysis
  

PK:

• Polar, does not enter CNS
  
• Duration of action 30 m – 2 h
  

Therapeutic effects:

• Stimulates bladder and GI tract
  
• Used as antidote for competitive neuromuscular blocking drugs
  
• Reduces symptoms of Myasthenia Gravis
  

Adverse effects:

• Similar to general cholinergic stimulation
  
• No CNS effects
  

Front 34

What is Myasthenia Gravis and Which Drugs Would You Use to Treat it?

Back 34

It's an autoimmune disease caused by antibodies attacking the nicotinic receptors in the NMJ, leading to muscle weakness.

Neostigmine is more potent, however Pyridostigmine has a longer duration of action. (3-4 hours).

Front 35

What is Demarcium and What Is It Used For?

Back 35

It's similar to Neostigmine in it's structure, MOA and AE.

Used in the treatment of chronic glaucoma

Used in diagnosis and treatment of accommodative esotropia

Front 36

Describe Edrophonium and it's TE and AE.

Back 36

Similar to Neostigmine but:

• More rapidly absorbed
  
• Short duration of action (10-20 min)
  

TE:

• Used in diagnosis of myasthenia gravis, Lambert-Eaton syndrome and other disorders characterized by muscle weakness
  
• IV dose leads to rapid increase in muscle strength
  

AE:

• Cholinergic Crisis with excessive dosing.
  

Front 37

Which Drugs Are Commonly Used to Treat AD, Dementia or PD?

Back 37

AchE Inhibitors such as Tacrine, Donepezil, Rivastigmine and Galantamine.

Front 38

Describe Rivastigmine and It's AE?

Back 38

• Oral and Transdermal Patch Formulations.
  
• Also Has effects on Butyrylcholine (more eff?)
• Less CV effects, but similar potency/efficacy as Donepezil and Galantamine.

AE: Diarrhea, Nausea, Vomiting, Cramps, Anorexia, Vivid Dreams.

Front 39

What is Aging and What Drug Can Be Used Against It?

Back 39

Aging is when strong covalent bonds between inhibitor and enzyme or loss of a functional group reders the complex irreversible.

Pralidoxime given before aging can reverse Organophosphate (Insecticides) Poisoning.

Front 40

Describe Malthion.

Back 40

Most commonly used organophosphate insecticide in the US.

Rapidly degraded by exposure to sunlight, but trace levels found in water run off

Linked to increased ADHD prevalence

Used in the treatment of head lice

Front 41

Describe Parathion?

Back 41

Similar to malathion, but only used as insecticide

Pharmacological effects:

-Parasympathetic effects

-Muscle paralysis Coma/death