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Cardio Block > Autonomic Drugs > Flashcards

Autonomic Drugs Flashcards

0
Q

Alpha 2 Receptors

A

PRESYNAPTIC, “autoreceptors” that perform feedback inhibition of adenylate cyclase to decrease levels of cAMP.
Can limit vasoconstriction by preventing further NE release from synapse

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1
Q

Alpha 1 Receptors

A

POSTSYNAPTIC, downstream signaling via DAG/IP3 leading to increased calcium.
Increase HR, vasoconstriction, leading to increased BP

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2
Q

Epinephrine

A

Targets both alpha and beta receptors. Therefore, it creates a limited increase in BP (vasoconstriction caused by alpha activation overcomes vasodilation from beta activation)

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3
Q

Contrast the effect of alpha- and beta- receptor blockade on epinephrine-induced change in BP and HR.

A

ALPHA receptor blockers - allow only the vasodilation effects due to epinephrine-stimulated beta-receptors to be seen, so you get BP decrease.

BETA receptor blockers - allow only the vasoconstrictive effects due to epinephrine-stimulated alpha-receptors to be seen, so see further increase in BP.

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4
Q

Norepinephrine

A

Selectively targets alpha receptors (but can target beta1 receptors). Therefore, it creates an increase in BP due to vasoconstriction from alpha activation.

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5
Q

Contrast the effects of alpha- and beta-receptor blockade on norepinephrine-induced change in BP and HR

A

ALPHA receptor blockers - prevent vasoconstriction due to alpha activation and (sense no beta affect really significant) does NOT cause vasodilation.

BETA receptor blockers - does NOT affect the vasoconstriction effects due to norepinephrine-stimulated alpha-receptors to be seen, so see no change in the increased BP.

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6
Q

What you see a deceleration in HR with alpha-receptors?

A

NO. Only administration of beta-blockers would cause a deceleration in HR. No alpha-receptors affect HR.

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7
Q

B-1 and 2 effects on heart

A

SA node - accelerates
Ectopic pacemakers - accelerates
Contractility - increases

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8
Q

Effects of receptor activation in blood vessels

A

Skin, splanchnic vessels - alpha causes contraction

Skeletal muscle vessels - B2 causes relaxation

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9
Q

Name the alpha blockers

A 
Doxazosin 
Terazosin 
Prozosin 
Phenoxybenzamine
Phentolamine
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10
Q

Identify relative receptor specificity of the alpha agents

A

a1&raquo_space;> a2 seen in doxazosin, terazosin, and prozosin
a1 > a2 seen in phenoxybenzamine
a1=a2 seen in phentolamine

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11
Q

Compare the differences in PK and dose schedule for principal alpha blockers

A 
Doxazosin (22 hr, daily)
Terazosin (12 hr, daily)
Prozosin (4 hr, q8hr)
Phenoxybenzamine (slow onset, 3-4 day duration)
Phentolamine (short acting)
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12
Q

Distinguish between alpha1 specific and alpha1/2 drugs with respect to mechanism of drug-induced changes in CO

A

a1 specific blockers work by blocking the binding of NE to post-synaptic nerve endings (so you don’t get vasoconstriction, leading to decreased peripheral resistance, which decreases BP).

Nonspecific alpha-blockade causes presynaptic a2-receptors to increase NE release (by blocking the negative feedback inhibition), resulting in increased CO, which tempers the BP lowering action you get from a1 blockers.

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13
Q

Adverse effects with alpha-blocker therapy

A 
First dose orthostatic hypotension: worse with prazosin (reduce dose, take with food, or take before bed)
CV problems (sinus-tach, syncope, vertigo): with non-specific alpha-blockers. These block feedback inhibition of a2 receptors, so you get increased release of NE and EPI that can act on beta receptors to cause tachycardia.
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14
Q

Evaluate the revised role of alpha-blockers as primary drug therapy for HTN

A

These are NOT as extensively used now, because of a trial that indicated that they were not as effective as diuretic agents in preventing heart attacks

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15
Q

What is the role of beta-adrenergic receptors in the heart

A

accelerates SA node
accelerates ectopic pacemaker
increase in contractility (beta1)

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16
Q

What is the role of beta-adrenergic receptors in the vascular system

A

releases skeletal muscle vessel (beta2)

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17
Q

What is the role of beta-adrenergic receptors in the juxtaglomerular cells

A

beta1 receptors stimulate renin release

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18
Q

Identify relative receptor specificity of the beta blockers

A

2nd generation: b1»>b2 seen with A, B, Ce, E, M, and Ne “olol’s”
1st generation: b1 = b2 seen with Ca, P, and T “olol’s”

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19
Q

Which beta-blockers have membrane stabilizing activity

A 
Carvediol, Albutol, and Propranolol 
Known as class I anti-arrhythmics because they bind to and block fast sodium channels responsible for rapid depolarization (phase 0) of fast-response cardiac APs
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20
Q

Which beta-blockers have intrinsic sympathomimetic activity

A

Pindolol, Albutolol
Some people on beta-blockers experience bradycardia at rest and need drugs with ISA. These are partial agonists that STIMULATE RESTING HEART but will antagonize stimulated heart.

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21
Q

Which beta-blockers have high lipid solubility

A

Penbutolol, Propranolol

Capable of crossing the BBB and tend to have worse CNS adverse effects (like depression and vivid dreaming)

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22
Q

Identify some extended pharmacologic action of the beta-blockers

A

NO production (carteolol)
Beta2 agonism for vasodilation (carteolol)
Alpha1 antagonist to prevent reflex vasoconstrictive effect resulting in BP rise that is produced by BB during first few doses (carvedilol, labetalol)
Ca2+ entry blockade to prevent vasoconstriction (carvedilol, betaxolol)
Anti-oxidant (carvedilol)

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23
Q

How does beta-blockers reduce BP with long-term use

A

BBs have no effect on the increase in BP d/t EPI and NE - however, over time they lead to a decrease in BP in pts with HTN only.

  • not reliant on renin (e.g. propranolol most effective in patients with elevated plasma renin)a
  • presynaptic auto-receptors enhance NE release
  • long-term admin leads to a fall in PVR to decrease BP
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24
Q

Adverse CV events of BB treatment

A

CHF
Bradycardia (especially with calcium channel antagonists; especially drugs impairing SA node fxn or AV conduction such as verapamil)
Cold extremities
Sudden angina and death if discontinue after long-term treatment (b/c you had upregulated receptors during treatment)

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25
Q

List the principal “OFF TARGET” effects of beta-blockers

A

LUNGS: non-selective BB NOT for people with asthma or COPD

CNS: depression, mental disorders, vivid dreams

GLUCOSE: hypoglycemia bc beta2 stimulates hepatic glycogenolysis and pancreatic glucagon release; diabetics must be cautious bc BB mask tachycardia of insulin-induced hypoglycemia

LIPID: beta receptors mediate lipolysis and BB increase TGs and decrease HDLs - not seen with drugs that are cardioselective and have ISA

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26
Q

Which BB has an extremely short half-life and is the only BB that must be administered by IV infusion?

A

Esmolol

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27
Q

Describe the off-target pulmonary effects of BB in detail

A

Blockade of bronchial smooth muscle B2 receptors –> these receptors promote bronchodilation in patients with bronchospastic disease.
Life-threatening increase in airway resistance
B1 selective drugs or those with ISA seem less likely to incude bronchospasm
Selectivity of current blockers is not absolute! SO, BB should be avoided if possible in asthmatics and those with COPD

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28
Q

Which BBs are more likely to be associated with off-target effects on CNS

A

more associated with lipophilic drugs –> CNS depression can occur, resulting in mental disorders, fatigue, and in some cases vivid dreams (less common with hydrophilic BB)

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29
Q

What are the symptoms of BB toxicity?

A 
Bradycardia
Hypotension
Arrhythmias
Hypothermia
Hypoglycemia
Seizures
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30
Q

Describe the prevailing autonomic tone of the principal organ systems and consequence of ganglionic blocker

A

Arterioles and Veins have predominantly SYMPATHETIC tone, such that when a ganglionic blocker is administered this will lead to loss of sympathetic tone (vasodilation –> reduction in BP)

Heart has PARASYMPATHETIC (or cholinergic) tone, so loss of parasympathetic tone can lead to tachycardia

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31
Q

What is the NT involved in sympathetic and parasympathetic ganglia

A

ACh binds to cholinergic (GPCR) and nicotinic (ligand-gated ion channels) receptors on postganglionic membrane to maintain vascular tone and contraction

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32
Q

Describe the MOA of ganglionic blockers

A

Ganglionic blockers are antagonists of cholinergic nicotinic receptors that impact vascular tone and nerves innervating the heart. TRIMETHAPHAN works as a competitive antagonist of ACh that blocks the binding site of the nicotinic receptor so that NO EPSP can form and NO ganglionic transmission can occur.

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33
Q

What is the primary effect of ganglionic blockers

A

Vasodilation –> increased peripheral blood flow, hypotension, decreased CP, decreased venous return, and venous pooling

34
Q

Why are ganglionic blockers no longer a common component of antihypertensive medication

A

You have VERY LITTLE CONTROL of which ganglia are affected when giving a ganglionic blocker. Therefore, you may block nicotinic receptor (and get vasodilation) or block muscarinic receptors (and get tachycardia). The lack of specificity givers these drugs lots of negative side effects (ranging from blurred vision to asthma to tremor) so they are not commonly used!

35
Q

Describe presynaptic alpha2 receptors

A

Alpha2 receptors are GPCRs that, if chronically stimulated, are inactivated by endocytosis (e.g. HF would lead to downregulation of the signaling mechanism and consequent loss of drug activity for the alpha2 agents). Exist on the PRESYNAPTIC nerve terminal where activation by released NE causes inhibition of further relase of this catecholamine.

36
Q

What can you consider the presynaptic alpha2 receptor

A

presynaptic autoreceptor that inhibits further release of catecholamine from presynaptic terminal to cause bradycardia and hypotension.

37
Q

What is one cavet to using presynaptic alpha2 receptors

A

CAN ONLY LOWER BP IF THEY CAN PENETRATE BBB

38
Q

What produces more activity: alpha2 agonists of heteroreceptors

A

the amount of activity produced by alpha2 agonists acting on autoreceptor signaling is relatively minor compared to action of these drugs on heteroreceptors

39
Q

Describe heteroreceptors

A

Heteroreceptors are alpha2 expression on non-adrenergic tissue. Using alpha2 agonists overwhelmingly affects the receptors via vagal activation (activation of parasympathetic system to slow the heart and cause sedation, brady, and hypotension)

40
Q

Name the alpha-2 adrenergic agonists

A

Clonidine - IV, patch, or oral (long-lasting)
Guanabenz - oral
Guanfaline - oral (longest half-life)
Methyldopa - IV

41
Q

Describe Methyldopa

A

prodrug with shortest half-life; good for infusion and tight control; NOT with iron supplements; dose adjustment in renal failure; NOT with pheochromocytoma.

drug of choice for decreasing HTN during pregnancy

42
Q

What do you need to prescribe with each of the alpha2 adrenergic agonists

A

Need to perscribe with diuretics becuase there is a dose-dependent salt and water retention. NO reflec tachycardia, CO and renal flow unaffected

43
Q

MOA of reserpine

A

Binds tightly to target (adrenergic storage vesicles) in central and peripheral adrenergic neurons, inhibits VMAT2 (vesicular catecholamine transporter), and leads to loss of capacity to concentrate and store NE and DA.

44
Q

Why does reserpine effects last for days to weeks?

A

Because vesicles have to be reformed (antihypertensive both centrally and peripherally)

45
Q

What are the adverse effects of alpha2 agonists

A

Major problem is withdrawal of SNS tone producing fall in PVR and BP. This may lead to ventricular hypertrophy. Also…

  • somnolence (avoid with CNS depressants, give before bed)
  • dry mouth (b/c alpha2 decreases salivary flow, more cavities)
  • abdominal pain, constipation, impotence
  • hypotension, sinus bradycardia
46
Q

What are the adverse effects specific to reserpine

A

Sedation
Increase suicidal ideation
Teratogen

47
Q

What is the current role of alpha2 agonists?

A

These are not frequently used in HTN, but they are very cheap! They should be considered in some patients.

48
Q

What happens with parasympathetic stimulation of M2 receptors

A

Decrease neuronal activity in SA node and decrease contractility in atrial tissue.

49
Q

What happens with parasympathetic stimulation of M3 and M5 receptors

A

synthesis and release of endothelin derived relaxing factor (EDRF), which is a vasodilating intermediate

50
Q

Describe how M2 receptors work

A

Couples by Gi/Go (PTX sensitive), with inhibition of AC and decrease cAMP. This leads to hyperpolarization of membranes.

  • stimulates K-ACh channels (inward K+ channels)
  • inhibits voltage gated, L-type calcium chanenls
51
Q

Effects of ACh on M2 receptors

A

slows SA node activity (decrease HR), slows AV node conduction velocity, decreases atrial contractility, NO REAL EFFECT on ventricle

52
Q

Describe how M3/M5 receptors work

A

Gq coupling pathway to increase IP3 and DAG which increases calcium and PKC

  • leads to depolarization (excitation) of membrane
  • increases synthesis and release of NO (vasodilation)
  • if direct endothelial injury, Ach can bind straight to M3 leading to vasoconstriction
53
Q

Adrenergic (sympathetic) and cholinergic (parasympathetic) nervous control of heart are controlled by both…

A

AUTORECEPTORS (feedback inhibition of their own release) and HETERORECEPTORS (inhibition of other system’s NT release).

Example: ACh can work directly to stimulate M2 receptors, can feedback to control ACh release on M2 autoreceptors, and can inhibit SNS activity via heteroreceptors that prevent NE release by opposing beta-1 increase in cAMP

54
Q

Contrast effects of ACh on intact vascular tissue vs. situations of endothelial damage

A

ACh will lead to increased synthesis and release of NO (vasodilator). But if endothelial injury occurs, ACh will bind directly to M3 receptors in vascular smooth muscle leading to vasoconstriction.

55
Q

Explain what happens with low doses of atropine

A

At LOW DOSES, atropine inhibits M1 AUTORECEPTORS and INCREASES ACh release to DECREASE HR

56
Q

Explain what happens with high doses of atropine

A

At HIGH DOSES, atropine blocks M2 on SA nodal cells to INCREASE resting HR (inhibits vagal tone)

57
Q

Explain the effect of atropine on vasculature

A

Does NOT have a large effect on vasculature, but at high enough doses it can dilate cutaneous blood vessels (as a compensatory reaction, because sweating is inhibited and body builds up heat that must be released) and lead to an “atropine flush”

58
Q

What is the clinical utility of atropine

A

Completely counters peripheral vasodilation and fall in BP caused by choline esters.
Abolishes reflex vagal cardiac slowing or asystole, and facilitates AV conduction in patients with inferior/posterior MI by relieving sinus/nodal bradycardia or AV block.

59
Q

Reserpine

A

deplete catecholamine stores by binding to storage vesicles in adrenergic neurons and destroying them so that neurons cannot aggregate or store NE or E

60
Q

What is a direct acting CV stimulant and what is the effect of reserpine

A

Direct Acting = stimulate post-synaptic membrane

Reserpine pre-treatment does NOT reduce CV stimulation (may actually increase it)

61
Q

What is a indirect acting CV stimulant and what is the effect of reserpine

A

Indirect Acting = stimulate heart by increasing the availability of NE via blocking metabolizing enzymes MAO or COMT or by blocking reuptake

Reserpine pre-treatment completly abolishes response (because no NE to increase)

62
Q

What is a mixed acting CV stimulant and what is the effect of reserpine

A

Mixed acting = stimulate post-synaptic membrane AND release endogenous NT from the presynaptic terminal

Reserpine pre-treatment blunts response but does not abolish it

63
Q

Alpha 1 mechanism of downstream signaling

A

formation of IP3 and DAG, increase intracellular calcium

64
Q

Alpha 2 mechanism of downstream signaling

A

inhibition of adenylyl cyclase, decrease cAMP

65
Q

Beta 1 mechanism of downstream signaling

A

stimulation of adenylyl cyclase, increase cAMP

66
Q

Beta 2 mechanism of downstream signaling

A

stimulation of adenylyl cyclase and increase cAMP

activates cardiac Gi under some conditions

67
Q

Beta 3 mechanism of downstream signaling

A

stimulation of adenylyl cyclase and increase cAMP

68
Q

D1 and D5 mechanism of downstream signaling

A

stimulation of adenylyl cyclase and increase cAMP

69
Q

D2 mechanism of downstream signaling

A

decrease of adenylyl cyclase and increase K+ conductance

70
Q

In summary, describe the overall mechanism of downstream signaling of beta receptor and alpha receptor

A

Increasing cAMP will increase intracellular Ca2+ levels. So beta receptors will have greater contractility and stimulation. Alpha2 receptors will have decreased cAMP which makes sense, because they work to feedback inhibit further NE release

71
Q

Influence of NE (alpha) upon CV system

A

Pulse Rate: Decrease (d/t baroreceptor reflex)
Systolic BP: Increase
Diastolic BP: Increase
Peripheral Resistance: Increase

72
Q

Influence of EPI (alpha and beta) on CV system

A

Pulse Rate: Increase (d/t beta1 receptor)
Systolic BP: Increase (d/t alpha1)
Diastolic BP: Decrease (d/t beta2)
Peripheral Resistance: Decrease (d/t beta2)

73
Q

Influence of Isoproterenol (Beta only) on CV system

A

Pulse Rate: Increase (d/t beta1)
Systolic BP: Slightly increase (d/t increase CO2)
Diastolic BP: Decrease (d/t beta2)
Peripheral Resistance: Decrease (d/t beta2)

74
Q

What is odd about the effect of low dose EPI

A

The effects of EPI on B2 receptor are stronger and more potent than those on alpha1 so at low doses, EPI may actually cause a decrease in BP

75
Q

IV delivery of EPI

A

increase in systolic BP is greater than the decrease in diastolic BP, so there is a NET INCREASE IN BP that may turn into a decrease in BP as the dosage wears off

76
Q

SC Delivery of EPI

A

Local vasoconstriction at the injection site because of alpha1 effects leads the drug to have poor uptake (so acts like drug was given at low dosage). You get a PREDOMINANT DECREASE IN DIASTOLIC BP (with increase in heart contractility from beta receptors) and only a slight increase in systolic BP (d/t compensatory response from increased HR)

77
Q

Dopamine on CV system

A

Intermediate in the tyrosine –> NE –> EPI pathway
Cannot penetrate BBB, so you must give it as a prodrug (carbidopa)
Historically used to maintain renal perfusion by dilating renal vessels
Dosage-dependent specificity: D1 > B1 > alpha

78
Q

Dobutamine on CV System

A 
Symapthetic agonist (B1 agonist, alpha1 agonist/antagonist) with NO effect on dopamine receptors
Given to patients with cardiac decompensation to increase CO/SV with no effect on HR
VERY short half-life so must be given by IV infusion
79
Q

Isoproterenol on CV System

A

Very specific for Beta receptors
Leads to increase in CO (B1) with a decrease in diastolic BP (B2)
Used for heart stimulation in patients with heart block or bradycardia - especially when you are planning on putting in a pacemaker

80
Q

Explain the dose-related differences in DA action

A

LOW DOSE: D1 effect on renal vasculature (dilation of vessels) and improve GFR
HIGH DOSE: activates D1and B1 to increase CO (contractility > HR) but also has vasodilation
VERY HIGH DOSE: activates alpha receptors to increase resistance and lead to renal vasoconstriction

81
Q

Phenylephrine

A

Affects alpha receptors only, leading to a potent vasoconstriction and decreased HR and COP as a compensatory baroreceptor reflex.
Used to control hypotension (including hypotension induced from anesthesia) –> IV, IM, SC
Lipophilic and has CNS adverse effects

82
Q

Ephedrine

A

Agonist of both alpha and beta receptors and works as a Cardiostimulant that also increases BP. It is used to treat hypotension but can lead to angina, palpitations, and arrhythmias
Oral Administration
Also found in cold medicines and is a component of METH

Cardio Block (6 decks)

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