Cholinergics Flashcards
Where are M (muscarinic) receptors located?
Muscarinic receptors are located:
- Effector tissues and innervated by parasympathetic fibers
- Very select postganglionic sympathetic targets (sweat glands)
- Endothelium (non-innervated tissue)
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What are sites of cholinergic action?
Cholinergic transmission occurs at neural junctions where acetylcholine is the neurotransmitter:
- All autonomig ganglia
- Postganglionic termini of parasympathetic fibers (post-synaptic)
- Postganglionic termini of sympathetic cholinergic fibers (sweat glands) (post synaptic)
- Adrenal medulla (specialized sympathetic ganglion)
- Termini of somatic motor nerves to skeletal muscle (neuromuscular junctions/motor end plates)
- CNS
What are the actual effects of IV Ach?
1) Hierarchy of accessibility from blood:
- Endothelial cells
- Parasympathetic/sympathetic effector tissues
- NMJ
- Ganglia
- CNS
2) Ach is rapidly cleared from the blood
- Plasma => pseudocholinesterase
- Further limits access to less perfused sites
What is cholinergic syndrome/ extreme muscarinic over activation?
DUMBBELLSS:
- Diarrhea (and Diaphoresis) and abdominal cramping
- Urination
- Miosis (pinpoint pupils)
- Bradycardia (muscarinic) or Tachycardia (nicotinic)
- Bronchorrea (increased secretions) or Bronchoconstriction (wheezing)
- Emesis (Nausea and Vomiting)
- Lacrimation
- Lethargy
- Salivation
- Sweating
or
SLUDGE:
- Salivation
- Lacrimation
- Urination (detrusor)
- Defecation (anal sphincter)
- GI
- Emesis
What are the clinical signs of muscarinic activation?
DUMBBELLSS/ SLUDGE
AND:
1) Hypotension
2) Paradoxical bradycardia
What is the pathophysiology of hypotension in muscarinic over activation?
- Activation of noninervated M3/M5 on endothelial cells
- Rapid activation of endothelial NO (nitric oxide) synthase
=\> NO diffuses into vascular smooth muscle cells =\> NO stimulates guanlylate cyclase (GTP -\> cGMP) =\> cGMP binds to myosin light chains to relax vascular smooth muscle cells --\> vasodilation --\> lowered BP
What are nonspecific receptor direct acting cholinomimetic drugs?
1) ACh
2) Carbachol
What are some important direct acting cholinomimetic muscarinic agonists?
1) Methacholine
- Methylated ACh, has quaternary ammonium so poorly absorbed
- Aerosol challenge to Dx bronchial hyperreactivity (asthma)
- Hyperreactive airways respond with bronchoconstriction to lower concentrations
2) Bethanechol
- Formerly used to relieve GI dysmotility syndromes such as postsurgical ileus
- Largely replaced by metoclopramide, stimulates presynaptic D2 receptors to trigger ACh release
3) Pilocarpine (plant alkaloid)
- Used topically in the eye to relieve glaucoma
What are some important direct acting cholinomimetic nicotinic agonists?
1) Nicotine
2) Varenicline (Chantix™)
What are some important indirect acting cholinomimetic cholinesterase inhibitors?
Short acting:
- Edrophonium
Intermediate acting
- Neostigmine
- Physostigmine
Long acting
- Echothiophate
- Parathion
- Malathion
- Sarin
- Soman
What are some important indirect acting cholinomimetic presynaptic drugs?
Metoclopramide
What are the characteristics of Nicotinic receptor agonists?
1) Nn receptors in all autonomic ganglia,
- Post synaptic, on efferents to soma of postganglionic neurons
- Also in the CNS
2) Nm at NMJ on skeletal muscle
3) 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
Why are muscarine and Ach not therapeutically useful?
1) THey do not arrive at junctions in the organized fashion needed fro a synchronized physiological response
2) Too many side effects
Describe the nicotine addiction mechanism.
Nicotine⇒nicotinic receptors in the nucleus accumbens and prefrontal cortex => increase in mesolimbic reward system => dopamine
- when dopamine falls =\> cravings
* Nicotine patches are used to help with nicotine addiction but there is a risk of nicotine poisoning (especially in children)
- Chantix works through different receptors and not through the reward system
What are the effects of nicotine receptor overactivation?
Initial activation –> subsequent deactivation:
- Initial depolarizatin leads to muscle fasciculations
- Prolonged receptor occupancy with Ach leads to receptor phosphorylation and inactivation (depolarization–desensitization blockade)
* Result is a paradosical flaccid paralysis which cannot be practically reversed until the agonist is cleared
- Most critical concern is the effect on skeletal muscle/diaphragm
How is nicotine generally absorbed in poisoning?
Nicotine is rapidly absorbed orally/through the skin.
- Poisoning leads to rapid stimulation of parasympathetic/sympathetic ganglia and adrenals
- This causes depolarization–desensitization blockade - Flaccid paralysis demands respiratory support
What are the major clinical signs of nicotine poisoning?
* Sympathetic tends to predominate
1) Tachycardia
2) Hypertension
3) Nausea/vomitting/diarrhea/salivation
4) Urinary incontinence
5) Cold sweat
6) Syncopy,collapse,unconsciousness
7) Flaccid paralysis
What is Varenicline/Chantix?
Varenicline is used to treat nicotine addiction. It is an anicotinic receptor partial agonist—it stimulates nicotine receptors more weakly than nicotine itself does.
As a partial agonist, it both reduces cravings for and decreases the pleasurable effects of cigarettes and other tobacco products.
What drug class is Varenicline?
Pharmacologic class: Very selective and potent competative partial agonist of a2-b4 nicotinic receptors
Therapeutic class: smoking cessation
Describe the pharmacodynamics of varenicline.
Pharmacodynamics:
- CNS mesolimbic dopamine
- Partial a4-b2 stimulation prevents low dopamine and cravings
- Prevents nicotine from creating dopamine surges
- No chemical reward
Describe the pharmacykinetics of varenicline.
Pharmacokinetics:
- Well absorbed
- Peak 4 h, t1/2 = 24 h
- Excreted primarily in urine as unchanged drug
What special considerations should be made for patients on varenicline?
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
What is the dose/route of varenicline?
Route/dose:
- 1 mg PO BID for healthy adults
- 0.5 mg PO BID for renal impairment CrCl < 50 ml/min
What should be monitored in patients on Varenicline?
Neuropsychiatric symptoms
What do cholinesterase inhibitors block?
Cholinesterase inhibitors block true AchE, plasma ChE, RBC AchE:
- Plasma ChE is inhibited first
- Plasma ChE neutralizes AChE inhibitors & protect neural AChE
- Assays available for plasma ChE and AChE on RBCs membranes
- Useful in diagnosis and prognosis of cholinesterase inhibitor poisonings
What are the side effects of AChE inhibitors?
1) Muscarinic side effects (DUMBBELSS)
- Reversible by muscarinic blocking drugs (next lecture)
2) Nicotinic effects
What is the mechanism for AChE?
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
How do short acting AChE inhibitors work?
1) Short acting are competitive inhibitors => do NOT form ester bond to AChE
2) Edrophonium
- Highly charged, does not cross BBB
- Given I.V. (onset 1 min) or I.M. (onset 2 – 10 min)
- Extremely short lived effects (5-10 min IV; 5-30 min IM)
- Dx of myasthenia gravis (90-95% accuracy)
Describe the salient features of myasthenia gravis.
1) Autoimmune disease
2) Antibodies against a thymocyte epitope cross react with NMJ
3) Attack and destroy 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
- Patients note rapid increase in muscle strength
What is the mechanism of action of intermediate AChE inhibitors (Carbamates)?
Mechanism of action:
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