m and m 14 - Adrenergic Agonists and Antagonists Flashcards
What is the major neurotransmitter for the sympathetic nervous system? What is the sympathetic tissue that doesn’t use this neurotransmitter?
Norepinephrine. Only exception where NE isn’t released at the end organ is eccrine sweat glands
What is the neurotransmitter for all the preganglionic sympathetic fibers and all the parasympathetic nervous system?
Acetylcholine
What spinal cord levels give rise to the sympathetic nervous system? The parasympathetic?
Sympathetic arises from T1-L3
Parasympathetic is cranio-sacral in distribution
What is a the major difference between the sympathetic and parasympathetic systems regarding location of the ganglion relative to the end organ innervated?
The sympathetic ganglion are usually paraspinal and thus very far from the end organ innervated, vs parasympathetic that are closer to the end organ
In what part of the sympathetic postganglionic nerve ending is norepi made? How is it released?
Made in cytoplasm, stored in vesicles and released by exocytosis
What is the major mechanism for terminating the activity of NE? What is a drug class that blocks this activity
Reuptake - can be blocked by tricyclic antidepressants
What are two enzymes that metabolize NE?
Catechol-O-Methyltransferase
Monoamine oxidase
What is the rate limiting step in the synthesis of norepinephrine?
Hydroxylation of tyrosine to dopa
Norepinephrine is the precursor to epinephrine. Where does this conversion occur?
In the adrenal medilla
What is the common end product of enzymatic metabolism of NE or epi?
Vanillylmandelic acid
What type of receptors are adrenergic receptors?
GPCRs
What are the associated g-proteins for alpha 1, alpha 2 and the beta receptors?
Gq, Gi and Gs, respectively
Where are alpha 1 receptors located? What is the effect of their activation?
Located in smooth muscle all across the body. Activation causes increase in intracellular calcium and muscle contraction
What is the effect of alpha 1 agonists on
- eye
- lungs
- vasculature
- uterus
- GI sphincters
- eye - mydriasis (pupil dilation from contraction of radial eye muscles)
- lungs - bronchoconstriction
- vasculature - vasoconstriction
- uterus - contractions
- GI sphincters - constrictions of sphincters
What is the effect of alpha 1 on insulin secretion and lipolysis?
It inhibits both of those processes
What is effect of alpha 1 agonists on peripheral vascular resistance, afterload and blood pressure?
Increases all of them
Are alpha 2 receptors presynaptic or postsynaptic? Where is the exception? What is the mechanism for its effect on NE?
Presynaptic (some post-synaptic is vascular smooth muscle)
Activation blocks adenylate cyclase activity, reduces calcium in the neuronal terminal, decreases release NE
What is the net effect of stimulation of alpha 2 in the CNS?
Sedation and decreased sympathetic outflow (decreased BP and lower blood pressure)
How many types of beta receptors are there? How does the potency of epi and NE compare with these receptors?
beta 1,2,3
NE and Epi equipotent on beta 1
Epi significantly more potent on beta 2
Where are beta 1 receptors located? What is the effect of their activation of chronotropy? dromotropy? inotropy?
Located on post synaptic membranes of the heart.
Activation increases chronotropy, dromotropy (conduction) and inotropy
Where are beta 2 receptor located?
Post synaptically on smooth muscles and gland cells
What is the effect of beta 2 activation on:
- lungs
- vasculature
- uterus
- bladder
- gut
Causes relaxation of all these muscles
What is the effect of beta 2 activation of glycogenolysis, lipolysis, gluconeogenesis and insulin release?
All increased / stimulated by beta-2 activation
What are the 2 known locations of beta 3 receptors?
Gall-bladder and brain adipose tissue
Activation of D1 causes vaso-[constriction/dilation] of 3 organ systems. What are they?
Vasoconstriction
Heart, kidneys and intestines
What is the significance of D2 receptors in anesthesiology?
Thought to play a role in antiemetic actions of droperidol
What are the 2 mechanistic ways that indirect agonists of adrenergic receptors work?
Increased release or decreased reuptake of norepinephrine
A patient who uses a monoamine oxidase inhibitor as an outpatient has intraoperative hypotension. What type of agonist [direct/indirect] should be used and why?
Should use direct agonist because the response to an indirect agonist is likely altered in this patient
What is the chemical group that distinguishes catecholamines? What structures confer specificity?
The 3,4 dihydrobenzene structure
The R 1,2,3 side chains confer specificity
Why are isoproterenol and dobutamine “special” compared to the other catecholamines?
These are synthetic catecholamines that were developed after changing the side chains of the naturally occuring catecholamines
What is the receptor target of phenylephrine? What is effect on SVR, BP, HR?
alpha 1 agonist
increases SVR and BP
Decreases HR (reflex bradycardia mediated by vagus nerve)
Phenylephrine can be used as a continuous infusion. What organ system may end up not getting enough blood flow? Why would you need to uptitrate dose of infusion?
Renal blood flow may go down
Tachyphylaxis a problem, may need to uptitrate dose
What are 3 uses of clonidine?
Antihypertensive
Negative chronotrope
Sedation / anxiolysis
What is a possible advantage of clonidine from a circulation perspective? what is the mechanism?
It enhances intraoperative circulatory stability by decreasing catecholamine levels
What is the effect of clonidine on a regional anesthetic?
Clonidine will prolong the block duration
3 possible benefits of intraoperative clonidine are?
Decreased post op shivering
Inhibition of opioid induced muscle rigidity
Attenuation of opioid withdrawal symptoms
Which has higher affinity at the alpha 2 receptor, clonidine or dexmeditomidine? Which is more selective (compared to alpha 1)? Which has a longer half life?
Dexmeditomidine has higher affinity and selectivity
Clonidine has higher half life
The sedative and analgesic effects of dexmeditomidine are mediated by alpha 2 receptors located where?
Brain (locus ceruleus) and spinal cord
True or false - both clonidine and dexmeditomidine can reduce anesthetic requirement?
True
Dexmeditomidine is useful for the sedation of patient undergoing awake fiberoptic intubation, or needing post-op sedation. What property of this drug make it useful in this setting?
It is a sedative that has minimal ventilatory depressive effects
What is the effect of abrupt discontinuation of clonidine or dexmeditomidine after long term use? Mechanism?
Hypertensive crisis
Mechanism is upregulation of adrenergic receptors, leading to supersensitization
What is the time line for hypertensive crisis after discontinuation of dexmeditomidine? Mechanism? Sooner or later than clonidine?
Hypertensive crisis can occur after using dex for 48 hours
Because of the higher affinity for alpha 2
Way faster than with clonidine
What is the mechanism of epinephrine increasing myocardial oxygen demand?
Increases contractility and heart rate
Epinephrine [increases/decreases] coronary perfusion pressure. Mechanism?
Increases perfusion pressure by increasing aortic diastolic pressure (diastole is when the coronaries are perfused)
What are 3 known complications of epinephrine?
Cerebral hemorrhage
Coronary ischemia
Ventricular Dysrhythmias (potentiated by volatile anesthetics, especially halothane)
What is the dosage of epinephrine for anaphylaxis?
100-500 mcg
Ephedrine and Epi have similar actions. Which is more potent? Longer duration of action?
Epinephrine is more potent
Ephedrine has a longer duration of action
True or false - ephedrine is a MAC sparing agent?
False - it stimulates the CNS, will therefore cause more anesthetic to be used (Raises the MAC)
What is the proposed mechanism of the indirect agonist properties of ephedrine?
Peripheral postsynaptic NE release or by inhibitionr of NE re-uptake
What are the preferred vasopressors for obstetric use? Why?
Phenylephrine and ephedrine - these 2 anesthetics are believed to not reduce uterine blood flow.
** Phenylephrrine preferred because of faster onset, shorter duration of action, better titratability and maintenance of fetal ph)
What are the 3 adrenergic subtypes that Norepi has effects on?
Works on beta 1, alpha 1 and 2. Minimal effect on beta 2
What is the effect norepi on cardiac output? Why?
No significant increase in CO. Despite its beta 1 effects, it will also increase systolic and diastolic BP, causing reflex bradycardia
What is the thinking re: norepinephrine in shock?
Not used because it decreases renal and splanchnic blood flow and increases myocardial oxygen demand
What is the net effect of low dose dopamine?
Vasodilates the renal vasculature
Promotes naturesis and diureses
What are the receptors that are targeted as you increase the doses of dopamine? What is the net effect?
DA-1 - vasodilates renal vasculature
Beta 1 - increases contractility, HR and CO
Alpha 1 - increases peripheral vascular resistance and decreases renal blood flow
What is the basis of the indirect effects of dopamine?
Can cause release of norepinephrine from the presynaptic nerve ganglion
When dopamine is used to treat patients in shock (improves CO, BP and maintain renal function), what else is co-administered to maximize cardiac output?
Usually used with a vasodilator (e.g. nitroglycerin or nitroprusside) to reduce afterload and further improve cardiac output
What are 2 known side effects of dopamine that may limit its use, especially in shock patients?
It increases chronotropy
It is pro-arrythmic
What is the receptor targeted by isoproterenol? What is the effect on HR, contractility, CO, peripheral vascular resistance and diastolic BP?
Pure beta agonist
Will increase HR, contractility and CO
Will decrease peripheral vascular resistance and diastolic BP (via beta-2 mechanism)
Why is a pure beta agonist, e.g. isoproterenol a poor inotropic choice in most situations?
While it will increase HR, myocardial O2 demand will increase while O2 supply will fall (will drop diastolic BP, perfusion of coronaries will drop)
Dobutamine binds which type of adrenergic receptor? Is there any subtype selectivity?
Will bind beta 1 and beta 2, more selective for beta 1 over beta 2
What is the effect of dobutamine on
- CO
- contractility
- peripheral vascular resistance
- LV filling pressures
- Coronary blood flow
- CO -> increases
- contractility -> increases
- peripheral vascular resistance -> decreases (beta 2)
- LV filling pressures -> decreases
- Coronary blood flow -> increases
Dobutamine is thought to be a good choice for the treatment of patients with CHF and CAD, especially if there is increased peripheral vascular resistance. Why?
It has a “favorable effect on myocardial oxygen balance” i.e. increases contractility and CO while increasing coronary blood flow
What is dopexamine? How is it different from dopamine?
It is a structural analogue of dopamine, but less beta -1 activity and less alpha 1 effects. Still has it “pro-renal” effects
What are the receptors affected by fenoldopam?
It is able to bind D1 as well as dopamine. It has little effect on the alpha, beta and D2 receptors
What is the effect of fenoldopam on
- peripheral vascular resistance
- Renal blood flow
- diuresis
- natriuresis
Decreases PVR, increases everything else
What type of patient (i.e. what constellation of circumstances) will particularly benefit from fenoldopam?
Patient undergoing aortic aneurysm repair with high risk of renal impairment.
** can also be used for severely hypertensive patients with suspected renal impairment **
What is an adrenergic agent that is indicated for prevention of contrast media induced nephropathy?
Fenoldopam
Phentolamine is a [competitive/non-competitive] blocker of what receptor(s)?
Competitive alpha-1 and alpha 2
What is the net effect of phentolamine use on the cardiovascular system (2 things)?
- peripheral vasodilation, decrease in BP (alpha 1 block)
- Reflex tachycardia (alpha 2 block and response to decreased BP - activation of alpha-2 decreases release of NE, phentolamine does opposite, therefore more NE released)
What 2 side effects limit the use of phentolamine in the tx of hypertension from too much alpha stimulation?
Postural hypotension
Reflex tachycardia
What are the targets of prazosin and phenoxybenzamine?
Both are also alpha antagonists, phenoxybenzamine is a non-competitive agent
What are the receptors blocked by labetalol? What is the net effect on the CV system?
Alpha 1, beta 1 and beta 2. Will decrease BP with minimal effect on HR and cardiac output
What are 3 potential (reported) side effects of labetalol?
Bronchospasm
Paradoxical hypertension
LV failure
Why should beta-2 blockers be used with caution in patients with peripheral vascular disease?
Blocking of beta 2 can theoretically reduce blood flow to the peripheral vasculature (blocking by beta 2)
What is the effect of beta 2 blockers on patients with glaucoma?
Can theoretically reduce intraoccular pressure in patients with glaucoma
What are the 3 beta blockers that are thought to be selective for beta 1? Which is a mixed antagonist? Which is more beta 2?
beta 1 - metop, esmolol and atenolol
mixed - labetalol and propranolol
What 3 beta blockers are metabolized by the liver? which is metabolized unchanged by kidneys? Which is metabolized in blood?
Liver - propranolol, metoprolol and labetalol
Kidneys - atenolol
Blood - esmolol
What is the major effect of esmolol on CV system?
Blocks increase in HR to lesser extent, BP. Beta 1 selective
What happens to esmolol as higher doses are used in patients?
At higher doses, will now become less selective for beta 1 and will start blocking beta 2 in the smooth muscles and bronchioles
How is esmolol metabolized?
Hydrolyzed by red blood cell esterases
What are 4 contraindications for esmolol?
Sinus bradycardia
More than 1st degree heart block
Heart failure
Cardiogenic shock
What is the receptor target of metoprolol? Does it have intrinsic sympathomimetic activity?
Beta 1 selective. No intrinsic sympathomimetic activity
What is the receptor target of propranolol?
Beta 1 and beta 2
What is the mechanism by which propranolol decreases BP (3)?
Decreased contractility
Decreased HR
Decreased renin release
(all above leads to decreased cardiac output and myocardial oxygen demand)
What beta blocker has the following characteristics?
- slows AV conduction and stabilizes cardiac membranes
- slows ventricular response in SVT
- Blocks beta effects in thyrotoxicosis and pheochromocytoma?
Propranolol
What are possible side effects of propranolol?
Bronchospasm
CHF
Bradycardia
AV block
What beta blocker may worsen the myocardial depression of halothane and unmask the negative inotropic characteristics of indirect cardiac stimulants?
Propranolol
What class of drug, when used with propranolol can synergistically depress HR, contractility and AV conduction?
Calcium channel blockers
What is the receptor target of nebivolol? What is unique about it?
- Highly beta 1 selective
- Unique in that it can directly cause vasodilation via stimulation of endothelial nitric oxide synthase
What is the receptor target of carvedilol? What are its inducations?
Mixed alpha and beta blocker
Indicated for CHF from cardiomyopathy, LV dysfunction after MI and hypertension
True or false - in a patient already on beta blockers, they should be asked to stop this medication before surgery?
False. These shouldn’t be stopped if pateints are using for tx of angina, symptomatic arrythmias, HF, HTN
What are potential complications of stopping beta blockers? What is the time line? Mechanism?
HTN, tachycardia and angina
24-48 hours
Possible upregulation
What is a pheochromocytoma?
An adrenal medulla tumor of chromaffin tissue that makes NE and epi
How is pheochromocytoma diagnosed?
Urinary excretion of vanillylmandelic acid is measure. Usually high in these patients
What is the perioperative drug of choice for treatment of pheochromocytoma?
Phenoxybenzamine
Why should the following drugs be avoided in a patient with pheochromocytoma?
Ketamine
Halothane
Vagolytics (anticholinergics and pancuronium)
Ketamine - a sympathomimetics
Halothane - sensitizes myocardium to arrhythmogenic effects of epinephrine
Vagolytics - will tip balance to increased tone
