Autonomic Drugs

Autonomic Physiology

• One adverse effect of anti-muscarinics is hyperthermia, especially in infants "Hot as a hare" due to inhibition of sweat glands (M3 receptors) Infants already have a lot of brown fat (contains thermogenin which is an oxidative uncoupler), so much more prone to hyperthermia
• The acetylcholine from pre-ganglionic neurons of the ANS binds to neural nicotinic (NN) receptors
• The acetylcholine from post-ganglionic neurons of the ANS binds to muscarinic (M) receptors
• What is the effect of parasympathetic innervation on salivary secretion? Increased secretion Via muscarinic receptors

Cholinergic Direct Agonists

• Carbachol contracts the pupillary sphincter muscle, which may be used to treat closed-angle glaucoma Also relieves intraocular pressure in open-angle glaucoma (by contracting ciliary muscles) Carbachol agonizes muscarinic and nicotinic receptors
• Is carbachol a muscarinic or nicotinic ACh agonist? Both :)
• Nerves and CNS
• Where are M2 receptors found?
• (1) Atria (2) SA (3) AV
• Where are M3 receptors found?
• (1) Smooth muscle (2) Glands
• How does M3 activation lead to vasodilation?
• NO release (Binding M3 on endothelium ⇒ NO release ⇒ Dilate smooth muscle)
• Indications (2) : Bethanechol
• (1) Non-obstructive GI dysmotility (2) Urinary retention
• How does Pilocarpine treat glaucoma?
• (1) Contract ciliary muscle (2) Constricts pupillae muscle (Ciliary muscle contraction ⇒ ↑ Aqueous humor outflow)
• MOA: Varenicline
• Nicotinic receptor PARTIAL agonist
• What cholinomimetic drug is used for asthma testing?
• Methacholine
• What cholinomimetic drug is used for smoking cessation?
• Varenicline
• What effect do muscarinic agonists have on the lens of the eye?
• Induce accomodation
• How does Pilocarpine increase the outflow of aqueous humor?
• Contracts the ciliary muscle
• Why is Pilocarpine helpful in acute angle-closure glaucoma?
• Contracts the sphincter pupillae m.
• MOA: Carbachol
• (1) Muscarinic agonist (2) Nicotinic agonist
• Name 2 cholinergic drugs used to treat acute angle-closure glaucoma
• (1) Pilocarpine (2) Carbachol
• What is the only cholinergic agonist used to treat xerostomia?
• Pilocarpine
• 1.1
• Cholinomimetics
• Do acetylcholinesterase inhibitors enhance ACh activity at muscarinic or nicotinic receptors? Both :)
• Through what receptor does the parasympathetic nervous system decrease heart rate? M2 muscarinic receptor
• Parasympathetic stimulation decreases atrial contractility via M2 receptors Decreases the inward Ca2+ current during the plateau of the cardiac action potential
• What G-protein is the M1 muscarinic receptor coupled to? Gq Works via induction of PLC to cleave PIP2 to IP3 and DAG to increase intracellular Ca2+ and activate PKC
• What G-protein is the M2 muscarinic receptor coupled to? Gi This works via inhibition of adenylyl cyclase, leading to reduction in intracellular cAMP
• What G-protein is the M3 muscarinic receptor coupled to? Gq Gq works by stimulating PLC which cleaves PIP2 to IP3 and DAG, which respectively lead to increased intracellular Ca2+ and stimulation of PKC
• M1 muscarinic receptors are found in the CNS and ENS ENS is the enteric nervous system
• What organ does the M2 receptor primarily affect? Heart
• What is the effect of M2 muscarinic agonists on heart rate? Decreased HR (SA node)
• What is the effect of M2 muscarinic agonists on conduction velocity? Decreased CV (AV node)
• The M3 muscarinic receptor is found in glands, the bladder, and smooth muscle
• In healthy patients, M3 receptor activation indirectly causes vasodilation via release of nitric oxide Acetylcholine acts on the endothelium to increase nitric oxide synthase activity
• In atherosclerotic patients, M3 receptor activation directly causes vasoconstriction In healthy patients, M3 receptor activation causes the vascular endothelium to produce nitric oxide
• What drug class does bethanechol belong to? Cholinomimetics (muscarinic agonists) Agonizes M1 & M3 receptors
• What drug class does pilocarpine belong to? Cholinomimetics (muscarinic agonists) Pilocarpine is an M3 receptor agonist
• Pilocarpine is a potent stimulator of tears, sweat, and salivary secretion Useful in the treatment of xerostomia (dry mouth) in Sjögren syndrome M3 receptors are found on glands
• What drug class does methacholine belong to? Cholinomimetics (muscarinic agonists) M3 receptor agonist
• Varenicline is a(n) nicotinic receptor partial agonist used for smoking cessation Reduces withdrawal and cravings and reduces the rewarding effects of nicotine May cause sleep disturbances and depressed mood as adverse effects
• What is the predominant autonomic receptor on the pupillary sphincter muscle? M3 Stimulation causes miosis; inhibition causes mydriasis
• What is the predominant autonomic receptor on the ciliary muscle? M3 Stimulation causes accommodation (near vision); relaxation allows focus for far vision M3 helps you see clearLY

Acetylcholinesterase Inhibitors

• The effects of cholinergic toxicity may be remembered with the mnemonic DUMBBELSS Diarrhea Urination Miosis Bronchospasm Bradycardia / Bradypnea Emesis Lacrimation Salivation Sweating Often due to organophosphates
• Acetylcholinesterase inhibitor poisoning causes flaccid paralysis due to NMJ nicotinic ACh receptor overactivation Give pralidoxime to treat flaccid paralysis due to organophosphate poisoning

Antimuscarinics (Anticholinergics)

• Urgency incontinence may be treated with M3 antagonists or β3 agonists M3 antagonists (e.g., oxybutynin) decrease parasympathetic tone of the detrusor muscle β3 agonists (e.g., mirabegron) cause relaxation of detrusor muscle
• The effects of cholinergic toxicity may be remembered with the mnemonic "DUMBBELSS": Diarrhea Urination Miosis Bronchospasm Bradycardia / Bradypnea Emesis Lacrimation Salivation Sweating Often due to organophosphates These are all muscarinic effects that can be reversed by atropine Nicotinic effects include neuromuscular blockade and require pralidoxime for reversal
• Organophosphate toxicity may be treated with pralidoxime, which regenerates acetylcholinesterase (AChE) at muscarinic and nicotinic receptors if given early Give atropine first because pralidoxime can cause transient inhibition of AChE Drug MOA Treats Other Pralidoxime Regenerates AChE Cholinergic toxicity (e.g., organophosphate / cholinesterase inhibitor toxicity) Pyridostigmine AChE inhibitor Myasthenia gravis Does not cross BBB Physostigmine AChE inhibitor Anticholinergic toxicity (e.g., atropine, Jimson weed) Crosses BBB
• Does pralidoxime reverse the flaccid paralysis associated with cholinesterase inhibitor poisoning? Yes Effective at both muscarinic and nicotinic receptors Physostigmine AChE inhibitor used to treat anticholinergic toxicity (e.g., atropine, Jimson weed) (crosses the BBB) Pyridostigmine long-acting AChE inhibitor for myasthenia gravis (does NOT cross the BBB) Drug MOA Treats Other Pralidoxime Regenerates AChE Cholinergic toxicity (e.g., organophosphate / cholinesterase inhibitor toxicity) Pyridostigmine AChE inhibitor Myasthenia gravis Does not cross BBB Physostigmine AChE inhibitor Anticholinergic toxicity (e.g., atropine, Jimson weed) Crosses BBB
• What drug class may be used in the treatment of urgency incontinence? Anti-muscarinic agents (e.g., oxybutynin) First-line treatment should consist of lifestyle modifications and/or bladder training A newer agent, mirabegron (β3-adrenergic agonist) may be offered to patients who cannot take antimuscarinic drugs (e.g., narrow angle glaucoma)
• Bladder training, mirabegron, and oxybutynin are used to treat urge incontinence First-line treatment should consist of lifestyle modifications + bladder training A newer agent, mirabegron (β3-adrenergic agonist) may be offered to patients who cannot take antimuscarinic drugs (e.g., narrow-angle glaucoma) Think about training the bladder to not be so hyperactive
• Scopolamine is a(n) nonselective muscarinic antagonist used for treating vestibular nausea (motion sickness) Though the anti-motion sickness is mediated via M1 receptors, it is non-selective and will induce other anticholinergic effects (pupil dilation, dry mouth, tachycardia)
• Nebulized ipratropium is a muscarinic antagonist that may be used to treat acute, severe asthma exacerbation
• Ipratropium is a competitive M3 receptor antagonist that is used to prevent bronchoconstriction in asthmatic and COPD patients
• In addition to asthma, ipratropium may also be used to treat COPD
• Suffix: AChE inhibitors "-stigmine" What drug is used for long-term treatment of myasthenia gravis? Pyridostigmine What drug is administered to test for myasthenia gravis? Edrophonium What does a negative tensilon test suggest? Cholinergic crisis Is Curare a depolarizing or non-depolarizing NMJ blocker? Non-depolarizing Is Succinylcholine a depolarizing or non-depolarizing NMJ blocker? Depolarizing What AChE inhibitor has CNS effects? Physostigmine What drug is used to reverse Atropine poisoning? Physostigmine Name two naturally occuring forms of Atropine (1) Belladona (2) Jimson weed Treatment: Organophosphate poisoning (1) Pralidoxime (2) Atropine Name three AChE inhibitors used to treat Alzheimers (1) Galantamine (2) Rivastigmine (3) Donepezil MOA: Pralidoxime Regenerates AChE Do AChE inhibitors reverse nondepolarizing or depolarizing neuromuscular blockades? Non-depolarizing Would an AChE inhibitor reverse the action of succinylcholine during phase 1 or phase 2 of the blockade? Phase 2 MOA: Organophosphates AChE inhibitor What determines whether Pralidoxime will be effective at treating organophosphate poisoning? Whether the organophosphate-cholinsterase complex has aged How can you tx overstimulation of muscarinic receptors via AChEi? glycopyrrolate How do AChEi cause syncope? Enhanced parasympathetic tone -> bradycardia and AV block 1.2 Acetylcholinesterase Inhibitors
• What drug class does atropine belong to? Antimuscarinics Inhibits all classes of muscarinic receptors (M1 → M5)
• Atropine is found in belladona flowers and jimson weed, which are natural antimuscarinic alkaloids "gardener's pupil": mydriasis due to plant alkaloids Jimson weed (Datura stramonium): Photo credit: No machine-readable author provided. Taka assumed (based on copyright claims)., CC BY-SA 3.0, via Wikimedia Commons Atropa belladonna: Photo credit: Danny S., CC BY-SA 3.0, via Wikimedia Commons
• What effect do antimuscarinics have on pupils? Dilation (mydriasis) Photo credit: Nutschig at the English-language Wikipedia, CC BY-SA 3.0, via Wikimedia Commons
• What effect do antimuscarinics have on heart rate? Increased HR Via blockage of parasympathetic activity of M2 receptors May be useful for treatment of bradycardia
• What effect do antimuscarinics have on AV conduction velocity? Increased conduction velocity Via blockage of parasympathetic activity of M2 receptors; may be useful for treatment of AV block
• Ipratropium and tiotropium primarily affect the lungs via inhibition of M3 muscarinic receptors Inhaled muscarinic antagonists
• Antimuscarinics may be used to dilate bronchial airways and to reduce secretions Useful in the treatment of COPD and asthma
• What drug class do oxybutynin, tolterodine, and solifenacin belong to? Oral M3 antimuscarinic
• Oxybutynin and tolterodine primarily affect the genitourinary system via inhibition of M3 muscarinic receptors
• Oxybutynin and tolterodine are primarily used to treat urgency incontinence (overactive bladder) Reduces bladder spasms and urgency incontinence (overactive bladder) via relaxation of the smooth muscle of the ureter and bladder wall (detrusor muscle)
• Benztropine and trihexyphenidyl primarily affect the CNS via inhibition of M1 muscarinic receptors
• M1 muscarinic antagonists (e.g., benztropine / trihexyphenidyl) can reduce pill-rolling tremors and cogwheel rigidity in Parkinson disease Tremor and rigidity may result from relative excess of cholinergic activity in the setting of deficient dopamine activity Parkinson tremor: Photo credit: Dr. Osama Shukir Muhammed Amin FRCP (Glasg), used with permission.
• Benztropine may be used to treat extrapyramidal side effects caused by antipsychotic drugs (e.g., dystonia, akathisia, parkinsonism) Helps re-establish dopaminergic-cholinergic balance
• What effect does atropine have on stomach acid secretion? Decreased acid secretion Atropine is a general muscarinic antagonist Inhibition of the vagus nerve on parietal cells
• What effect does atropine have on gut motility? Decreased motility
• Atropine may be used to decrease urinary urgency in cystitis
• Which cholinergic effects are NOT alleviated by atropine administration in cholinesterase inhibitor poisoning? Nicotinic effects (e.g. muscle weakness) i.e., excitation of skeletal muscle
• One adverse effect of antimuscarinics (e.g., atropine) is tachycardia Can be useful in the treatment of bradycardia
• Antimuscarinics cause hyperthermia due to inhibition of sweat glands via antagonism of M3 receptors "Hot as a hare"
• Adverse effects of antimuscarinics include dry eyes and mouth "Dry as a cracker" Due to decreased salivation and lacrimation
• One adverse effect of antimuscarinics is dry, flushed skin "red as a beet"
• Adverse effects of antimuscarinics on the eye and its muscles (not including glands) include mydriasis and cycloplegia "Blind as a bat"
• One adverse effect of antimuscarinics is acute closed-angle glaucoma, especially in elderly patients AntimusCArinics: Acute Closed-Angle
• Antimuscarinics may cause acute closed-angle glaucoma due to decreased outflow of aqueous humor, secondary to mydriasis "high-pressure as a kettle"
• β-blocker toxicity is treated with glucagon, saline, or atropine Glucagon has receptors on the heart and stimulates the Gs cascade, therefore it bypasses the β receptor Gs blockade, increasing cAMP in cardiac myocytes
• The extrapyramidal symptoms of antipsychotics may be managed with an M1 antagonist such as benztropine Also trihexyphenidyl Helps restore the cholinergic-dopaminergic balance; other treatment options include benzodiazepines and β-blockers
• Benztropine and trihexyphenidyl are antimuscarinic agents used to treat parkinsonism, especially tremor and rigidity Help restore the cholinergic-dopaminergic balance
• Organophosphate toxicity may be treated with atropine, which is a competitive inhibitor at muscarinic receptors only Treat with atropine first because pralidoxime can cause transient inhibition of AChE
• Does atropine reverse the flaccid paralysis associated with cholinesterase inhibitor poisoning? No, only effective at muscarinic receptors
• Treating organophosphate poisoning is two fold: - Atropine, which inhibits all subtypes of muscarinic receptors - Pralidoxime, which if given early, regenerates acetylcholinesterase (AChE) Organophosphates induce cholinergic toxicity Treat with atropine first, because pralidoxime can cause transient inhibition of AChE, which will worsen symptoms Drug MOA Treats Other Pralidoxime Regenerates AChE Cholinergic toxicity (e.g., organophosphate / cholinesterase inhibitor toxicity) Pyridostigmine AChE inhibitor Myasthenia gravis Does not cross BBB Physostigmine AChE inhibitor Anticholinergic toxicity (e.g., atropine, Jimson weed) Crosses BBB
• Drugs with anticholinergic properties can cause urinary retention by preventing detrusor muscle contraction and urinary sphincter relaxation Treatment of patients experiencing urinary retention involves urinary catheterization and discontinuing the medication
• What is the likely diagnosis in an elderly patient taking several medications that develops abdominal pain and suprapubic fullness? Urinary retention Treat with catheterization and discharge medication Due to anticholinergic properties of drugs such as TCAs, which prevent detrusor muscle contraction and urethral sphincter relaxation → cannot void
• Symptomatic bradycardia is managed initially with IV atropine Acute inferior wall myocardial infarction often causes sinus bradycardia due to an increase in vagal tone triggered by sinoatrial node and right ventricular wall ischemia Intravenous atropine is the initial treatment of choice in patients with hemodynamically significant bradycardia (e.g., pulmonary edema, hypotension) due to inferior wall myocardial infarction In patients with inadequate response, further treatment options include IV epinephrine or dopamine, or transcutaneous pacing| Review Epinephrine Review Dopamine
• What class of autonomic drugs should be avoided in patients with acute angle-closure glaucoma? Antimuscarinics (e.g., atropine) Also avoid using trihexyphenidyl for treating Parkinson disease tremors Photo credit: Jonathan Trobe, M.D., CC BY 3.0, via Wikimedia Commons Closed-angle glaucoma in the right eye: Photo credit: James Heilman, MD, CC BY-SA 3.0, via Wikimedia Commons

Adrenergic Agonists

• Rank the following receptors for affinity to norepinephrine, from highest to lowest: β1, α1, α2, α1 > α2 > β1
• Isoproterenol causes decreased mean arterial pressure Via β2-mediated vasodilation Isoproterenol only agonizes β1 and β2 receptors (both equally), NOT alpha (unlike dobutamine)| Review Isoproterenol
• Hypokalemia may be caused by increased intracellular entry of K+, which can occur with insulin, β-adrenergic agonists, and hematopoiesis May also occur with GI losses and renal K+ wasting (e.g., hyperaldosteronism, diuretics) “Beta brings in, Alpha allows out” ECF → ICF (insulin, β-agonists) ICF → ECF (hyperosmolarity, exercise, cell lysis)| Review Insulin Overview Watch Albuterol vs Salmeterol

Alpha Blockers

• Phentolamine is a non-selective reversible α1 and α2 adrenergic receptor antagonist Review Phentolamine
• Is phentolamine (α-blocker) reversible or irreversible? Reversible Non-selective, reversible α-blocker vs phenoxybenzamine which is non-selective, irreversible α-blocker| Review Phentolamine
• Is phentolamine (α-blocker) selective or non-selective? Non-selective Non-selective, reversible α-blocker| Review Phentolamine
• Phentolamine causes vasodilation α1 antagonist effect Given to patients who are on MAOIs who want to eat tyramine containing foods (cheeses)| Review Phentolamine
• Phenoxybenzamine is a non-selective irreversible α1 and α2 adrenergic receptor antagonist Review Phenoxybenzamine
• Is phenoxybenzamine (α-blocker) reversible or irreversible? Irreversible Non-selective irreversible α-blocker| Review Phenoxybenzamine
• Is phenoxybenzamine (α-blocker) selective or non-selective? Non-selective Non-selective irreversible α-blocker| Review Phenoxybenzamine
• Phentolamine may be given to patients on MAO inhibitors who eat tyramine-containing foods (e.g., wine, cheese) Review Phentolamine
• α-receptor antagonists may cause orthostatic hypotension as an adverse effect e.g., phenoxybenzamine, phentolamine, prazosin, tamsulosin, mirtazapine| Review Phentolamine Review Phenoxybenzamine
• α-receptor antagonists may cause reflex tachycardia as an adverse effect Review Phentolamine Review Phenoxybenzamine
• What drug class do prazosin, terazosin, doxazosin, and tamsulosin belong to? Selective α1 antagonists ("-osin")
• Selective α1 adrenergic antagonists (except tamsulosin) may be used to treat hypertension Use terazosin in patients with BPH and hypertension Tamsulosin is used to treat BPH only, and has little effect on blood pressure| Review -osin Drugs
• Prazosin is a selective α1 antagonist that may be used to treat nightmares related to post-traumatic stress disorder Review -osin Drugs
• What drug may be used to reduce nightmares in PTSD? Prazosin SSRIs/SNRIs remain first-line for treatment for PTSD| Review -osin Drugs
• Tamsulosin is a(n) selective α1A/D receptor antagonist used to treat benign prostatic hyperplasia (BPH) α1A receptor: prostate α1B receptor: blood vessels Terazosin: selective for α1 and non-selective for subtypes (α1A-D) Tamsulosin: selective for α1 and selective for subtypes α1A and α1D (no α1B antagonism therefore does not affect blood pressure)| Review -osin Drugs
• Terazosin is a(n) selective α1 receptor antagonist used to treat benign prostatic hyperplasia (BPH) in patients with hypertension Non-selective for α1A, α1B and α1D → therefore also relaxes vascular smooth muscle and lowers blood pressure| Review -osin Drugs

Beta Blockers

• A useful initial therapy for hyperthyroidism is a(n) β-adrenergic blocking agent, such as propranolol Due to thyroid hormones upregulation of β1 adrenergic receptors
• Prior to removal of a pheochromocytoma, irreversible α-blockers, such as phenoxybenzamine are administered, followed by β-blockers α-blockade must be achieved before giving β-blockers to avoid hypertensive crisis May use phentolamine (a shorter acting α-blocker) intraoperatively if needed| Review Phentolamine Review Phenoxybenzamine
• Metoprolol, propranolol, and esmolol are all examples of class II antiarrhythmics
• Atenolol, timolol, and carvedilol are all examples of class II antiarrhythmics
• What is the effect of β1-blockade on contractility (and SV)? Decreased contractility Decreased cAMP leads to decreased Ca2+| Review Beta-1 Selective Beta Blockers
• IV β1 antagonists, such as esmolol and metoprolol, can be used for hypertensive emergency Cardioselective β1 antagonists can be remembered with "A-BEAM"| Review Beta-1 Selective Beta Blockers
• Labetalol, an α- and β-antagonist, can be used for hypertensive emergency Carvedilol is not indicated for this use| Review Dual Alpha Beta Blockers
• β-blockers may decrease BP by inhibiting β1 receptors of the JGA, thus decreasing renin release Review Beta-1 Selective Beta Blockers Review Nonselective Beta Blockers
• Administration of β-blockers for cocaine intoxication causes extreme hypertension due to unopposed α1 activation
• α-antagonists (e.g., phentolamine) can be used to treat cocaine toxicity First-line → Benzodiazepines Second-line → α-antagonists (e.g., phentolamine) Avoid selective β-blockers → Risk of hypertension from unopposed α stimulation| Review Phentolamine
• β-blockers all have a(n) "-lol" suffix Review Beta-1 Selective Beta Blockers Review Nonselective Beta Blockers Watch Class 2 Antiarrhythmics
• β-blockers decrease cardiac contractility Via β1 antagonism| Review Side Effects of Beta Blockers Review Beta-1 Selective Beta Blockers
• β-blockers may cause bradycardia as a direct adverse effect Due to SA nodal inhibition| Review Side Effects of Beta Blockers Review Beta-1 Selective Beta Blockers
• β-blockers can cause or exacerbate heart block due to excessive AV nodal inhibition
• β-blockers are useful in the management of chronic, stable angina
• β-blockers treat angina by reducing heart rate and contractility, thus decreasing myocardial O2 demand
• What type of β-blocker is atenolol? Selective β1 antagonist (cardioselective) Selective β1 antagonists may be remembered with the mnemonic A-BEAM (atenolol, betaxolol, esmolol, acebutolol, metoprolol)| Review Beta-1 Selective Beta Blockers
• What type of β-blocker is betaxolol? Selective β1 antagonist (cardioselective) Selective β1 antagonists may be remembered with the mnemonic A-BEAM (atenolol, betaxolol, esmolol, acebutolol, metoprolol)| Review Beta-1 Selective Beta Blockers
• What type of β-blocker is esmolol? Selective β1 antagonist (cardioselective) Selective β1 antagonists may be remembered with the mnemonic A-BEAM (atenolol, betaxolol, esmolol, acebutolol, metoprolol) Esmolol is usually given IV| Review Beta-1 Selective Beta Blockers
• What type of β-blocker is acebutolol? Selective β1 partial agonist (cardioselective) Therefore contraindicated in ischemic heart disease due to partial β1 agonism Selective β1 antagonists may be remembered with the mnemonic A-BEAM (atenolol, betaxolol, esmolol, acebutolol, metoprolol)| Review Beta-1 Selective Beta Blockers
• What type of β-blocker is metoprolol? Selective β1 antagonist (cardioselective) Selective β1 antagonists may be remembered with the mnemonic A-BEAM (atenolol, betaxolol, esmolol, acebutolol, metoprolol)| Review Beta-1 Selective Beta Blockers
• β1 selective antagonists primarily suppress adrenergic stimulation of the heart (cardioselective) Selective β1 antagonists may be remembered with the mnemonic A-BEAM (atenolol, betaxolol, esmolol, acebutolol, metoprolol)| Review Beta-1 Selective Beta Blockers
• Cardioselective β-blockers are useful in the acute treatment of MI and other ACS (e.g., unstable, NSTEMI) Cardioselective = β1-selective
• Cardioselective (β1-selective) β-blockers are useful in the management of chronic heart failure Selective β1 antagonists may be remembered with the mnemonic A-BEAM (atenolol, betaxolol, esmolol, acebutolol, metoprolol)| Review Beta-1 Selective Beta Blockers
• Which nonselective β-blocker may be used in the treatment of CHF? Carvedilol Nonselective β-antagonist and selective α1-antagonist| Review Dual Alpha Beta Blockers
• What type of β-blocker is carvedilol? Nonselective β-antagonist and selective α1-antagonist Review Dual Alpha Beta Blockers
• Do cardioselective β-blockers reduce mortality in CHF and post-MI? Yes Cardioselective β1 antagonists can be remembered with "A-BEAM" Decreased CHF mortality is also associated with carvedilol (nonselective β-blockers) Carvedilol, metoprolol succinate, and bisoprolol provide a survival benefit by preventing sympathetic nervous system (SNS) remodeling of myocardium| Review Beta-1 Selective Beta Blockers Review Dual Alpha Beta Blockers
• β-blockers are useful in the treatment of chronic stable angina and hypertension, especially in patients with heart failure or post-MI β-blockers decrease cardiac output and renin secretion
• β-blockers inhibit production of renin Via antagonism of β1 receptors at the JGA| Review Beta-1 Selective Beta Blockers
• What type of β-blocker is labetalol? Non-selective β-antagonist and selective α1-antagonist
• Which two β-blockers are nonselective β-antagonists and selective α1-antagonists? - Labetalol - Carvedilol
• Labetalol causes vasodilation Via antagonism of α1 receptors| Review Dual Alpha Beta Blockers
• Which β-blocker is used to treat hypertension during pregnancy (AKA gestational hypertension)? Labetalol "La-baby-lol" Hypertension drugs in pregnancy can be remembered with: He Likes My Neonate Hydralazine Labetalol α-Methyldopa Nifedipine| Review Dual Alpha Beta Blockers
• β-blockers are useful in the management of hypertrophic obstructive cardiomyopathy and dilated cardiomyopathy Due to increased time in diastole & increased LV preload, which decreases LVOT obstruction| Review Beta-1 Selective Beta Blockers
• Propranolol is a β-blocker that is useful for the treatment of thyroid storm Blocks increased sympathetic activity as well as inhibiting 5'-deiodinase Also may be useful for symptomatic relief of hyperthyroidism (e.g., hypertension, tachycardia, heat intolerance); does not help with exophthalmos or myxedema One of the "4 P's" to treat thyroid storm: Propranolol Propylthiouracil (antithyroid agent) Prednisolone (corticosteroid) Potassium iodide (lugol iodine)
• What respiratory disorders may be exacerbated by non-selective β-blockers? Asthma and COPD Due to β2 antagonism| Review Side Effects of Beta Blockers Watch Class 2 Antiarrhythmics
• Timolol is a topical non-selective β-blocker that is used to treat glaucoma Antagonizes β2 receptors on ciliary epithelium causing decreased aqueous humor production| Review Nonselective Beta Blockers
• β-blockers can cause erectile dysfunction in men as an adverse effect "Floppy tromboner"| Review Side Effects of Beta Blockers Review Beta-1 Selective Beta Blockers Watch Class 2 Antiarrhythmics
• Which three β-blockers have partial agonist activity? Celiprolol, acebutolol, and pindolol "Put a CAP on β-blocker agonists"| Review Beta-1 Selective Beta Blockers Review Nonselective Beta Blockers
• Acebutolol and pindolol are contraindicated in heart failure, MI, and angina Due to partial β agonist activity| Review Beta-1 Selective Beta Blockers Review Nonselective Beta Blockers
• β-blockers may have CNS adverse effects, including seizures, sedation, and sleep alterations Review Side Effects of Beta Blockers Review Beta-1 Selective Beta Blockers Watch Class 2 Antiarrhythmics
• Metoprolol is a β-blocker that is associated with dyslipidemia as an adverse effect Review Beta-1 Selective Beta Blockers Watch Class 2 Antiarrhythmics
• β-blockers may mask symptoms of hypoglycemia However still not contraindicated benefits outweigh risks β₂ = ↑ insulin release α₂ =↓ insulin release| Review Side Effects of Beta Blockers Review Beta-1 Selective Beta Blockers Watch Class 2 Antiarrhythmics
• Propranolol is a β-blocker that may exacerbate vasospasm in Prinzmetal angina AKA vasospastic angina
• β-blockers may cause unopposed α1 agonism if given alone for cocaine toxicity or pheochromocytoma Give Alpha blockers Ahead of Beta blockers Exceptions: labetalol and carvedilol which are non-selective α1- and β-antagonists| Review Nonselective Beta Blockers Review Dual Alpha Beta Blockers
• Aqueous humor production is decreased with β antagonists e.g., timolol
• What is the first-line treatment for essential tremor? Non-selective β-blockers (e.g., propranolol) Also may use primidone (a barbiturate)| Review Nonselective Beta Blockers
• β-blockers (e.g., propranolol) can block peripheral conversion of T4 into T3 by inhibiting 5'-deiodinase Thus can be used to treat hyperthyroidism| Review Nonselective Beta Blockers
• Selective β-blockers are contraindicated in acute cocaine intoxication Treatment = benzodiazepines (alleviate psychomotor agitation and sympathomimetic effects) Nonselective α/β antagonists such as labetalol can be used Cocaine = sympathomimetic = vasoconstriction; don't want unopposed α constriction of coronary vessels Cocaine prevents the reuptake of serotonin, dopamine, and norepinephrine having many adrenergic agonist effects Vessels expresses α1 and β2 receptors and as norepinephrine has an affinity α>β cocaine causes hypertension By giving β-blockers, vasodilatory effect of β2 agonists is inhibited on the vessels thus leaving unopposed α1 agonism → vasoconstriction → HTN urgency/emergency

Clinical Applications

• The smooth muscle of the conducting airways of the lung constricts in response to parasympathetic activation of muscarinic (M3) receptors e.g., due to acetylcholine
• Urgency incontinence is due to an overactive bladder (detrusor muscle overstimulation) Thus, also known as "overactive bladder syndrome"; triggers include running water, hand washing, exposure to cold weather Can diagnose with urodynamic testing
• Activation of β1 adrenergic receptors on the SA node causes increased heart rate
• One adverse effect associated with selective α1 adrenergic antagonists is 1st-dose orthostatic hypotension Also may experience dizziness and headaches| Review -osin Drugs

High-Yield Pearls

• β-adrenergic antagonists cause K+ to shift out of cells, causing hyperkalemia This effect is mediated by blockade of β2 receptors “Beta brings in, Alpha allows out” ECF → ICF (insulin, β-agonists) ICF → ECF (hyperosmolarity, exercise, cell lysis)
• β-adrenergic agonists cause K+ to shift into cells, causing hypokalemia “Beta brings in, Alpha allows out” ECF → ICF (insulin, β-agonists) ICF → ECF (hyperosmolarity, exercise, cell lysis)
• Activation of the α1 adrenergic receptor causes vasoconstriction Thus increasing systemic vascular resistance (SVR)
• Activation of β1 adrenergic receptors on the cardiac myocytes causes increased cardiac contractility
• Activation of β2 adrenergic receptors causes coronary and skeletal muscle vasodilation