Adrenergic drugs in CV Pharm DSA Flashcards
Agonist drug examples
Epinephrine (alpha 1,2; Beta 1,2,3) Norepinephrine (alspha 1,2; Beta 1,3) Isoproterenol (all betas) Dobutamine (beta 1) Dopamine (D1> beta 1 > alpha1) Fenoldopam (D1) Clonidine (alpha 2) Methyldopa (alpha 2)
Alpha Receptor Antagonists
Prazosin (alpha 1)
Phentolamine (alpha 1, 2)
Beta receptor antagonists
Nonselective: Propranolol Nadolol Timolol *Pindolol *Carteolol Sotalol
Cardioselective
Atenolol
*Acebutolol
Metoprolol
Third Generation Labetalol Carvedilol Betaxolol Carteolol
Epinephrine (EPI)
Pharmacodynamics:
Epi is a full agonist at all adrenergic receptors
Cardiac Effects of EPI:
Most important: beta 1 receptors in myocardium (atria, ventricles, SA node, AV node, Purkinje fibers)
- -> increased inotropy, chronotropy
- -> systole is shorter, more powerful, CO enhanced, work of heart and oxygen consumption increased
- shortens duration of acction potential and refractory period
- increases membrane potential and improves conduction
- sometimes supraventricular arrhythmias occur with combo of epi and cholinergic stimulation
Vascular effects of EPI
- activates vasoconstriction via alpha , vasodilation via beta 2 in skeletal and splanchinc beds. (at low infusion rates) Diastolic pressure drops
- chief vascular action: smaller arterioles and precap sphincters. Differential expression of slpha and beta receptors (density). Net result–> redistribution of blood flow
- blood flow to skeletal muscles increased (due to powerful beta vasodilator action; after a beta 2 antagonist mainly constriction occurs)
Therapeutic Uses of Epinephrine:
• Restoration of cardiac rhythm in patients with cardiac arrest (ACLS protocols).
o During CPR for persistent or recurrent VT/VF (Pulseless Ventricular Tachycardia/ Ventricular Fibrillation) after 1-2 cycles of defibrillation & CPR.
o During CPR for PEA (Pulseless Electrical Activity)
o Following CPR and Transcutaneous Pacing (TCP) for Asystole.
o To treat bradycardia with serious signs and symptoms (along with atropine and dopamine).
rapid response to anaphylaxis
- prolongation of anesthtics (local)
- topical hemostatic agent on bleeding surfaces
- via nebulizer for pediatric asthma
Norepinephrine pharmacodynamics
NE is a full agonist at all adrenergic receptors, but has low affinity at beta 2 receptors, and thus, has very little effect at these receptors at normal doses.
NE CV effects
- Systolic and diastolic pressures, and usually pulse pressure, are increased by NE infusion.
- Cardiac output is unchanged or decreased, and total peripheral resistance is raised.
- Compensatory vagal reflex activity slows the heart, overcoming a direct chronotropic effect, and stroke volume is increased.
- Peripheral vascular resistance increases in most vascular beds, and renal blood flow is reduced, in response to NE infusion. NE constricts mesenteric vessels and reduces splanchnic and hepatic blood flow. Coronary flow usually is increased, probably owing both to indirectly-induced coronary dilation, and to elevated blood pressure. Unlike EPI, small doses of NE do not cause vasodilation or lower blood pressure, since the blood vessels of skeletal muscle constrict (1) rather than dilate (2), in response to NE.
Therapeutic Uses of Norepinephrine
• NE may be used as a vasoconstrictor to raise or to support blood pressure under certain intensive care conditions. In shock, the level of circulating catecholamines is already usually high and NE may further decrease perfusion to tissues, especially the kidney.
Other alpha-Adrenergic Agonist Pressor Agents
Metaraminol, mitodrine, ephedrine and other drugs with direct alpha-agonist activity and/or that indirectly release NE are sometimes used to support blood pressure during spinal anesthesia or shock.
Dopamine pharmacodynamics
- precursor for NE and EPI.
- full agonist at all dopaminergic receptors (D1, D2, D3, D4, D5). At higher concentrations, dopamine can also activate beta 1 receptors on the heart and at even higher concentrations it activates vascular alpha 1 receptors, –> generalized vasoconstriction.
*** D1 receptors mediate vasodilation in the renal and mesenteric vascular beds. Dopamine and its five receptors constitute major signalling pathways in the CNS.
Dopamine CV effects
low doses of DA causes an increase in glomerular filtration rate, renal blood flow, and Na+ excretion. These effects are especially useful in the management of states of low cardiac output, i.e., shock or CHF.
*** DA has desirable effects in the management of states of low cardiac output associated with compromised renal function, such as severe congestive heart failure and cardiogenic shock.
*** high concentrations–> positive inotropic effect (beta1 receptors) –> increase CO, contributes to its beneficial effects in the treatment of cardiogenic shock.
*** TPR usually unchanged at low/ int doses; ability of DA to reduce regional arterial resistance in some vascular beds, such as mesenteric and renal
Dobutamine
beta 1 receptor agonist
complicated; different isomers at alpha receptors cancel each other out
CV effects o dobutamine
more inotropic than chronotropic
enhances automaticity of the sinus node (less than isoproterenol)
dobutamine Therapeutic Uses
*** short-term treatment of cardiac decompensation that may occur after cardiac surgery or in patients with congestive heart failure or acute myocardial infarction.
Dobutamine increases cardiac output and stroke volume, usually without a marked increase in heart rate.
Isoproterenol
potent, non-selective beta receptor agonist, very low affinity for alpha 2 receptors.
Isoproterenol pharmacodynamics
isoproterenol lowers peripheral vascular resistance, primarily in skeletal muscle but also in renal and mesenteric vascular beds via activation of beta 2 receptor vasodilation. Diastolic pressure falls. Systolic blood pressure may remain unchanged or rise, although mean arterial pressure typically falls. Cardiac output is increased because of the positive inotropic and chronotropic effects of the drug in the face of diminished peripheral vascular resistance. The cardiac effects of isoproterenol may lead to palpitations, sinus tachycardia, and more serious arrhythmias.
isoproterenol therapeutic uses
• Isoproterenol can be used in emergencies to stimulate heart rate in patients with bradycardia or heart block, usually just before placement of a pacemaker or in patients with torsades de pointes.
Methyldopa is a preferred treatment for
hypertension in pregnant patients.
Centrally-Acting Alpha2-Receptor Agonist Sympatholytic Agents
clonidine and methyldopa
• Clonidine is the prototypic 2 agonist, was initially developed as a vasoconstricting nasal decongestant.
therapeutic uses of clonidine
- The major therapeutic use of clonidine is in the treatment of hypertension.
- Clonidine is used “off-label“ for a variety of disorders, including: treatment of diarrhea due to autonomic neuropathy in diabetics; withdrawal from narcotics, alcohol and tobacco; preoperative sedation; as a patch to treat postmenopausal hot flashes; differential diagnosis of pheochromocytoma; ADHD; Tourette’s syndrome; restless leg syndrome, and other disorders.
- Other 2 receptor agonists with action similar to clonidine include guanfacine and guanabenz.
Alpha Receptor Antagonists
prazosin (alpha 1)
phentolamine (alpha 1 and 2- reversible)
phenoxybenzamine (IRREVERSIBLE alpha 1 and 2 blocker)
nonselective beta receptor antagonists
propanolol
pindolol
carteolol
block all three subtypes of beta adrenergic receptors.
cardioselective beta receptor antagonists
acebutolol
atenolol
metoprolol
Selection of a beta Receptor Antagonist
- The various beta receptor antagonists that are used for the treatment of hypertension and angina appear to have similar efficacies. Selection of the most appropriate drug for an individual patient should be based on pharmacokinetic and pharmacodynamic differences among the drugs, cost, and whether there are concurrent medical problems.
- For some diseases, e.g., myocardial infarction, migraine, cirrhosis with varices, and congestive heart failure), it should not be assumed that all members of this class of drugs are interchangeable; the appropriate drug should be selected from those that have documented efficacy for the disease.
- beta 1-Selective antagonists are preferable in patients with bronchospasm, diabetes, peripheral vascular disease, or Raynaud’s phenomenon.
- Third-generation beta antagonists that block a 1 receptors, stimulate b 2 receptors, enhance NO production, block Ca2+ entry, open K+ channels, or possess antioxidant properties may offer therapeutic advantages.
Cardiovascular System Effects of Beta Receptor Blockers
• Beta blockers reduce sinus rate, decrease the spontaneous rate of depolarization of ectopic pacemakers, slow conduction in the atria and in the AV node, and increase the functional refractory period of the AV node.
beta blocker adverse effects
blockade of beta receptors may cause or exacerbate heart failure in patients with compensated heart failure, acute myocardial infarction, or cardiomegaly.
Nonetheless, there is convincing evidence that chronic administration of beta receptor antagonists is effective in prolonging life in the therapy of heart failure in selected patients
- Bradycardia is a normal response to beta blockade.
- Abrupt discontinuation of beta receptor antagonists after long-term treatment can exacerbate angina and may increase the risk of sudden death.
- Beta blockers treatment leads to decreased exercise tolerance.
caution beta blocker use in
diabetes
bronchial diseases
Therapeutic Uses of Beta Adrenergic Antagonists/’ Cardiovascular Diseases
beta Receptor antagonists are used extensively in the treatment of hypertension, angina, acute coronary syndromes, and congestive heart failure.
beta blockers and CHF
that certain beta blockers are highly effective treatment for patients with all grades of heart failure secondary to left ventricular systolic dysfunction. The drugs have been shown to improve myocardial function, to improve life quality, and to prolong life.
• There also is a reduction in the hospitalization of patients along with a reduction in mortality with fewer sudden deaths and deaths caused by progressive heart failure.
*** Start low and go slow!
beta blockers in ischemic heart disease
- administered early and continued long-term may decrease mortality by 1/4
- nonetheless, many patients with MI do not receive a beta blocker
Use of beta antagonists in other CV diseases
propanolol– vs hypertrophic obstructive cardiomyopathy
B blockers frequently used in managing acute dissecting aortic aneurysm
symptoms of hyperthyroidism are related to increased sympathetic nervous system activity
Carvedilol
carvedilol improves ventricular function and reduces mortality and morbidity in patients with mild to severe congestive heart failure.
3rd generation beta receptor ntagonist, membrane-stabilizing but lacks ISA
antioxidant and anti-inflammatory effects
