Flashcards in Adrenergic Agonists Deck (41)
First lets start off with the basics of adrenergic receptor function. Beta 2 receptors favor which catecholamine?
norepinephrine has little effect on B2 receptors
--therefore it has little capacity to increase bronchial air flow since receptors in bronchial smooth muscle are largely beta 2.
Epinephrine and isoproterenol are potent??
Cutaneous blood vessels almost exclusively favor which receptor?
Alpha 1 receptors: this norepinephrine and epinephrine cause constriction of such vessels.
B2 receptors cause vasodilation and activation of alpha 1 receptors causes vasoconstriction. So which one gets activated first?
--Threshold concentration for activation of Beta2 receptors by epi is lower than that for alpha 1 receptors
--therefore low concentrations of epi will cause vasodilation in vascular smooth muscle.
(physiological concentrations of epi cause primary vasodilation)
In response to high concentrations of epi, both alpha 1 and beta 2 receptors are activated, so what happens?
The response to alpha 1 receptors predominates, therefore vasoconstriction results
What are the Catecholamines?
What properties do the catecholamines share?
1. High potency
2 .Rapid inactivation: metabolized by COMT postsynaptically and by MAO intraneuronally (ineffective when given orally due to inactivation)
3. Poor penetration into the CNS: catecholamines are polar, thus they do not penetrate well into the CNS but most of these drugs have some chemical effects attributable to actions of the CNS
What are the non-catecholamines ?
How are these (non catecholamines) sympathomimetics different?
Increased liposolubility permits greater access to the CNS
--some of these compounds may act indirectly by causing release of stored catecholamines
There are three different classes of adrenergic agonists, direct, indirect and mixed. First lets discuss the drugs that fall under direct acting adrenergic agonists. These are your endogenous catecholamines. First lets discuss epinephrine, what is its purpose?
--Synthesized from tyrosine in the adrenal medulla
--Released along with norepinephrine into the blood
--Agonist at alpha and beta receptors
--acts as a hormone on distant cells
What are some of the effects of Epi on the cardiovascular system?
1. Increases contractility of myocardium -- B1 (+ inotropic)
2. Increased contraction rate - B1 (+ chronotropic)
3. Increased cardiac output -- leads to increase of oxygen demand of the myocardium
4. Increase renin release (B1)
5. Constricts arterioles in skin, mucous membranes and viscera - alpha 1
6. At low doses dilates blood vessels going to the skeletal muscle and liver - B2
A low dose of epi may cause the blood pressure to fall why?
--Greater sensitivity to epinephrine of vasodilator B2 receptors than of vasoconstrictor alpha 1 receptors
--Beta 2 is predominating
Explain the graph in the slides in regards to low dose epi in relation to BP and HR
1. Peripheral resistance decreases due to a dominant action on Beta2 receptors of blood vessels in skeletal muscle, where blood flow is enhanced so as a consequence diastolic pressure falls
2. Systolic pressure increases due to increased cardiac contractile force and a rise in cardiac output (B1)
3. Heart rate increases (B1)
When low dose epi is given the mean blood pressure is not greatly elevated therefore what does this explain?
Explains why the heart rate is still high
--compensatory baroreceptors reflexes do not appreciable antagonize the direct cardiac actions
A large dose of epinephrine given IV causes an increase in blood pressure. The increase in systolic pressure is greater than the increase in diastolic pressure. Explain this
Increased ventricular contraction (B1) so that increases systolic blood pressure
Increased heart rate (B1) -- however when the baroreceptor reflex kicks in the HR may slow markedly
Vasoconstriction (alpha1) that increases blood pressure
What are the effects of epi on smooth muscles?
1. Powerful bronchodilation by acting directly on bronchial smooth muscle B2
2. Relaxes GI smooth muscle (alpha 1 and 2, beta 2) -- intestinal tone and frequency and amplitude of spontaneous contraction are reduced and sphincters a re contracted (Alpha 1)
3. Detrusor muscle of the bladder relaxes (B2) and the trigone and sphincter contract (Alpha 1)
What are the effects of epi on the CNS?
Epi is polar so it does not enter the CNS in therapeutic doses.
Epi causes hyperglycemia due to what?
1. Increase of glycogenolysis (breakdown of glycogen to glucose) in liver B2
2. Increase of glucagon release by activation of B2 receptors on alpha cells of pancreatic islets
3. Insulin secretion is inhibited by activation of alpha 2 receptors and enhanced by B2 receptors. Predominant effect is inhibition of insulin secretion.
Epi causes lipolysis due to what?
Activation of B3 receptors in adipose tissue
--increase in cAMP --- activates hormone sensitive lipase --- hydrolyzes TAGs to yield free fatty acid and glycerol
concentration of free fatty acids in blood increases
What is the metabolism of EPI?
Metabolized by COMT and MAO
--final metabolites found in urine
--metanephrine and vanillyl-mandelic acid (VMA)
What are the various uses for EPI?
1. Anaphylactic shock
2. Tx acute asthma attacks
3. Cardiac arrest
4. Local anesthetics (produces vasoconstriction at the site of injection, allowing the local anesthetic to persist at the site before being absorbed)
What are the pharmacokinetics for epi?
Rapid onset and brief duration
Oral administration is ineffective because epinephrine is inactivated by intestinal enzymes
What are the adverse effects of epi?
CNS disturbances: anxiety, fear, tension, headache and tremor
Hemorrhage: may induce cerebral hemorrhage due to increase in blood pressure
Cardiac arrhythmias: particularly if the patient is receiving digitalis
What is the interaction of epi with hyperthyroidism?
-Increase in production of adrenergic receptors on the vasculature of the hyperthyroid individual -- leading to a hypersensitive response
What is the interaction of epi with cocaine?
--Epi produces exaggerated CV actions, due to the ability of cocaine to prevent re-uptake of catecholamines into the adrenergic neuron
What is the interaction of epi with beta blockers?
--beta blockers prevent epi's activation of beta receptors leaving alpha receptor activation unopposed
--this leads to an increase in peripheral resistance and blood pressure
Moving on to the next adrengergic agonist is norepinephrine, which receptor does it usually hit?
--In therapeutic doses the alpha adrenergic receptor is the most affected
alpha 1 -- alpha 2 --- beta 1 and little effect on beta 2 receptors
What is the cardiovascular action of norepinephrine?
Vasoconstriction: increases peripheral resistance due to vasconstriction of most vascular beds, including kidney
--both systolic and diastolic blood pressure increases
Explain the baroreceptor reflex in regards to increased blood pressure and HR.
Increased blood pressure activates the baroreceptors in the carotid sinuses and inhibits sympathetic activity and stimulates parasympathetic activity
--this activation of parasympathetic activity decreases the HR and decreases the force of contraction
Norepinephrine causes hyperglycemia and other metabolic effects similar to those produced by epinephrine , but ?
--these are observed only when large doses are given
--norepinephrine is not as effective a hormone as epinephrine
What are the effects of norepinephrine?
Used for blood pressure control in certain acute hypotensive states
--also used for treatment of cardiogenic and septic shock
Explain the IV infectious chart for norepinephrine
Peripheral resistance due to alpha 1 and beta 1
Increase in blood pressure due to alpha and beta 1
--initially heart rate increases due to beta 1 however once the baroreceptor kicks in the heart rate decreases
Finally dopamine is another catecholamine and adrenergic agonists, why is it ineffective when given orally?
---substrate for both MAO and COMT and thus is ineffective when given orally
What are the cardiovascular effects of low dose dopamine?
Low rate of infusion:
--dopamine selectively activates D1 receptors in renal and vascular beds, leading to vasodilation and increase in GFR, renal blood flow and sodium excretion
What are the cardiovascular effects of intermediate rates of infusion of dopamine?
--dopamine activates B1 receptors in the heart
--also causes release of norepinephrine from nerve terminals
--increases systolic blood pressure, diastolic pressure is usually not affected.
What are the cardiovascular effects of higher rate of infusion of dopamine?
--dopamine activates vascular alpha 1 receptors, leading to vasoconstriction and a rise in blood pressure.
Does dopamine cross the blood brain barrier?
What is dopamine used for?
1. Tx of severe congestive heart failure
2. Tx of cardiogenic and septic shock
What are the adverse effects of dopamine?
--Overdose of dopamine produces the same effects a sympathetic stimulation
--rapidly metabolized to homovanillic acid, its adverse effects
A related drug to dopamine is called fenoldopam, what type of drug is this?
--D1 receptor selective agonist, which selectively leads to peripheral vasodilation in some vascular beds