Cholinergic Agonists Flashcards
Describe the Cycle of Acetylcholine
ACH is synthesized in the mitochondria of neurons catalyzed by choline O-acetyltransferase
ACh is stored and released in vesicles
Action potential stimulates the release of ACh into synaptic cleft
ACh binds to muscarinic or nicotinic acetylcholine receptors
ACh is broken down by AChE and components are recycled
What are the 2 types of receptors that bind ACh and where are they found
Muscarinic - effector organs
Nicotinic - ganglion of autonomic nervous system
What are the 2 key actions at muscarinic sites?
muscarnic receptors are activated on target organs and organ function is altered by positive stimulus
bind to receptors on nerve terminals to INHIBIT relase of other neurotransmitters; alters organ function by creating negative stimulus
What is the difference between positive and negative response?
positive response = activate; contraction or release of something
negative response = relaxation
Where are nicotinic receptors located?
ganglionic level of both parasympathetic and sympathetic sides of the autonomic nervous system
What do nicotinic receptors do?
bind ACh released from pre-ganglionic neurons and pass message on to post ganglionic neurons
Do nicotinic receptors have inhibitory capabilities?
No, only relay efferent message sent from CNS
Where are nicotinic receptors in the somatic nervous system located?
at the neuromuscular junction of skeletal muscle
What do the nicotinic receptors in the somatic nervous system do?
binding of ACh –> depolarization of nerve cell or neuromuscular end plate membrane –> positive stimulus (muscle contraction)
What happens if there is prolonged ACh binding to nicotinic receptors in the somatic nervous system?
postganglionic neuron will stop firing
skeletal muscle will relax
muscle paralysis; prevents further depolarization (negative stimulus)
What are the 5 types of muscarinic receptors?
M1 - M5
What do each of the muscarinic receptors do?
M1, M3, M5 –> cellular excitation
M2 and M4 –> inhibit cellular excitability
Where are muscarinic receptors found?
Effector Organs:
Heart
Smooth Muscle
Brain
Exocrine glands
What are the 2 types of nicotinic receptors?
Nm
Nn
Where are Nm receptors located?
neuromuscular junction
Where are Nn receptors located?
CNS
Adrenal Medulla
Autonomic Ganglia
**Nn = NON muscular
What are the 2 groups of direct acting cholinomimetics?
Esters of Cholines - acetylcholine
Alkaloids - muscarine and nicatine (comes from plants)
Are Choline Esters lipophilic? And what consequence does this have in the body?
No they’re hydrophilic
Can’t cross the BBB –> don’t produce CNS side effects like sedation
How are choline esters classified chemically?
quarternary ammoniums
What are the characteristics of quaternary ammoniums?
Hydrophilic
Hydrolyzed by acetylcholinesterase (AChE)
Variations in chemical structure alter characteristics like potency and susceptibility to hydrolysis by AChE
How are cholinomimetic alkaloids classified chemically? What about Muscarine?
Tertiary amines
Muscarine = quarternary amines
What are the 4 examples of cholinomimetic alkaloids that are quaternary amines?
Muscarine
Pilocarpine
Nicotine
Lobeline
What are the characteristics of cholinomimetic alkaloids?
well absorbed after oral administration
lipid soluble –> larger volume of distribution; cross into BBB (even muscarine)
Not susceptible to acetylcholinesterase
What is the Mechanism of Indirect Acting Cholinomimetics
Act by inhibiting AChE
What is the consequence of inhibiting AChE
prolongs the presence and actions of ACh @ ALL ACh-R (muscles, neurons, neural muscular junction, brain)
What are the 3 types of AChE inhibitors, and what are some examples?
Simple alcohols w/ a quarternary ammonium - Edrophonium
Carbamate esters of alcohols with quaternary or tertiary ammonium - neostigmine, physostigmine, pyridostigmine
Organophosphates - Echothiophate, Isoflurophate
What is the binding affinity of simple alcohols and AChE?
weak affinity –> bind weakly
reversible
half life = short
What is the binding affinity of carbamate esters and AChE?
higher affinity for AChE than simple alcohols
still reversible
half life = 30 minutes - 6 hour half life
What is the binding affinity of organophosphates and AChE?
HIGH affinity –> bind covalently
very long half-life
can only be overcome with new production of AChE
Which effector organs do direct and indirect cholinomimetics have similar effects on?
Eye
Respiratory System
GI tract
GU tract
Which effector organs do direct and indirect cholinomimetics have different effects on?
CV system
Secretory Glands
CNS
Peripheral NS
Neuromuscular junction
What are the cholinomimetic effects on the eye?
Contraction of iris sphincter smooth muscle –> mitosis (pupillary constriction)
Contraction of Ciliary muscle –> accommodation (focusing on object; muscarinics = close objects)
What does the contraction of the iris sphincter smooth muscle and the ciliary muscle do in the eye?
facilitate flow of aqueous humor out of anterior chamber
alter amount and focus of light reaching retina
Which type of cholinomimetics is the eye sensitive to?
Muscarinic agonists
AChE inhibitors
What is the clinical use of cholinomimetics in the eye?
Glaucoma –> Pilocarpine, Physostigmine
What is the action of cholinomimetics on glaucoma?
Muscarinic agonists/AChE inhibitors increase outflow of aqueous humor –> reduce intra-ocular pressure
What are the actions of cholinomimetics on the respiratory system?
contraction of smooth muscle –> restrict airflow
stimulate secretions from tracheobronchial mucosa
**ACh agonists aren’t used much in respiratory medicine
What are the cholinomimetic effects on the GI tract?
Increase secretory and motor activity in the gut
Stimulate salivary/gastric glands, pancreas, small intestine
increase peristalsis
relaxes most GI sphincters –> GI contents pass along freely
Clinically when would you use cholinomimetics for GI disorders?
When you want to correct depressed smooth muscle activity and increase motility
Post-op ileum (neostigmine)
Congenital mega colon
What are the cholinomimetic effects on the GU tract?
Trigger voiding of bladder
stimulate detrusor muscle (contraction) and relax trigone and sphincter muscles of bladder
When would you clinically use cholinomimetics for GU disorders, and name 2 drugs that are used?
treat urinary retention: post-op, post pardum; spinal cord injuries; neurogenic bladder
bethanecol, neostigmine
What are the direct cholinomimetic effects on the cardiovascular system?
reduce peripheral vascular resistance: vasodilation = reduced BP; drop in BP can cause indirect reflex increase in HR
Decrease heart rate: decrease SA node firing = bradycardia, reduces cardiac output
ACh agonists not used a lot for CV medicine because their results are unpredictable
What are the effects of indirect cholinomimetics on the Cardiovascular system?
Increase cholinergic activity
work on sympathetic and parasympathetic nerves:
negative chronotropic –> bradycardia
negative inotropic (squeeze of heart) –> drop in cardiac output
What are the cholinomimetic effects on secretory glands?
stimulates sweat gland production –> help regulate body temp
stimulate lacrimal glands
stimulate nasopharyngeal glands
REMEMBER: Tears, Sweat, Snot
What are the effects of direct cholinomimetics on the nicotinic receptors in central nervous system?
Induce tremor
stimulate emesis (vomitting)
stimulate respiratory center
What are the effects of direct cholinomimetics on the muscarinic receptors in central nervous system?
induce tremor
cause hypothermia
interfere w/ nociception (pain sensation)
What are the effects of indirect cholinomimetics on the central nervous system?
need high concentration to stimulate effect
convulsions
coma
respiratory arrest
What are 2 clinical uses of cholinomemetics in the CNS?
Alzheimer’s
Smoking cessation
How would cholinomemetics help in Alzheimer’s?
AChE inhibitors allow ACh to hang out in synaptic cleft for longer to reach receptors and produce effect
Pallative effect, not a cure
How do cholinomemetics help with smoking cessation?
Direct nicotinic agonists help to decrease cravings and pleasurable effects of cigarettes
How do cholinomimetic’s indirectly effect the peripheral nervous system?
cause discharge of both sympathetic AND parasympathetic nervous systems
What are some of the indirect effects of cholinomemetics on the peripheral nervous system?
Increase BP
Sympathetic tachycardia or vagal induced bradycardia
Parasympathetic effects on GI tract –> nausea, vomitting, diarrhea, urinary voiding
Describe how ACh acts @ the neuromuscular junction
ACh is released from presynaptic neurons
ACh binds to nicotinic cholinergic receptors on the muscle fiber –> depolarization of muscle fiber –> contraction of skeletal muscle
What is the low dose effect of AChE inhibitors @ the neuromuscular junction?
prolong the effects of ACh –> increase strength of muscle contraction
What is the medium dose effect of AChE inhibitors @ the neuromuscular junction?
can cause muscles to fibrillate –> muscle = less effective
What is the high dose effect of AChE inhibitors @ the neuromuscular junction?
block muscle depolarization –> muscle paralysis
What is Myasthenia Gravis?
Autoimmune disorder; antibodies target nicotinic receptors –> block ACh binding
Which drug type is useful in treating Myasthenia Gravis and why is it an effective treatment?
AChE inhibitors are drug of choice
blocks AChE and allows ACh time to find and bind receptors that aren’t blocked by antibodies
When would you use the drug neostigmine and what does it do?
following surgery, reverses neuromuscular paralysis
What are the consequences of excessive anticholinergic actions?
Can be lethal in kids
cause arrhythmias in adults
How would you want to treat anticholinergic intoxication?
AChE inhibitors
want to increase amount of ACh @ receptor site
What is the toxicity of cholinomimetics dependent on?
Receptor type: Muscarinic vs Nicotinic
Mechanism of Action: Direct cholinomimetic vs AChE inhibitor
What are some signs of direct muscarinic agonist toxicity?
Nausea
Vomitting
Diarrhea
Urinary urgency
Salivation
Sweating
Cutaneous vasodilation
Bronchial Constriction
How would you treat direct muscarinic agonist toxicity?
Anticholinergic –> Atropine
What are some of the signs of acute nicotine toxicity?
Infants = vomitting (ingestion of 2 cigarettes which contain fatal dose of nicotine)
Large doses:
CNS stimulation (convulsions, coma, respiratory arrest)
Skeletal muscle depolarization –> blockade/ respiratory paralysis
hypertension/cardiac arrhythmias
How would you treat acute nicotine toxicity?
supportive treatment until drug is metabolized (several hours)
What are some of the effects of chronic nicotine toxicity?
nicotine addiction
What is the most common cause of toxicity caused by cholinesterase inhibitors?
pesticide exposure
What are some of the symptoms of cholinesterase inhibitor toxicity?
Muscarinic excess:
Miosis (pupillary constriction)
Salivation
Sweating
Bronchial constriction
Diaphragm paralysis
Vomitting
Diarrhea
Convulsions
How would you treat cholinesterase inhibitor toxicity?
Monitor Vital Signs
Decontaminate if possible
Antidote w/ parenternal atropine or pralidoxime (2-PAM)
2-PAM reactivates inhibited AChE before full covalent bond forms through “aging”
