Peripheral Neuropharmacology and Acetycholine Agonists Flashcards
Muscarinic receptors - MoA
Stimulation leads to activation of G proteins which increase or decrease formation of second messengers
Which muscarinic receptors are coupled with Gq proteins, and what happens when they are activated?
M1, M3 and M5. Stimulates Phospholipase C –> Formation of IP3 and diacylglycerol (DAG)
Which muscarinic receptors are coupled with Galpha,i proteins, and what happens when they are activated?
M2 and M4. Decreases cAMP levels by inhibiting adenylate cyclase and increases potassium efflux.
Effects of M2 and M3
Mioisis, accomodation, lacrimation, mucus secretion, salivation, bronchoconstriction, increased hydrochloric acid secretion, increased motility
Effects of M2
Decreased AV conduction and decreased HR
Effects of M3
Micturation, erection,
Contracion of smooth muscles and stimulation of glandular secretions. Vasodilation
M1 - Location and MoA
Neural (autonomic ganglia, presynaptic nerve terminals and CNS).
Stimulates Phospholipase C –> Increases formation of IP3 and diacylglycerol (DAG)
Effects of M1
Modulation of neurotransmission
M2 - Location and MoA
Cardiac tissue (SA and AV node) Decreases cAMP levels by inhibiting adenylate cyclase and increases potassium efflux.
M3 - Location and MoA
Glandular, found in smooth muscle and glands + vascular smooth muscle
Increases IP3 and cGMP as a result of NO stimulation
Nicotinic receptors - Location (type) + MoA
Muscle type (somatic neuromuscular junctions) Ganglionic type (autonomic ganglia) CNS type Activation leads to sodium influx and membrane depolarization --> release of Ca from sarcoplasmic reticulum --> muscle contraction
Muscle type nicotonic receptor - Effects
Muscle contracion
Ganglionic and CNS type nicotinc receptor - Effects
Excitation of neurons
Direct-Acting Acetylcholine receptor agonists - Groups + synthetic drugs
Choline esters
Plant alkaloids
Cevimeline
Varenicline
Choline esters
Acethylcholine
Carbachol
Bethanecol
Choline esters - Effects
Ocular: Increased lacrimal gland secretion. Stimulates contraction of iris sphincter muscle (miosis) and ciliary muscles (accommodations of lens to focus close objects).
Respiratory: Increased bronchial muscle contraction and mucus secretion.
Cardiac: Decreased impulse formation in SA node by decreasing rate of diastolic depolarization –> slow the heart rate. Slow conduction of cardiac action potential through AV node –> increased PR interval
Vascular: vasodilation(M3 receptor), formation of NO
GI and UT: stimulate salivary, gastric secretion. Increased contraction of GI smooth muscle(Except sphincters) by stim ENS in gut wall –> Increased GI motility.
Stimulate bladder detrusor muscle, promotes emptying of the bladder.
What can high doses of choline esters lead to?
Excessive salvation, diarrhea, intestinal cramps and urinary incontinence.
Which choline esters activate both muscarinic and nicotinic receptors?
Acetylcholine and Carbachol
What is the name of the choline ester that selectively activates muscarinic receptors?
Bethanecol
Acetylcholine - Indication
Miosis during ophthalmic surgery
Diagnostic coronary angiography
Diagnose vasospastic angina pectoris
Carbachol - Indication
Miosis during ophthalmic surgery
Bethanecol - Indication
GI and urinary stimulation. Postop or postpartum to increase bladder muscle tone in pt with nonobstructive neurogenic urinary retention after anesthetics.
Postop adynamic ileus
Atonic stomach (gastroparesis)
Congenital megacolon
Bethanecol - Contraindication
IV adm –>leads to hypotension and bradycardia
Obstruction, BPH, PUD, COPD, Ischemic heart disease, Hyperthyroidsm, Parkinson
Plant alkaloids
Muscarine
Nicotine
Pilocarpine
Where is muscarine found and what is its adverse effects?
Found in toxic mushrooms.
Diarrhea, sweating, salivation and lacrimation
Nicotine - Indication
Smoking cessation programs
Pilocarpine - MoA
Greater affinity for muscarinic receptor
Pilocarpine - Indication
2nd line drug for chronic open angle glaucoma and acute angle closure glaucoma (by lowering intraocular pressure)
Xerostomia (by stimulating salivary gland secretion)
Pilocarpine - Adverse effects
Decreased night vision (caused by miosis)
Difficulty focusing on distal objects (lens accommodates for close vision)
Seizures
CNS damage
Cevimeline - MoA
Selectively activates M3 receptors
Cevimeline - Indication
Xerostomia in pt who have had radiation therapy for head/neck cancer
Pt with sjögren syndrome
Cevimeline - Adverse effects and Contraindication
Increased sweating,
Nausea,
Visual disturbances
Used cautiously in pt with asthma or cardiac arrhythmias
Varenicline - MoA
Partial agonist at the nicotinic receptor subtype found in the brain that mediates reinforcing effects of nicotine in smokers
Varenicline - Indication
Smoking cessation
Indirect-acting acetylcholine receptor agonist - MoA
Affect neurotransmitter synthesis, storage, release or metabolism
Edrophonium - MoA
Inhibits cholinesterase, preventing the breakdown of acetylcholine at all cholinergic synapses –> rapidly increases acetylcholine concentration
Edrophonium - Indication
Diagnosis of Myasthenia Gravis
Distinguish between myasthenia crisis and cholinergic crisis in pt treated with cholinesterase inhibitors
Anesthesia (reverse effect of neuromuscular blockade)
Physostigmine, Neostigmine and Pyridostigmine - MoA
Inh acetylcholinesterase which is responsible for the degradation of acetylcholine
Physostigmine - Indication
Myasthenia gravis
Reverse seizures and other CNS effects antimuscarinic drugs
Stimulate bladder and bowel
Overdose of atropine, phenothiazine, tricyclic antidepressants
Neostigmine - Indication
Myasthenia gravis Lambert-Eaton syndrome Diplopia Blurred vision Postop urinary retention and abdominal distention Tubocurarine toxicity Stimulate bowel and bladder
Neostigmine and Pyridostigmine - Adverse effects
In case of too high dose: increased muscle weakness due to neuromuscular blockade resulting from excessive ACh
Which drugs are used during surgery to reverse the effect of curariform when muscle relaxation is no longer required?
Edrophonium
Neostigmine
Pyridostigmine
Pyridostigmine - Indication
Myasthenia gravis (chronic)
Diplopia
Blurred vision
Which drugs are used for Alzheimer disease?
Donepezil
Galantamine
Rivastigmine
Donepezil, Galantamine, Rivastigmine - MoA
Crosses the blood brain barrier and act to increase the concentration of Ach at central cholinergic synapses
Echothiophate, Isoflurophate, Malathion - MoA
Irreversible acetylcholinesterase inh.
Echothiophate - Indication
Pesticide
Chronic glaucoma
Stabismus
Echothiophate - Adverse effects
Organophosphate toxicity
Systemic exposure: effects of muscarinic receptor activation; salivation, lacrimation, miosis, accommodative spasm, bronchoconstriction, intestinal cramps, urinary incontinence
Isoflurophate - Indication
Chronic glaucoma
Malathion - Indication
Pesticide, head lice
Type 5 phosphodiesterase inhibitors - MoA
ACh activates M3 receptors which leads to increased NO –> NO binds to guanylate cyclase and increase synthesis of cGMP. Type 5 phosphodiesterase inhibit breakdown of cGMP leading to increased smooth muscle relaxation –> increased blood flow into penis and erection.
Type 5 phosphodiesterase inhibitors - Adverse effects
Headache, Nasal congestion, dyspepsia, myalgia, backpain, visual disturbances.
Reduces supine blood pressure(blood pressure when lying on back)
Augments hypotensive effect of vasodilators (alpha-adrenoceptor antagonist) —> used to treat symptoms of urinary obstruction in men with BPH
Type 5 phosphodiesterase inhibitors - Contraindication
Men who use nitroglycerin or other organic nitrate. Leads to hypotension, reflex tachycardia, worsening of angina pectoris
Quasireversible cholinesterase inhibitors
Echothiophate
Isoflurophate
Malathion
Type 5 phosphodiesterase inhibitors
Sildenafil
Tadalafil
Vardenafil
Avanafil
Sildenafil - Indication
Erectile dysfunction
Pulmonary arterial hypertension
Which type 5 phosphodiesterase inhibitor should not be taken with high-fat meal and why?
Sildenafil, absorption is reduced
Tadalafil - Indication
Symptoms of BPH
Pulmonary arterial hypertension
Riociguat - MoA
Increases cGMP by directly stimulating guanylate cyclase
Riociguat - Indication
Pulmonary arterial hypertension
Riociguat - Contraindication
Not use with phosphodiesterase inhibitors due to resulting systemic hypotension
Indirect-Acting Acetylcholine Receptor Agonists groups
Reversible cholinesterase inhibitors Quasireversible cholinesterase inhibitors Hemicholinium Vesamicol Botulinum toxin Latrotoxin (Black Widow Spider)
Reversible cholinesterase inhibitors
Edrophonium Physostigmine Neostigmine Pyridostigmine Donepezil Galantamine Rivastigmine
Hemicholinium - MoA
Inhibit choline trasporters which will inhibit Acetylcholine synthesis
Vesamicol - MoA
Inhibit choline proton transporters on the vesicular membrane, so storage is inhibited
Botulinum toxin - MoA
Inhibits release of Acetylcholine from vesicles, causes muscle paralysis
Latrotoxin (Black Widow Spider) - MoA
Release massive amount of Acetylcholine which causes cholinergic crisis
