Pharmacology- Autonomic drugs Flashcards
Acetylcholine receptors
Nicotinic
Nicotinic ACh receptors are ligand-gated Na+/K+ channels.
Two subtypes: NN (found in autonomic ganglia, adrenal medulla) and NM (found in neuromuscular junction of skeletal muscle).
Acetylcholine receptors
Muscarinic
Muscarinic ACh receptors are G-protein–coupled receptors that usually act through 2nd messengers.
5 subtypes: M1–5 found in heart, smooth muscle, brain, exocrine glands, and on sweat glands (cholinergic sympathetic).
G-protein–linked second messengers
α1 (Q)
α2 (i)
β1 (s)
vascular smooth muscle contraction, mydriasis, Increase intestinal and bladder sphincter muscle contraction.
Decrease sympathetic (adrenergic) outflow, Decrease insulin release, Decrease lipolysis, Increase platelet aggregation, Decrease aqueous humor production.
Increase: heart rate, contractility, renin release, lipolysis.
G-protein–linked second messengers
β2 (s)
β3 (s)
Vasodilation, bronchodilation (two lungs), Increase lipolysis, Increase insulin release, Increase glycogenolysis, decrease uterine tone (tocolysis),
Increase aqueous humor production, Increase cellular K+ uptake.
Increase: lipolysis, thermogenesis in skeletal muscle, bladder relaxation.
G-protein–linked second messengers
M1 (Q)
M2 (i)
M3 (Q)
Mediates higher cognitive functions, stimulates enteric nervous system
Decrease heart rate and contractility of atria
Increase: exocrine gland secretions, gut peristalsis, bladder contraction, bronchoconstriction, miosis, accommodation, insulin release.
G-protein–linked second messengers
D1 (s)
D2 (i)
Relaxes renal vascular smooth muscle, activates direct pathway of striatum.
Modulates transmitter release, especially in brain, inhibits indirect pathway of striatum
G-protein–linked second messengers
H1 (q)
H2 (s)
Increase: nasal and bronchial mucus production, vascular permeability, bronchoconstriction, pruritus, pain.
Gastric acid secretion
G-protein–linked second messengers
V1 (Q)
V2 (s)
vascular smooth muscle contraction
H2O permeability and reabsorption via upregulating aquaporin-2 in collecting twobules (tubules) of kidney.
“After QISSeS (kisses), you get a QIQ(kick) out of SIQ(sick) SQS(super qinky sex).”
pag. 234
Release of norepinephrine from a sympathetic nerve ending
is modulated by NE itself, acting on presynaptic α2-autoreceptors, negative feedback.
Autonomic drugs
Pag. 235
Cholinomimetic agents
Direct agents
Bethanechol
Carbachol
Methacholine
Pilocarpine
Bethanechol
- Action
- Applications
Activates bowel and bladder smooth muscle; resistant to AChE. No nicotinic activity.
Postoperative ileus, neurogenic ileus, urinary
retention
Carbachol
- Action
- Applications
Carbon copy of acetylcholine (but resistant to AChE).
Constricts pupil and relieves intraocular pressure in open-angle glaucoma.
Methacholine
- Action
- Applications
Stimulates muscarinic receptors in airway when inhaled.
Challenge test for diagnosis of asthma
Pilocarpine
- Action
- Applications
Contracts ciliary muscle of eye (open-angle glaucoma), pupillary sphincter (closed-angle glaucoma); resistant to AChE, can cross bloodbrain barrier (tertiary amine).
Potent stimulator of sweat, tears, and saliva. Open-angle and closed-angle glaucoma, xerostomia (Sjögren syndrome).
Cholinomimetic agents Indirect agonists (anticholinesterases)
Donepezil, rivastigmine, galantamine Edrophonium Neostigmine Physostigmine Pyridostigmine
Donepezil, rivastigmine, galantamine
- Clinical use
DONa RIVA dances at the GALA: alzheimer
Edrophonium
- Clinical use
Historically used to diagnose myasthenia gravis; replaced by anti-AChR Ab (anti-acetylcholine receptor antibody) test.
Neostigmine
- Clinical use
Postoperative and neurogenic ileus and urinary retention, myasthenia gravis, reversal of neuromuscular junction blockade (postoperative).
- No CNS penetration (quaternary amine)
Physostigmine
Antidote for anticholinergic toxicity; physostigmine “phyxes” atropine overdose.
*CNS (tertiary amine).
Pyridostigmine
Myasthenia gravis (long acting);
*does not penetrate CNS (quaternary amine).
Cholinesterase inhibitor poisoning
- Clinical Manifestations
- Etiology
- Antidote
DUMBBELSS:
Diarrhea, Urination, Miosis, Bronchospasm, Bradycardia, Emesis, Lacrimation, Sweating, and Salivation.
Often due to organophosphates, such as parathion. often components of insecticides; poisoning usually seen in farmers.
Antidote—atropine (competitive inhibitor) + pralidoxime (regenerates AChE if given early).
Muscarinic antagonists (names, applications)
- Eye
- CNS
- GI, Respiratory
- GI
Atropine, homatropine, tropicamide: Produce mydriasis and cycloplegia.
Benztropine, trihexyphenidyl: Parkinson disease (“park my Benz”). Acute dystonia.
Glycopyrrolate: Parenteral: preoperative use to reduce airway secretions. Oral: drooling, peptic ulcer.
Hyoscyamine, dicyclomine: Antispasmodics for irritable bowel syndrome.
Muscarinic antagonists (names, applications)
- Respiratory
- Genitourinary
- CNS
Ipratropium, tiotropium: COPD, asthma
Oxybutynin, solifenacin, tolterodine: Reduce bladder spasms and urge urinary. incontinence (overactive bladder).
Scopolamine: Motion sickness
Atropine adverse effects
Side effects: Hot as a hare Dry as a bone Red as a beet Blind as a bat Mad as a hatter Full as a flask
Jimson weed (Datura) produce gardener’s pupil (mydriasis due to plant alkaloids).
Direct Sympathomimetics: Names and action
Albuterol, salmeterol, terbutaline (β2 > β1) Dobutamine (β1 > β2, α) Dopamine (D1 = D2 > β > α) Epinephrine (β > α) Fenoldopam (D1) Isoproterenol (β1 = β2) Midodrine (α1) Mirabegron (β3) Norepinephrine (α1 > α2 > β1) Phenylephrine (α1 > α2)
Albuterol, salmeterol, terbutaline (β2 > β1)
- Clinical use
- Albuterol for acute asthma or COPD.
- Salmeterol for long-term asthma or COPD management.
- Terbutaline for acute bronchospasm in asthma and tocolysis.
Dobutamine (β1 > β2, α)
Dopamine (D1 = D2 > β > α)
Heart failure (HF), cardiogenic shock (inotropic > chronotropic), cardiac stress testing.
Unstable bradycardia, HF, shock; inotropic and
chronotropic effects at lower doses due to β effects; vasoconstriction at high doses due to α effects.
Epinephrine (β > α)
Fenoldopam (D1)
Anaphylaxis, asthma, open-angle glaucoma; α effects predominate at high doses. Significantly stronger effect at β2-receptor than norepinephrine.
Postoperative hypertension, hypertensive crisis. Vasodilator (coronary, peripheral, renal, and splanchnic). Promotes natriuresis. Can cause hypotension and tachycardia.
Isoproterenol (β1 = β2)
Midodrine (α1)
Mirabegron (β3)
Electrophysiologic evaluation of tachyarrhythmias. Can worsen ischemia.
Autonomic insufficiency and postural hypotension. May exacerbate supine hypertension.
Urinary urge incontinence or overactive bladder.
Norepinephrine (α1 > α2 > β1)
Phenylephrine (α1 > α2)
Hypotension, septic shock
Hypotension (vasoconstrictor), ocular procedures
(mydriatic), rhinitis (decongestant), ischemic priapism.
Indirect sympathomimetics (clinical uses)
- Amphetamine
- cocaine
- ephedrin
Narcolepsy, obesity, ADHD.
Causes vasoconstriction and local anesthesia. Caution when giving β-blockers if cocaine intoxication is suspected
Nasal decongestion (pseudoephedrine), urinary incontinence, hypotension.
Norepinephrine vs isoproterenol
NE Increase systolic and diastolic pressures as a result of α1-mediated vasoconstriction and increase mean arterial pressure and reflex bradycardia.
isoproterenol (rarely used) has little α effect but causes
β2-mediated vasodilation, resulting in low mean arterial pressure and high heart rate through β1 and reflex activity.
Sympatholytics (α2-agonists) (uses and toxicity)
- Clonidine, guanfacine
Hypertensive urgency (limited situations), ADHD, Tourette syndrome, symptom control in opioid withdrawal.
CNS depression, bradycardia, hypotension, respiratory depression, miosis, rebound hypertension with abrupt cessation
Sympatholytics (α2-agonists) (uses and toxicity)
- α-methyldopa
Hypertension in pregnancy
Direct Coombs ⊕ hemolysis, drug-inducedlupus
Sympatholytics (α2-agonists) (uses and toxicity)
- Tizanidine
Relief of spasticity
Hypotension, weakness, xerostomia
α-blockers Nonselective (clinical uses and toxicity)
- Phenoxybenzamine
- Phentolamine
Irreversible. Pheochromocytoma (used preoperatively) to prevent catecholamine (hypertensive) crisis.
Reversible. Give to patients on MAO inhibitors who eat tyramine-containing foods and for severe cocaine-induced hypertension (2nd line).
Adverse effects: Orthostatic hypotension, reflex tachycardia
α-blockers α1 selective (-osin ending) (clinical uses and toxicity)
- Prazosin, terazosin, doxazosin, tamsulosin
Urinary symptoms of BPH; PTSD (prazosin); hypertension (except tamsulosin).
1st-dose orthostatic hypotension, dizziness, headache
α-blockers α2 selective (clinical uses and toxicity)
- Mirtazapine
Depression
Sedation, High serum cholesterol, increase appetite
Effects of α-blocker (eg, phentolamine) on BP responses to epinephrine and phenylephrine.
Epinephrine response exhibits reversal of mean arterial pressure from a net increase (the α response) to a net decrease (the β2 response).
Phenylephrine response is suppressed but not reversed because it is a “pure” α-agonist (lacks β-agonist properties).
β-blockers Applications:
- Angina pectoris
- Glaucoma
- Heart failure
- Hypertension
Reduce heart rate and contractility, resulting in lower O2 consumption.
Reduce production of aqueous humor. Timolol
Decrease mortality. Bisoprolol, carvedilol, metoprolol
Decrease cardiac output, decrease renin secretion
β-blockers Applications:
- Hyperthyroidism
- Hypertrophic cardiomyopathy
- Myocardial infarction
- Supraventricular tachycardia
- Variceal bleeding
Symptom control ( heart rate, tremor), thyroid storm. Propranolol
Decrease heart rate increasing filling time, relieving
obstruction.
Reduce mortality
Decrease AV conduction velocity (class II antiarrhythmic). Metoprolol, esmolol
Decrease hepatic venous pressure gradient and portal hypertension (prophylactic use). Nadolol, propranolol, carvedilol
β1-selective antagonists (β1 > β2)
acebutolol (partial agonist), atenolol, betaxolol, bisoprolol, esmolol, metoprolol.
“go from A to M” (β1 with 1st half of alphabet)
Nonselective antagonists (β1 = β2)
nadolol, pindolol (partial agonist), propranolol, timolol.
“go from N to Z” (β2 with 2nd half of alphabet)
Nonselective α- and β-antagonists
carvedilol, labetalol
Nevibolol
“Nebivolol increases NO”
β1‑adrenergic blockade with stimulation of β3‑receptors (activate nitric oxide synthase in the vasculature and decrease SVR)
Beers criteria
Widely used criteria developed to reduce potentially inappropriate prescribing and harmful polypharmacy in the geriatric population. Includes > 50 medications that should be avoided in elderly patient. Examples:
α-blockers (risk of hypotension).
Anticholinergics, antidepressants, antihistamines, opioids (risk of delirium, sedation, falls, constipation, urinary retention).
Benzodiazepines (risk of delirium, sedation, falls)
NSAIDs (risk of GI bleeding, especially with concomitant anticoagulation)
PPIs (risk of C difficile infection)
Ingested seafood toxins
- Histamine (scombroid poisoning)
Spoiled dark-meat fish such as tuna, mahimahi, mackerel, and bonito.
Bacterial histidine decarboxylase converts histidine to histamine.
Mimics anaphylaxis, May progress to bronchospasm, angioedema, hypotension.
Antihistamines. Albuterol and epinephrine if needed.
Ingested seafood toxins
- Tetrodotoxin
Pufferfish
binds fast voltagegated Na+ channels in cardiac/nerve tissue, preventing despolarization.
Nausea, diarrhea, paresthesias, weakness, dizziness,
loss of reflexes.
Supportive
Ingested seafood toxins
- Ciguatoxin
Reef fish such as barracuda, snapper, and moray eel.
Opens Na+ channels, causing depolarization.
Nausea, vomiting, diarrhea; perioral numbness; reversal of hot and cold sensations; bradycardia, heart block, hypotension.
Supportive
