Cholinergic Agonists Flashcards
Describe the cycle of ACh
- Step 1: acetyl-CoA + choline –> Ach
- Step 2: ACh stored in neurons
- Step 3: ACh released via action potential stimulation
- Step 4: ACh binds to receptor (ACh-R)
- Step 5: AChesterase breaksdown ACh
- Step 6: acetyl-CoA and choline recycled
What are the types of receptors that bind ACh?
- muscarinic
- nicotinic
Define parasympathomimetic
- produce actions that mimic those seen when ACh binds to muscarinic receptors of the parasympathetic NS
What is an example of a parasympathomimetic agent?
- muscarine
- nicotine
Where are muscarinic receptors located?
- postganglionic parasympathetic
i. e. autonomic effector organs
What are the differences in muscarinic receptor types?
- M1, M3, & M5 lead to cellular excitation
- M2 & M4 inhibit cellular excitability
What role does ACh have at muscarinic receptors in the parasympathetic NS?
- activate muscarinic receptors on target organs
OR - binding receptors inhibits release of other NT
Where are nicotinic receptors located?
- ganglionic level of both parasympathetic and sympathetic sides of ANS
What are the differences in nicotinic receptors?
- Nm are located at somatic, neuromuscular junction (not in ANS)
- Nn are located in CNS, adrenal medulla, and autonomic ganglia
What is ACh role at nicotinic receptors in the somatic NS?
- primarily present at neuromuscular junction of skeletal M.
- binding of ACh creates positive stimulus (i.e. skeletal M. contraction)
What do nicotinic receptors at neuromuscular junction bind?
- only ACh
Define cholinomimetic agent
- nonACh compounds that mimic actions of ACh
What is the function of direct cholinomimetic agonists (i.e. stimulants)?
- direct binding to ACh-R
What is the function of indirect cholinomimetic agonists (i.e. cholinesterase inhibitors)?
- indirect cholinergic action by inhibiting ACh breakdown
[if ACh does not get broken down, it stays in synapse longer and continues to produce an effect]
What are the direct acting cholinomimetic groups with examples?
- esters of choline i.e. ACh
- alkaloids i.e. muscarine & nicotine
What are the characteristics of choline esters?
- hydrophilic (i.e. lipid insoluble)
- hydrolyzed by AChesterase (AChE)
- variations alter potency & susceptibilty to AChE
Describe choline esters
- quaternary ammoniums
Describe alkaloids
- typically tertiary amines but could be quaternary amine
What are the characteristics of alkaloids?
- well absorbed after oral admin
- hydrophobic (i.e. lipid soluble)
- not susceptible to AChE
What is an advantage of being hydrophobic or lipid soluble?
- able to cross BBB
What is the mechanism of action (MOA) of indirect acting cholinomimetics?
- inhibit AChE thereby prolonging the presence and action of ACh at all ACh-R
What are the types of AChE inhibitors?
- simple alcohols
- carbamate esters
- organophosphates
Describe the difference in binding among the AChE inhibitors
- simple alcohols bind weakly and reversibly
- carbamate esters bind reversibly but tighter
- organophosphates bind nearly irreversibly
Which systems have similar effects for direct and indirect cholinomimetics?
- eye
- respiratory
- GI
- GU
Which systems have different effects for direct and indirect cholinomimetics?
- CV
- secretory glands
- NS
- neuromuscular junction
What is the eye sensitive to?
- muscarinic agonists
- AChE inhibitors
What are the effects of cholinomimetics on the eye?
- contraction of iris sphincter resulting in miosis
- contraction of ciliary M. resulting in accommodation
Overall: pupilary constriction
What is the clinical significance of the effect of cholinomimetics on the eye?
- assist with aqueous humor outflow to decrease IOP
What is the clinical use of cholinomimetics on the eye?
- muscarinic agonists and AChE inhibitors decrease IOP in glaucoma patients
- only given as drops to reduce risk of side effects to the heart
What are examples of drugs used as cholinomimetics on the eye?
- pilocarpine
- physostigmine
What are the effects of cholinomimetics on the respiratory system?
- bronchoconstriction
- stimulates mucus secretion in tracheobronchial tree
What are the clinical uses of cholinomimetics on the respiratory system?
- none
- anticholinergics increase airflow
What are the effects of cholinomimetics on the GI tract?
- increase secretory and motor activity & peristalsis
- relaxes sphincters
What are the clinical uses of cholinomimetics on the GI tract?
- use agents to correct depressed smooth muscle activity and increase motility
- i.e. post-op & in patients with congenital megacolon
What is an example of a cholinomimetics used on the GI tract?
- neostigmine
What is the effect of cholinomimetics on the GU tract?
- triggers voiding the bladder via contraction of detrusor muscle and relaxation of trigone and sphincter muscles
What are the clinical uses of cholinomimetics on the GU tract?
- use agents to correct depressed smooth muscle activity
- i.e. treat urinary retention
What are examples of cholinomimetics used on the GU tract?
- bethanecol
- neostigmine
What are the effects of direct cholinomimetics on the CV system?
- two effect of muscarinic agonists
- reduce peripheral vascular resistance through vasodilation which decreases BP which can cause an indirect reflex increase in HR
- decreased HR through decreased rate of SA node firing leading to bradycardia which reduces CO
Why are direct cholinomimetics not often used on the CV system?
- there are other drugs that do the same effect but better and more predictably
What are the effects of indirect cholinomimetics on the CV system?
- AChE inhibitors increase cholinergic activity
- both sympathetic and parasympathetic actions on the heart lead to negative chronotropic and ionotropic effects (bradycardia and decreased CO, respectively)
Which has a greater effect on the heart, sympathetic or parasympathetic?
- parasympathetic –> observe more parasympathetic results
What is the effect of an indirect cholinomimetics on the cardia and vascular smooth muscle?
- modest drop in BP
What does chronotropic refer to?
- HR
What does inotropic refer to?
- contractility
What are the effects of cholinomimetics on misc. secretory glands?
- sweat glands causing diaphoresis to regulate T
- increased lacrimation
- increased mucus in nasopharynx
What are the effects of direct cholinomimetics on the nicotinic receptors in the CNS?
- induce tremor
- stimulate emesis (vomit)
- stimulate respiratory center
What are the effects of direct cholinomimetics on the muscarinic receptors in the CNS?
- induce tremor
- cause hypothermia
- interfere with nociception
What is the effect of indirect cholinomimetics on the CNS?
- [low] have little effect
- [high] can causes convulsions, coma, & respiratory arrest
What are two clinical indications for cholinomimetics for CNS conditions?
- alzheimer’s
- smoking cessation
What is the effect of ACh at the neuromuscular junction?
- contraction of skeletal m.
What is the effect of low dose indirect cholinomimetics on the neuromuscular junction?
- prolong effects of ACh thereby increasing strength of m. contraction
What is the effect of medium does indirect cholinomimetics on the neuromuscular junction?
- may cause m. to fibrillate making the m. less effective
What is the effect of high does indirect cholinomimetics on the neuromuscular junction?
- blocks m. depolarization leading to paralysis
What is the pathophysiology of myasthenia gravis?
- autoimmune - antibodies target nicotinic receptors on skeletal m. and block ACh binding
- cholinomimetics effective tx
What are examples of drugs used to tx myasthenia gravis?
- pyridostigmine
- neostigmine
What is an effective treatment for anticholinergic intoxication?
- cholinomimetics
- increase the amount of ACh
- AChE inhibitors (i.e. physostigmine)
What are the types of cholinomimetics toxicities?
- receptor (muscarinic v. nicotinic)
- MOA (direct cholinomimetics v. AChE inhibitor)
What are the signs of toxicity of direct muscarinic agonists?
- SLUG (salivation, lacrimation, uriniation, defecation)
- N/V, diarrhea, uriniary urgency, sweating, cutaneous vasodilation, bronchial constriction)
What is the treatment for toxicity of direct muscarinic agonists?
- atropine, an anticholinergic
What are the signs of acute nicotine toxicity?
- CNS stimulation (convulsions, coma, respiratory arrest)
- skeletal m. depolarization (stops contractions)
- HTN & cardiac arrhythmias
What is the treatment for acute nicotine toxicity?
- supportive
What are the symptoms of cholinesterase (AChE) inhibitor toxicity?
- DUMBBELSS
- diarrhea, urination, miosis, bradycardia, bronchoconstriction, emesis, lacrimation, salivation, sweating
What are the treatments for AChE toxicity?
- monitor vitals
- decontaminate
- antidote with 2-PAM
What is 2-PAM an antidote for and how does it work?
- organophosphates
- reactivates inhibited AChE before the full covalent bond forms through “aging”
Where are cholinergic receptors found in the ANS?
- preganglionic sympathetic and parasympathetic
- postganglionic parasympathetic
What type of neurons release NE?
- postganglionic sympathetic
What effect would a muscarinic agonist have on the sympathetic portion of the autonomic nervous system?
- none, trick question
What is the name of the enzyme that metabolizes ACh?
- acetylcholinesterase (AChE)
Why do organophosphates inhibit AChE for so long compared to other types of AChE inhibitors?
- covalent bonding
What effect does nicotine have in toxic concentrations in humans?
- seizures, coma, respiratory arrest
