9-14 Adrenergic Receptor Agonists & Antagonists - Martin Flashcards
What are some important adrenergic agonists that we should know? What receptors do they work on?
Epinephrine
Norepinephrine
(a1, a2, b1, b3)
Isoproterenol (b1, b2, b3)
Dobutamine (b1)
Dopamine (D1 > b1 > a1)
Fenoldopam (D1)
Clonidine (a2)
Methyldopa (a2)
(a1, a2, b1, b2, b3)
What are 2 important alpha receptor antagonists? What receptors do they work on?
Prazosin (a1)
Phentolamine (a1, a2)
What are is an important alpha receptor agonist? What other class of drugs are alpha receptor agonists?
Phenylephrine
Other Pressor Agents
What are some non-selective beta blockers?
Propranolol
Nadolol
Timolol
*Pindolol
*Carteolol
Sotalol
*= Intrinsic Sympathomimetic Activity (ISA)
What are some important cardioselective beta receptor antagonists?
Atenolol
*Acebutolol
Metoprolol
Esmolol
What are some third generation beta receptor antagonists?
Labetalol
Carvedilol
Betaxolol
Carteolol
What is an important effect of dopamine that is outside of the nervous system? What receptor is this effect mediated by?
Renal Afferent Blood Vessels
D1 – Dilation
Increase blood flow to kidney
What is the role of dopamine in the nervous system? What receptors does it work on?
CNS
D1, D2, D3, D4, D5
Essential neurotransmitter in many different neural circuits
Nerve Endings
D2 – Modulate neurotransmitter release
What is the effect of the following receptors after stimulation:
beta 1
muscarinic
beta 1: stimulation of heart rate & force
muscarinic: decrease in heart rate
What receptors are the afferent arms of the baroreceptor reflex pathway? What does stimulating these receptors cause?
Stretch receptors in aortic arch (via X) or in carotid sinus (via IX) respond to changes in blood pressure
increased BP will cause PNS to be stimulated
SNS tone will be reduced/inhibited
decreased BP will reduce stimulation of PNS
SNS tone will be un-inhibited
What is the effect of NE on pulse rate, BP and peripheral resistance?
decreased pulse rate
increased BP - systolic & diastolic
INCREASED peripheral resistance
(at low doses)
What is the effect of Epi on pulse rate, BP and peripheral resistance?
increased pulse rate
similar BP - increased systolic, decreased diastolic
decreased peripheral resistance
What is the effect of isoproterenol on pulse rate, BP and peripheral resistance?
INCREASED pulse rate
decreased BP - increased systolic and more decreased diastolic
DECREASED peripheral resistance
What is another name for alpha 1 adrenergic agents?
pressor agents
What is the prototypical pressor?
Phenylephrine (neosynephrine)
an OTC nasal decongestant
What is midodrine indicated for? What receptors does it work on?
Midodrine (Pro Amatine)
oral – pts w/ autonomic insufficiency
alpha 1 adrenergic agonist
What is a mixed acting alpha agonist?
metaraminol (Aramine)
What are the effects of phenylephrine? What is it blocked by?
vasoconstriction
increase peripheral resistance; increase BP
increased blood pressure causes reflex bradycardia (blocked by atropine)
Other than a nasal decongestant, what is phenylephrine used for?
maintain BP in hypotensive states
- spinal anesthesia
paroxysmal atrial tachycardia
- induces baroreceptor reflex slowing of rate
What vascular beds does dopamine dilate? Via what receptors?
vasodilates renal, coronary, & mesenteric vascular beds (D1 receptors)
In addition to increasing blood flow to the kidney, what is the effect of dopamine in the periphery?
increase blood flow to kidney
heart: mild increase in rate & force (partial agonist b1 and increases release of NE)
blood vessels: high doses cause vasoconstriction & increased BP (a1)-in the situation of “shock”, this is an undesirable effect bec. Decrease tissue perfusion
What are the clinical uses for dopamine? What are the ultimate effects?
Shock; cardiogenic shock, unstable CHF
Sometimes used in manage acute crisis in chronic CHF
Increases cardiac output and enhances perfusion of kidney
What should you do when giving dopamine?
Must monitor BP carefully because higher infusion rate or dose causes vasoconstriction and decreased tissue perfusion
What are the pharmacological effects of dobutamine?
b1-selective agonist
actually complicated b1 agonist,
a1 agonist/antagonist
What are the clinical effects of dobutamine?
Clinically mostly b1-effects
positive inotropic & some increase in rate
Cardiac output increases
little vascular effect
What are the clinical uses of dobutamine?
dobutrex:
Clinical Use: cardiogenic shock, MI, CHF
What are the adverse effects associated with dobutamine?
Adverse effects: may increase size of infarct
potential arrhythmias
Increases the work/O2 requirement
What are the clinical uses for alpha-1 selective receptor blockers?
Clinical use = 2nd or 3rd line treatment of essential hypertension; added to other agents from different class
What are the effects of a1-selective receptor blockers?
↓PVR, ↓venous return, ↓ preload
Usually do not ↑ heart rate or cardiac output
Do not ↑ NE release (no a2 block)
Favorable effects on lipids
- ↓LDL & triglycerides; ↑HDL
What are the adverse effects associated with a1-seletive receptor blockers? How are these effects minimized?
Can cause marked postural hypotension & syncope, orthostatic hypotension, especially with initial doses
Usually given at bedtime to minimize hypotensive effects
What are some important a1-selective receptor blockers, and what are some pharmacological differences between them?
Prazosin (Minipress)
- 100x a1 selective
- Short t1/2, BID or TID dosing, titrate upward
Terazosin (Hytrin)
- Like prazosin but long t1/2 & high bioavailability allows QD dosing
Doxazosin (Cardura)
- Like prazosin but long t1/2 & high bioavailability allows QD dosing
What are some mechanisms of vasodilation activated by 3rd generation beta blockers?
blockade of L-type VGCC
- reduced smooth mm contraction
agonist at beta 2 receptors
- increased cAMP, cGMP causes vasodilation
antioxidant effects
- reduced LDL oxidation, lipid peroxidation, endothelial dysfxn, apoptosis
What are the clinical uses of beta blockers in heart patients?
Hypertension. Decreases CO and produces slow decrease in peripheral resistance.
Ischemic Heart Disease: Angina, myocardial infarction, acute coronary syndromes. Reduces cardiac work and O2 consumption.
MI & Post-MI prophylaxis
- protects against arrhythmias & limits infarct size
- Acute MI: assess LV function
- 5-12 days after MI, reduces O2 demand & spread of infarct zone
Congestive Heart Failure
- Improves morbidity and mortality
Arrhythmias: sinus tachycardia and supraventricular ectopic beat
- Recurrent VT, VF - especially when due to ischemia
In addition to heart problems, beta blockers are also useful in helping to treate what conditions?
Thyrotoxicosis:
- hyperthyroid patients have increased b receptor sensitivity
- Beta blockers reduces sensitivity of myocardium to adrenergic stimulation in hyperthyroid patients.
Adjunctive treatment for anxiety (panic) attacks
- reduces peripheral sympathetic signs and symptoms, e.g., palpitations
Migraine headache (Prophylactic treatment)
nPheochromocytoma
What is the mechanism of beta adrenergic receptor blockers? What is the prototypical beta blocker?
Mechanism: competitive antagonists at b-1, b-2, & b-3 receptors.
b blockers differ in their degree of receptor selectivity
Propranolol (Inderal) is the prototype
What is the effect that some beta blockers have on membranes?
Some b blockers have intrinsic sympathomimetic activity (ISA), i.e., partial agonist activity
Some b blockers at high therapeutic doses may also have a non-receptor related quinidine-like or membrane-stabilizing effects.
When would beta blockers have a greater pharmacological effect? Would the effects be the same for everyone?
The effect of antagonists are due to blocking existing sympathetic tone.
Effects are greater if sympathetic tone is high, e.g., during stress (MI) or exercise.
Effects are different in normal subjects compared to patients with hypertension or myocardial ischemia.
What are the effects that beta blockers have on the heart?
Pharmacological Effects - depend on existing sympathetic tone
Decreases in the heart:
¯ heart rate and cardiac output
¯ exercise tolerance
¯ rate of depolarization of ectopic pacemakers
¯ O2 demand
¯ AV nodal conduction (can produce AV block)
¯ infarct size & re-infarction- prevent sudden death
What are the short and long-term cardiovascular effects of beta blockers?
Cardiovascular Effects
Short term - ↓CO, ↓HR
- PVR ↑ to maintain BP as a result of blockade of b2 receptors & compensatory reflexes
Long term – PVR returns to initial values or ↓ in patients with hypertension (HTN)
- a/b blockers – CO is maintained with greater ↓ in PVR
What are the effects of beta blockers on rhythm and automaticity of the heart?
↓sinus rate
↓spontaneous rate of depolarization of ectopic pacemakers
Slow conduction velocity in the atria and AV node
↑ functional refractory period of AV node
What are the effects of beta blockers on exercise tolerance?
b blockers blunt the increase in HR and contractility that normally occurs with exercise
Cardiac output (CO) is less affected because stroke volume is increased
b blockers decrease work capacity
b1-selective agents have lesser effects on exercise tolerance than nonselective agents
Beta blockers will generally decrease myocardial O2 demands, but what paradoxical effect can happen? What is the net effect?
However, b blockers may tend to ↑ oxygen demand by increasing end-diastolic pressures and systolic ejection time period
Usually, the net effect is to improve the relationship between cardiac supply and demand; exercise tolerance is improved in patients with angina, whose capacity to exercise is limited by chest pain
Do beta blockers lower BP in normotensive people?
b blockers do not usually lower BP in patients with normal BP but are effective treatment for patients with HTN
Mechanisms for this effect are not well understood
What is the effect of gradually increasing propranolol over weeks on:
max exercise heart rate
BP
plasma renin concentration
HR - decreases
BP - decreases systolic more, and some diastolic
renin - gradual but significant decrease
How do beta blockers cause a decrease in renin?
Catecholamines stimulate b1 receptors in kidney juxtoglomerular apparatus to increase release of renin; b blockers block this increase in renin
Beta blockers will decrease renin release from JG cells in the kidney. What is the relevance of this effect on BP? Why?
Relevance of this effect to BP lowering is not clear.
However, BP is decreased the most in pts with elevated renin
b blockers are effective in lowering BP in patients with low or normal renin levels
Pindolol is an effective antihypertensive agent even though it has little effect on renin levels
Do beta blockers have an effect on vascular smooth mm?
Although b blockade would not be expected to decrease contractility of vascular smooth muscle, long term administration of these drugs to hypertensive pts ultimately leads to ↓ PVR
The mechanism for this effect is not known, but ↓ PVR in the face of persistent reduction in CO appears to account for much of the antihypertensive effect.
A CNS effect has been hypothesized – but there is little evidence to support this idea and drugs that penetrate into the CNS poorly are still effective.
What are some non-selective vasodilating beta blockers?
Carteolol, carvedilol, bucindolol, labetolol
What are some beta-1 selective vasodilating beta blockers?
Betaxolol, celiprolol, nebivolol
How do non-selective and b1 selective vasodilating beta blockers produce peripheral vasodilation?
- ↑NO
- Activate b2 receptors
- Block of a1 receptors
- Block Ca++ entry
- Open K+ channels
- Antioxidant activity
- Antiproliferative effects
Vasodilating beta blockers are also associated with a decreased incidence of:
Bronchospasm, impaired lipid metabolism, impotence, reduced regional blood flow, increased vascular resistance, and withdrawal symptoms.
What patients and conditions would vasodilating beta blockers be helpful for?
particularly beneficial in patients with insulin resistance, diabetes mellitus, and metabolic syndrome.
These effects are also being intensively investigated in relation to treatment of patients with congestive heart failure and peripheral arterial disease.
What drugs are helpful in treating chronic coronary aa disease/stable angina?
aspirin
beta blockers
nitrates
Ca++ channel blockers
ACE inhibitors
ranolazine
What drugs are helpful in treating unstable angina or non-ST elevation MI?
aspirin
beta blockers
nitrates
+
heparin
GPIIb-IIIa antagonist
- or -
bivalirudin
ADP receptor antagonist
What drugs are helpful in treating a STEMI in addition to a thrombolytic agent?
aspirin
beta blockers
nitrates
+
(thrombolytic agent)
heparin
ADP receptor agonist
What drugs are helpful in treating a STEMI in addition to angioplasty?
aspirin
beta blockers
nitrates
+
heparin
GIIb-IIIa antagonist
ADP receptor antagonist
- or -
bivalirudin
ADP receptor antagonist
What drugs are useful for post-MI infarction management?
beta blockers
statin
ACE inhibitor
Aldosterone receptor antagonist
aspirin
ADP receptor antagonist
(lots of conflicting messages about this subject, check UpToDate and edit as needed - 9/18 KMS)
Why are beta blockers so beneficial in treating patients with MI or ischemic heart disease?
b blockers are effective in reducing the severity and frequency of attacks of exertional angina & in improving survival in patients who have had an MI.
- Not useful for vasospastic angina –may worsen
Which beta blockers are cardioprotective?
Timolol, metoprolol, atenolol, and propranolol
The beneficial effects of beta blockers for MI or angina are due to what?
Fall in myocardial oxygen demand & increased flow to ischemic areas
↓HR, ↓contractility, ↓arterial BP (especially during exercise or stress
What types of heart patients are beta blockers not good for?
In patients with limited cardiac reserve who are critically dependent on sympathetic stimulation, b blockade can result in profound decreases in left ventricular function.
Can also worsen vasospasm-mediated angina
In addition to reduced mortality, what other effects of beta blockers are beneficial to MI patients?
Antiarrhythmic effects are also beneficial in MI patients
Despite this clear evidence many patients who experience an MI do not receive b blockers
What are the results of beta blockers in CHF treatment?
Beta blockers prevent HF in >50%, strokes reduced by >38%, occurrence of CAD and other CV events significantly decreased, improve ventricular remodeling
Mortality rate reduced 65% by carvedilol, 34% by metoprolol, 33% by bisoprolol – hospitalization reduced
How do beta blockers help treat CHF?
increase LVEF, cause beneficial remodeling of heart
What types of CHF should you use beta blockers with? What other drugs should you use in addition?
Use only in stable CHF (class II & III), gradually titrate dose
Patients also treated with diuretic, ACE inhibitors, & digoxin
What are some relative contraindications of beta blockers? Why?
Bronchial Smooth Muscle
- Block sympathomimetic bronchodilation
- precaution or contraindication in asthma & COPD
Metabolic
- Blocks beta receptor effects on lipolysis and glycogenolysis.
- May mask signs of hypoglycemia, e.g., tachycardia, BP changes, tremor. Delays recovery from insulin-induced hypoglycemia.
What are some common side effects of beta blockers?
dizziness, fatigue, diarrhea, constipation, nausea, depression, sexual dysfunction, bizarre dreams
What are some rare but severe side effects of beta blockers?
purpura, rash, fever
What metabolic effects can result from chronic use of beta blockers?
May Interfere with SGOT and BUN tests
Chronic use VLDL & ↓HDL
- effects vary among agents
Sudden withdrawal of beta blockers can result in what?
Sudden Withdrawal: rebound hypertension, anginal attack & possibly MI if drug suddenly withdrawn after chronic therapy.
Beta receptor synthesis is increased by beta blocker use. Example of receptor up-regulation, supersensitivity.
In addition to asthma, DM, and COPD what are some more contraindications for beta blockers?
Acute treatment of decompensated heart failure; 2nd and 3rd degree heart block, and cardiogenic shock.
What are some interactions between beta blockers and other medications?
Other hypotensive medications
- reserpine, guanethidine, methyldopa
Other antiarrhythmic agents
- calcium channels blockers
- lidocaine
Insulin and oral hypoglycemic drugs
- prolongs hypoglycemia and masks signs
Masks symptoms of hyperthyroidism
Beta1 selective blockers are more potent at what receptor? How is this beneficial for relative contraindicatoins?
at higher doses, block b2 as well
lessen risk of bronchospasm -still contraindicated in asthmatic
do not usually prolong hypoglycemia
What is important about the pharmacokinetics of esmolol? What receptors does it work on? What is it used for?
Very rapid onset & short duration of action
b1-selective
Used as IV infusion for peri-operative tachycardia and hypertension, arrhythmias
Used in electroconvulsive therapy
What receptors does labetolol work on? What are the clinical uses?
Normodyne, Trandate
Selective a 1 blocker
Nonselective b1 & b2 blocker
Partial agonist at b2
Clinical Uses:
hypertension
pheochromocytoma
What receptors does carvedilol work on? What are some of the chemical and pharmacodynamic properties of the drug? What condition does it help?
Coreg
Nonselective b-blocker + a-blocker
Very lipid soluble
Also has antioxidant properties
Very dramatic results in CHF clinical trials
Decreased mortality by 65%
What receptors does clonidine work on?
alpha2 adrenergic receptor agonist
What are the effects of clonidine with the different routes of administration?
IV- increase BP (peripheral a2B) followed by decreased BP (central a2A)
Oral - decreased BP (decreased C.O., preload)
Patch - same as oral
What are the clinical uses for clonidine?
Essential hypertension (very little use now)
adjunct for narcotic, alcohol, & tobacco withdrawal and many other “off label” uses
What are the side effects associated with clonidine?
dry mouth, sedation, impotence - same as methyldopa
sudden withdrawal causes hypertensive crisis
