APEX - ANS Pharmacology & Pathophysiology

Methacholine

-Muscarinic receptor (M3) agonist. -Used in bronchial challenge test to help diagnose asthma.

The ANS relies on two neurotransmitters

ACh (acetylcholine) and NE (norepinephrine)

Which CCB is devoid of chronotropic effects and is ideally suited for IV infusion?

Clevidipine

Which selective alpha-2 agonist is more highly protein-bound?

Dexmedetomidine

Types of ACE inhibitors

Enalapril Captorpil Lisinopril

Which is not an endogenous sympathomimetic?

Ephedrine

If there is a phenylephrine overdose, what is the best course of action?

Given the direct activity of phenylephrine, an A2 adrenergic receptor antagonist, such as phentolamine is appropriate

Dopamine also undergoes metabolic degradation by COMT and MAO to form the end product

Homovanillic acid (HMA)

What are the best agents to augment the HR in the patient with heart transplant

Isoproterenol Epinephrine

Is phenylephrine arrhythmogenic?

It is not

Types of ARBs

Losartan Valsartan

Low dose NE vs High dose

Low dose favors B1 stimulation (increased HR, CO, inotropy, dromotropy) High Dose favors B1 and A effects (systemic vasoconstriction, except for coronary arteries and decreased HR)

Low dose epi vs high dose epi

Low dose favors beta stimulation (increased HR, CO, inotropy, and pulse pressure, decreased SVR) High dose = alpha receptors (increased SVR and decreased CO)

What enzyme metabolizes phenylephrine

MAO

Bethanachol

MOA: Cholinergic, stimulates M3/cholinergic/parasympathetic USES: post op and neurogenic ileum and urinatry retention fix

What CCB is often prescribed for Raynaud's disease

Nifedipine

Control of vascular tone with calcium channel blockers

Nifedipine and nicardipine are vasodilators and are best used in treatment of HTN from elevated SVR

Only CCB proven to reduce morbidity and mortality from cerebral vasospasm

Nimodipine

Which specific PDE inhibitors prevent platelet aggregation?

PDE3 inhibitors

Non-selective alpha-1 and alpha-2 antagonist

Phenoxybenzamine & Phentolamine

This is a synthetic catecholamine is almost exclusively a pure a1-agonist causing venous and arterial vasoconstriction that is useful in treating low resistance states?

Phenylephrine

There are 3 alpha-selective drugs:

Phenylephrine: a-1 selective Clonidine: a-2 selective Dexmedetomidine: a2-selective

Rapid administration of dexmedetomidine can stimulate

Postsynaptic alpha-2 receptors in the arterial and venous circulations leading to vasoconstriction and hypertension

Selective alpha -receptor antagonist

Prazosin, Tamsulosin, Yohimbine

The alpha-2 receptor is present throughout the body, and we can classify these locations in 3 ways:

Presynaptic - NE-releasing neurons in the CNS and PNS (negative feedback mechanisms reduce NE release) Postsynaptic - Smooth muscle and several organs Nonsynaptic - Platelets

Which beta-adrenergic non-selective antagonist may aggrevate Raynaud's disease and peripheral vascular disease

Propranolol

Non-selective Beta-adrenergic antagonist

Propranolol (prototype) nadolol pindolol timolol Carvedilol sotalol

Calcium channel blockers and contractility

Pt's w/ reduced EF, you want to preserve contractility while reducing HR Ca+2 impair contractility (highest to lowest) (verapamil>nifedipine>diltiazem>nicardipine In patient with decreased contractility - diltiazemis better than verapamil

Vasopressin acts specifically on

V1 - mediate CV effects such as increased SVR V2 - primarily function in the kidney as ADH V3 - pituitary gland and modulate autocoids

Since epi and norepi are blocked by the use of phenoxybenzamine, what is the best treatment for phenoxybenzamine-induced hypotension

Vasopressin and fluids

The dry cough associated with an ACE-inhibitor is MOST likely due to?

accumulation of bradykinin

Post-ganlionic PNS neurotransmission is

acetylcholine

Post-ganglionic sympathetic neurotransmission is

adrenergic (NE)

Short acting B2 agonist

albuterol, Terbutaline, Levalbuterol

Tamsulosin

analong of prazosin *Terazosin is less potent and longer acting, main use is treating prostate hypertrophy *Doxazosin and Tamsulosin have weaker vascular effects and are used primarily in treating prostate hypertrophy as large numbers of a1a receptors are located there **anesthetici-induced hypotension may be exacerabted

All three drugs (Atropine, glycopyrrolate, scopalamine) have

antisialagogue effect *glycopyrrolate is preferentially used d/t its lack of CNS effects and less effect on increasing HR

Which b-receptor antagonist undergoes renal metabolism

atenolol

atenolol

b1 receptor antagonist used to manage hypertension, chronic angina, follow-up in those who survived MI some benefits in cases of a-fib dosed by mouth (25-200 mg once or twice/day)

Significant reflex bradycardia may occur with phenylephrine d/t

baroreceptor activity

Ca+ Channel blockers

block biochemical pores preventing the movement of ions across biological membranes Target L(long) forms Treat HTN, arrhythmias, peripheral vascular disease, cerebral vasospasm, and angina

Low dose atropine (<0.1mg) may cause or worsen

bradycardia by blocking presynaptic M1 receptors

Esmolol

cardioselective B1 receptor antagonist that blocks epi/norepi largely replaced propranolol in perioperative anesthesia and is the first-line drug for rapid perioperative HR and BP control Laryngoscopy, intubation, surgical stimulation, sympathetic tachycardia associated with ECT specific esterases found in RBCs 10-80mg or as infusion (50-300mcg/kg/min)

Paragangliomas rarely secrete vasoactive substances, but when they do, norepinephrine secretion is most common

causes HTN serotonin/kallikrein may be released from a paraganglioma and cause carcinoid-like symptoms (bronchconstriction, diarrhea, headache, flushing, HTN) Octreotide can be used to treat carcinoid-like syndrome

All ganglionic neurotransmission is?

cholinergic (ACh)

B2 agonist

commonly used to treat asthma, COPD, and airway reactivity under anesthesia bronchodilation and minimize cardiac stimulation and arrhythmia

Metoprolol

competitive, cardioselective B1 receptor antagonist preventing the action of epi and norepi and can be administered orally or IV useful in ischemic heart disease similar to propranolol but less likely to trigger bronchospasm 2.5-5mg to max of 15 mg Prophylactic drug to avoid increases in HR or to maintain a stable and desirable rate once a crisis has resolved

ACE inhibitors

decrease generation of angiotensin reduce LV afterload cause plasma aldosterone levels to fall Decrease water and Na+ retention No orthostatic hypotension

Isoproterernol

derived from dopamine IV dose - 0.015-0.15 mcg/kg/min potent sympathomimetic - B1 abd B2 activity

Dobutamine

derived from isoproterenol enhances myocardial contractility and, at the same time, reduces vascular tone IV dose -2-20 mcg/kg/min "pharmacologic stress test" - chemical stress in place of exercise

3 major classes of calcium channel blockers

dihydropyridines (nifedipine, nimodipine, nicardipine, clevidipine) Benzothiazepines (diltiazem) Phenylalkylamines (verapamil)

Ephedrine

direct and indirect actions on the adrenoreceptors with indirect actions predominating IV dose =5-25mg Directly stimulates (a) and (b) receptors *thought to preserve uterine blood flow over phenyephrine in OB but phenylephrine is now preferred

Dopamine

dopaminergic and andrenergic receptors, but increases CO by its positive chronotropy, inotropic, and dromotropic activity via the B1 adrenergic receptor

Central anticholinergic syndrome phrase

dry as a bone, red as a beet, blind as a bat, hot as a hare, mad as a hatter dry mouth, lack of sweating Tachycardia, mydriasis, restlessness, confusion hot flushed skin, hallucinations, coma, death

Side effects of ACE inhibitors

dry cough - accumulation of bradykinin angioedema (life-threatening) - accumulation of bradykinin profound hypotension may occur with vasodilating general anesthesia that can be refractory to phenylephrine, ephedrine, and norepi Vasopressin (V1) may be the best treatment approach

Dopamine and the kidney

evidence that low dose infusion (<3ug/kg/min) in healthy patients increases renal blood flow and urine output *data is conclusive that dopamine doesnt prevent or reverse acute kidney injury or failure *can be associated with CV, pulmonary, GI, Immune and endocrine complications

Nitroglycerin

greater on venules than arterioles liberation of nitric oxide arterial BP and CO decrease in response to decrease preload Improves imbalance of mycoardial O2 supply and demand - dilates both normal and stenotic coronary arteries, preventing spasm; thus, excellent first-line treatment of cardiac ischemia

Prozonsin

highly selective a-1 receptor antagonist decreases peripheral vascular resistance in arterioles and veins, which increases venous capacitance, decreases preload and BP with little change in HR

Angiotensin Receptor Blockers (ARBs)

impair activity at AT1 receptor only while ACE inhibitors impair both AT1 and AT2 receptors may account for less side effects when compared to ACE inhibitors *not available as parenteral agents

B2 agonism works through

increasing intracellular cAMP, in uterine muscle, increased cAMP leads to decreased Ca+2 levels - uterine smooth muscle relaxation and a tocolytic effect

The transplanted heart is severed from autonomic influence, so the HR is determined by

intrinsic rate of SA node *resting tachycardia often (100-120bpm)

Which beta-blocker has intrnsic sympathetic activity (ISA)

labetalol

Low dose dopamine vs high dose

low dose - stimulates D1 receptors, resulting in vasodilation and increased renal and splanchnic blood flow high dose - pure A1 agonist - BP

Propranolol's use as an antidysrhythmic is BEST related to

membrane stabilizing ability (MSA)

Selective beta-adrenergic antagonist

metoprolol atenolol acebutolol esmolol bisoprolol

PDE3 inhibitors

milrinone & cilostazol increase levels of cAMP and cGMP; used in those with CV disease increased inotropy and relaxation of vascular and smooth muscle airway

Adrenergic agonist

mimic SNS effects via direct receptor activation or by encouraging endogenous catecholamine release cause profound, body-wide effects that must be carefully monitored to avoid adverse events like ischemia and arrhythmias Valuable in the clinical scenario that benefit from the stimulation of the mycardium, bronchodilation, and vasoconstriction

norepinephrine (NE)

mostly a1 and B1 effects. It has minimal B2 effects; 0.01-0.22 mcg/kg/min

Paraganglioma (glomangiomas)

neuroendocrine tumor that arises from neural crest cells *like pheochromocytoma except exist in extra-adrenal locations (surrounding the aorta or within the lungs, as well as the head and neck near the carotid artery, glossopharyngeal nerve, jugular vein, and middle ear)

Which is not a competitive inhibitor of acetylcholine

nicotine (cholinergic agonist)

Labetalol

non-selective adrenergic antagonist acute hypertension adequate HR present before administration may produce bronchospasm in patients with COPD or asthma

A common side effect of prazosin is:

orthostatic hypotension

What drugs is used virtually exclusively in the preoperative management of pheochromocytoma to normalize BP and prevent episodic HTN

phenoxybenzamine

Treatment for anticholinergic syndrome

physostigmine 1-2mg IV

Carvedilol

possesses antioxidant and anti-inflammatory properties considerable success in managing HF, LV dysfunction, HTN and acute MI

The most common side effect of prazosin is

postural or orthostatic hypotension

Multiple system atrophy

previously known as Shy-Drager Syndrome Urinary retention Bowel dysfunction Impotence postural hypotension pupillary reflex may be sluggish

Carbamycholine & Pilocarpine

produces miosis and have applications treating glaucoma. May be some use in treating cognitive issues in alzheimer's disease also

Phenoxybenzamine

prototype for this family of drugs - administered orally blocks a-mediated activity of norepinephrine and epinephrine resulting in lowering peripheral vascular resistance and BP Bonding of phenoxybenzamine to the receptor is irreversible

Propranolol (inderal)

prototype non-selective b-adrenergic antagonist orally or IV competitive B1/B2 antagonism that prevents epi, norepi, dopamine, dobutamine, and isoproterernol can produce bronchoconstriction, hypoglycemia, peripheral vascular constriction from B2 antagonism

Epinephrine

prototypical sympathomimetic - 0.01-0.2 mcg/kg/min a1, b1, & b2 agonist effects - more potent than norepi at beta receptors Potent vasoconstriction and bronchodilation

Black box warning with longer acting B2 selective agents (salmeterol and formoterol)

risk of asthma-related death possibly d/t the development of airway hyperresponsiveness

PDE4 inhibitors

roflumilast, apremilast, ibudilast increase levels of cAMP, targeting airways, skin, and immune system smooth muscle relaxation in those w/ hyperreactive airways useful in inflammatory states that affect skin, bowel, and joints

The A2 agonist have long been used in treating HTN, attention-deficit/hyperactivity sydromes, panic disorders, and drug and alcohol withdrawal. More recently, they have been expanding in providing

sedation, sympatholysis, and reducing anesthetic requirements

When using NTG, be cautious with nitric oxide liberation drugs like ____________ d/t risk of severe hypotension

sildenafil

PDE5 inhibitors

sildenafil, tadilafil, vardenafil increase levels of cGMP and target lungs and penis (viagra)

Phentolamine has an affinity for 5-HT receptors which?

stimulates stomach acid secretion and induces mast cell degranulation

The administration of Epi may cause significant metabolic changes

stimulation results in increase in blood glucose hypokalemia occurs d/t a transcellular potassium shift

Problems with isoproterenol

tends to precipitate supraventricular and ventricular arrhythmias and has been largely replaced by transcutaneous or transvenous pacing

Side effects of B2 stimulation

tremor, anxiety, restlessness *can be minimized with aerosolized administration

Phentolamine

unlike phenoxybenzamien, its receptor interaction can be overcome using an a-receptor agonist such as phenylephrine or norepinephrine much shorter duration of action with half-life <10 minutes can be used as a local infiltration after IV extravasation of a vascocontrictor like epi, norepi to prevent tissue necrosis

Epinephrine and norepinephrine undergo metabolism via catechol-o-methyl transferase (COMT) & monoamine oxidase (MAO) to yield a common metabolite

vanillylmandelic acid

Which calcium channel blockers are great choices to reduce HR in the patient with tachycardia, a-fib, or a-flutter

verapamil and diltiazem