Cholinergic Agents 3 Flashcards
Describe the major pharmacologic manipulations of the cholinergic system.
Examine the structure of a direct acting cholinergic agonist and identify the major structural features responsible for the drug’s activity.
Explain the molecular basis for the interactions of acetylcholine
and related drugs with muscarinic receptors with particular
emphasis on stereochemical requirements of the drugs.
Given a chemical modification to the structure of a direct acting cholinergic agonist, predict the effect on the molecule’s activity and sensitivity to acetylcholinesterase.
Given a clinical condition, choose an appropriate cholinergic
agonist to treat that condition
Explain why parasympathomimetic drugs should not be used asthma, peptic ulcer, or bowel and urinary obstructions.
Explain the molecular basis for the interactions of acetylcholine
and related drugs with nicotinic receptors.
What is parasympathomimetic action?
It is an agonists that through activation is to mimic parasympathetic activation.
What does a direct agonist do to acetylcholine receptors?
It activates cholinoceptors.
What does an indirect agonist do to acetylcholine receptors?
It will stimulate acetylcholine release and inhibit acetylcholinesterase (AChE)
What is parasympatholytic action?
It is an antagonists to the cholinergic receptor and can act through direct or indirect action.
Out of the muscarinic and nicotinic receptor, which one does acetylcholine have higher affinity for?
The muscarinic receptor.
Where are nicotinic receptors found? What is their response to acetylcholine?
The only nicotinic receptors are found in muscle are in skeletal muscle. Their response is motor end-plate depolarization contraction and the mechanism is through ligand-gated opening of Na+/K+.
The 2 neural tissues where nicotinic receptors are is postganglionic and the adrenal medulla. In the postganglionic tissue the response is depolarization. In the adrenal medulla the response is catecholamine secretion. The mechanism is based on the ligand-gated opening of Na+/K+.
Where are M1 muscarinic receptors located, their function and how they do it?
M1 receptors are located in postganglionic tissue and they function in depolarization. This happens through the GPCR mechanism of Gq (excitatory) which increases PLC, IP3, DAG and Ca2+.
Where are M2 muscarinic receptors located, their function and how they do it?
M2 receptors are located in the heart and they function in inhibition. This happens through the GPCR mechanism of Gi (inhibitory) by inhibiting adenylyl cyclase and the activation of K+ channels.
Where are M3 muscarinic receptors located, their function and how they do it?
M3 receptors are located in smooth muscles, exocrine glands and the endothelium. In the smooth muscle their function is contraction, in exocrine glands their function is secrtetion and in the endothelium their function is relaxation. This happens through the GPCR mechanism of Gq (excitatory) by increasing PLC, IP3, DAG and Ca2+. Additionally there is the releases of NO and increase in GC.
Where are M4 muscarinic receptors located, their function and how they do it?
M4 receptors are found in the CNS and function in hyperpolarization. This happens through the GPCR mechanism of Gi (inhibitory) by inhibiting adenylyl cyclase.
Where are M5 muscarinic receptors located, their function and how they do it?
M5 receptors are found in the CNS and function in depolarization. This happens through the GPCR mechanism of Gq (excitatory) by increasing PLC, IP3, DAG and Ca2+.
How does choline made it into the presynaptic neuron?
Choline is transported into the presynaptic nerve terminal by a sodium-dependent choline transporter (CHT).
Once inside the presynaptic neuron, how does choline become acetylcholine?
The enzyme choline acetyltransferase (ChAT) combines choline and acetyl-CoA to make acetylcholine.
Where does acetylcholine bind on the postsynaptic cell?
Cholinoreceptors.
How is the action of acetylcholine terminated?
The enzyme acetylcholinesterase (AChE) will hydrolyze acetylcholine into acetate and choline.
What are the muscarinic agonist effects of the heart?
The M2 receptors found on the heart when activated leads to DECREASE in HR, conduction and force also known as BRADYCARDIA.
What are the muscarinic agonist effects of the exocrine glands?
The M3 receptors found on these glands INCREASE in SECRETION.
This can be lacrimal (tear) glands, tracheobronchial (mucus) glands, salivary (saliva) glands, digestive glands and sweat glands.
What are the muscarinic agonist effects of the smooth muscles?
The M3 receptors found on the smooth muscles INCREASES in CONTRACTION.
What are the muscarinic agonist effects of the sphincter muscles?
The M3 receptors activate RELAXATION.
What are the muscarinic agonist effects of the CNS?
Not all muscarinic agonist are able to reach the CNS.
The CNS is primarily mediated by the M1 receptor.
Activation will produce tremors, hypothermia, increased locomotor activity and improved cognition.
What are the 4 cholinoreceptor (muscarinic) agonists that have esters?
Acetylcholine
-acetyl group + choline
Methacholine
-acetylcholine derivative with additional beta methyl
Carbachol
-carbamate + choline
Bethanechol
-carbachol derivative with additional beta methyl
What do acetylcholine and carbachol have in common?
Active at both nicotinic and muscarinic receptors.
What is the selectivity of receptor once you add a beta substitution to acetylcholine?
Selectivity of the muscarinic receptor becomes favored.
Selectivity becomes reduced for nicotinic receptor and acetylcholinesterase.
What is the selectivity of receptor once you add a alpha substitution to acetylcholine?
Selectivity is retained for the nicotinic receptor.
Selectivity becomes reduced for the muscarinic receptor.
What happens if you change the acetyl group on acetylcholine to a carbamate group?
The molecule becomes resistant to acetylcholinesterase.
What happens if you change the acetyl group on acetylcholine to a carbamate group?
The molecule becomes resistant to acetylcholinesterase.
What are the 3 cholinoreceptor (muscarinic) agonists that have are alkaloids and synthetic analogs?
Muscarine (+)
-choline that becomes tetrahydrofuran
Pilocarpine
-combination of a imidazole with methyl group and tetrahydrofuran with a carbonyl group
Nicotine
-pyridine connected meta to pyrrolidine with methyl on carbon
How is pilocarpine helpful in gluacoma?
There is no quaternary amine and therefore no charge allowing for pilocarpine to cross BBB.
The ester remains.
The ciliary muscle in the eye has the M3 receptor which pilocarpine can act on.
-its action facilities outflow of the aqueous humor leading to a decreased intraocular pressure.
Why are antimuscarinic drugs contraindicated in glaucoma?
An antimuscarinic drug acting on the M3 receptor in the ciliary muscle would cause the muscle to relax, not allowing outflow of the aqueous humor and therefore increasing intraocular pressure.
In what order do muscarinic agonist have susceptibility to acetylcholinesterase?
Acetylcholine has an intense susceptibility to AChE.
Methacholine has a moderate susceptibility to AChE.
Carbachol has a mild susceptibility to AChE.
Bethanecol and Pilocarpine are not affected by AChE.
In what order do muscarinic agonist have muscarinic effects on the cardiovascular system?
Methacholine has an intense effect to M2 on the heart causing a fall in BP and HR.
Acetylcholine has a moderate effect to M2 on the heart causing a fall in BP and HR.
Carbachol has a mild effect to M2 receptor on the heart causing a slight fall in BP and HR.
Bethanecol and Pilocarpine cause little to no effect on the M2 receptor on the heart.
In what order do muscarinic agonist have muscarinic effects on the gastrointestinal system?
Carbachol and Bethanecol have an intense effect to M3 receptor in the G1 causing smooth muscle contraction and sphincter relaxation.
Acetylcholine, Methacholine and Pilocarpine have a moderate effect to the M3 receptor in the GI causing slightly less smooth muscle contraction and sphincter relaxation.
In what order do muscarinic agonist have muscarinic effects on the bladder?
Carbachol and Bethanecol have an intense effect to M3 receptor in the G1 causing smooth muscle contraction and sphincter relaxation.
Acetylcholine, Methacholine and Pilocarpine have a moderate effect to the M3 receptor in the GI causing slightly less smooth muscle contraction and sphincter relaxation.
In what order do muscarinic agonist have muscarinic effects on the eye?
Pilocarpine has an intense effect on the M3 receptor located on the eye causing miosis or constriction of the pupil.
Carbachol and Bethanecol have a moderate effect on the M3 receptor located on the eye causing slightly less miosis or constriction of the pupil.
Acetylcholine and Methacholine have a mild effect on the M3 receptor located on the eye causing slightly less miosis or constriction of the pupil.
In what order do muscarinic agonist have muscarinic effects on the eye?
Pilocarpine has a moderate effect on the M3 receptor located on the sweat glands causing and increase in sweat production.
Acetylcholine, methacholine, carbachol and bethanecol all have a mild effect on the M3 receptor located on the sweat gland causing a slight less increase in sweat production.
What level does atropine act as an antagonist to the muscarinic agonist?
Atropine is an intense antagonist to Acetylcholine, Methacholine and Bethanecol.
Atropine is a moderate antagonist to pilocarpine.
Atropine is a mild antagonist to carbachol.
Do any of the muscarinic agonist also cause nicotinic effects?
Carbachol also causes intense nicotinic effects.
Acetylcholine also causes moderate nicotinic effects.
Methacholine and pilocarpine also cause mild nicotinic effects.
Bethanechol does not cause nicotinic effects.
What are the clinical uses for pilocarpine?
Open-angle glaucoma, dry mouth due to hypofunction of salivary glands.
What are the clinical uses for bethanechol?
GI stimulation or treatment of urinary retention.
What are the clinical uses for methacholine?
Provocative test for hyperactive airways
What are the clinical uses for carbachol?
Ocular (surgery, glaucoma)
What are the common side effects of muscarinic agonist?
PS effects depending on agonist such as DUMBBELS.
Diarrhea
Urination
Miosis
Bradycardia
Bronchoconstriction
Emsis
Lacrimation
Salivation+Sweating
SS effect to watch out for in caution with patients with
Asthma
Coronary insufficiency
Peptic ulcer
Cardiovascular
Respiratory
What is important to know about nicotinic receptors?
Ionotropic (Na+ ion channels) with 5 subunits - only ion channel receptor.
Response to acetylcholine and nicotine.
-open ligand-gated Na+ channels, depolarization
-lead to opening of voltage-gated sodium channels to produce action potential
Where are nicotinic receptors located?
Muscle and Neuronal locations.
Muscle: skeletal muscle endplate.
-when stimulated, Na+ will depolarized the membrane resulting in muscular contraction.
Neuronal:
All peripheral autonomic ganglia (ANS)
-receptor on postganglionic SYM and PARA neurons
-when stimulated, Na+ will depolarize the membrane resulting in action potential to continue down the neuron.
+Adrenal medulla
-Preganglionic SYM neuron releases acetylcholine binding to nicotinic receptor on chromaffin cell. Stimulation results in epinephrine
Brain (CNS)
What does the nicotine molecule look like?
Two ringed structure that is dibasic.
A pyridine on the left connected to a tetrahydrofuran on the left with the oxygen replace with a nitrogen and methyl.
What are nicotine effects?
Low doses: stimulate reticular activating system (alerting) and dopamine release (addictive)
High doses: cardiovascular effects such as HTN or tachycardia (increased HR)
What happens with toxic doses of nicotine?
Toxic dose: seizures, neuromuscular blockade, loss of receptor selectivity leading to
-bronchorrhea
-excessive secretions
-GI disturbance (including nausea and vomiting)
Acute toxicity:
-Convulsion
-Coma
-Hypertension
-Arrhythmias
-Neuromuscular failure
What are the problems with nicotine and abuse?
Overtime, you produce a tolerance requiring more nicotine to produce the same response.
This eventually causes a physical dependence and leads to withdrawal symptoms.
These can be irritability, anxiety, difficulty concentration…ect
To reduce smoking cessation you need to reduce craving and inhibit reinforcing effects.
What are the pharmacological interventions for nicotine dependence?
Varenicline (Chantix)
Bupropion (Wellbutrin)
Nicotine-replacement therapy
How does Chantix (varenicline) work?
It is a partial agonist to alpha4 beta2 neuronal nicotinic receptor.
It produces low to moderate release of dopamine at the brain’s reward centers. This drug mimics nicotine’s effects and reduces withdrawal symptoms.
Additional it blocks nicotine from binding inhibiting reinforcing effects.
three 6 cyclic hydrocarbons
What are the adverse effects of chantix (varenicline)?
With a 1/2 life of 24 hours it can cause nausea, headache, abnormal dreams, constipation and vomiting.
It is more effective than nicotine patches, gum and maybe even bupropion.
It is rarely used now and has a box warning as it can cause depression and suicidal ideation.
How does Wellbutrin (bupropion) work?
Weakly inhibits NET and DAT resulting in increased levels of NE and DA in synaptic cleft.
Clinically used for depression and smoking cessation.
Are there any problems with Wellbutrin (bupropion)?
There can be a delay in effect by a few weeks.
At high doses there is a lowered seizure threshold.
Can cause HTN crisis with MAOIs.
May be less effective than varenicline (Chantix)
What is nicotine replacement therapy?
Prescription and non prescription forms.
Prescription includes nicotrol inhaler and nicotrol nasal spray.
Non prescription includes nicorette gum and nicoderm/nicotrol transdermal patches.
What is the relationship between size and activity of modifications to the trimethylammonium head?
There is an inverse relationship between size and activity.
Nitrogen > Phosphorus > Arsenic > Sulfur»_space;> Carbon
What is pilocarpine clinically used for?
Treats hypo (low) function of salivary glands.
Xerostomia (dry mouth, cottonmouth)
-Pilocarpine used to treat xerostomia following head and neck radiation treatments (M3 receptor agonist)
Sjogren’s syndrome (autoimmune in women where secretions of salivary glands are reduced)
-Pilocarpine increases secretions.
