Adrenergic Agonists week 1 Flashcards
Describe the affinity of each of the adrenergic receptors for NE and Epi.
Describe the affinity of NE and E for each of the receptors.
Alpha 1: NE > Epi
Alpha 2: NE = Epi
Beta 1: NE = Epi
Beta 2: Epi >>> NE
Beta 3: NE >>> Epi
First aid: Epinephrine β > α
NE α1 > α2 > β1
Explain the effects of DA on the body.
. State what SANS receptors it can bind to and the effects of this.
State a clinical situation where dopamine is used and why.
Dopamine plays a minor role in SANS function, but does serve to vasodilate renal arterioles and preserve renal function through DA receptors located in the arterioles. DA also stimulates natriuresis and diuresis via activation of enzymes involved in second messenger systems (i.e. adenylate cyclase and phospholipase C). Dopamine is a natriuretic hormone, increasing sodium excretion by diminishing reabsorption, primarily in the proximal tubule. DA also dilates coronary vessels. These effects predominate at low administered doses (given i.v.). At higher doses, DA has direct inotropic effects mediated by beta 1 receptors. At higher doses, DA stimulates alpha-1 receptors as well. These beta and alpha effects are a consequence of DA’s direct stimulatory effect (albeit <<< than NE and Epi) on these receptors. DA is also present in the chain ganglia in small intensely fluorescent (SIF) cells and high dose, iv drip is used for shock treatment secondary to severe blood loss to cause positive inotropy while maintaining blood flow to kidneys.
- Although used extensively in intensive care units, hypovolemic shock is generally first treated with fluid replacement and care must be taken to balance the cardiac output effects of DA (positive inotropy and chronotropy) vs workload on the heart and effects on total peripheral resistance (TPR). Regardless, when you need to increase cardiac output without causing renal arteriolar constriction as would occur with an alpha or beta drug, DA infusion is the treatment of choice. DA increases cardiac output while maintaining kidney perfusion!
Explain the ability of DA, Epi, and NE to enter the brain. What does this mean for the effects they have in the CNS?
NE, DA and Epi are released peripherally and can circulate prior to their biotransformation (Epi >> NE =DA). However, because of their hydrophilic structure, they do not enter the brain. There is some controversy regarding Epi, which at higher doses may enter brain somewhat. However, there are regions of the brain that are not protected by the blood brain barrier (BBB) where all three can act. This is especially true in the hypothalamus and the area postrema (floor of 4th ventricle and often called the chemoreceptor trigger zone (CTZ)) which is rich in DA receptors and initiates emesis. Epi likely has effects in the hypothalamus as well, many parts of which are not protected by the BBB.
What signaling cascade occurs when alpha-1 receptors are bound?
State the effects of alpha-1 receptor binding.
Alpha-1 Receptors: are G-protein coupled receptors that lead to increased IP3 and DAG via Gq.
- Vascular smooth muscle contraction (arterioles and venules) – increased TPR
- Pupillary dilator contraction – mydriasis
- Heart –mild positive inotropy
- Bladder trigone and sphincter contraction – urinary retention
- ENS sphincter contraction – increased transit time/reduced motility
- Arrector pili muscle – erects hair
- Apocrine gland secretion – stress related sweating
- Penis and seminal gland – ejaculation
- Adipose tissue – glycogenolysis and gluconeogenesis
What signaling cascade occurs when alpha-2 receptors are bound?
State the effects of alpha-2 receptor binding.
Alpha-2 Receptors: inhibit adenylyl cyclase, decreasing cAMP via Gi.
- Autoreceptor function to reduce future NE release
- Heteroreceptor function to reduce release of ACh and other neurotransmitters. This is a characteristic feature of the ANS where increasing SANS tone will, via heteroreceptors, reduce ACh release in terminals nearby. Similarly, ACh acting through heteroreceptors can reduce NE release. Recall the cholinergic link concept.
- Platelets – aggregation
- There are alpha-2 postsynaptic receptors that produce a very mild vasoconstriction that is generally of no clinical consequence. There are alpha-2 post-synaptic receptors within the CNS as well.
- decreased insulin release, decreased lipolysis
What signaling cascade occurs when B 1,2,and 3 receptors are bound?
What are the effects of binding to eahc of these receptors?
Beta receptors: All three beta receptors (1, 2, and 3) activate adenylyl cyclase increasing cAMP via Gs. Three receptor subtypes have different distributions allowing for selective functions:
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Beta-1: heart
a. heart – positive inotropy, chronotropy and dromotropy
b. juxtaglomerular cells – increased renin release -
Beta-2: smooth muscle relaxation
a. bronchioles – reduced airway resistance
b. arterioles in muscle – increased vascular flow to striated muscles
c. liver – glycogenolysis - Beta-3: fat lipolysis
Explain the difference in effects with a lower level of SANS activation vs higher levels of SANS activation.
- The magnitude of the response is dependent upon the degree of activation:
a. lower levels of SANS activation primarily initiate release of NE producing alpha 1 effects similar to beta-1 and much more than beta-2
b. further increases in SANS activation leads to Epi release which brings in full beta 1 and beta-2 stimulation in addition to alpha effects.
receptor selectivity/preference vs receptor specificity
Receptor selectivity or preference reflects a preference for binding one type of receptor over another whereas receptor specificity implies a significant selectivity. Generally, specificity is used for molecules that have a 1,000 fold higher affinity for one receptor relative to another.
Explain the receptor selectivities of NE and E for adrenergic receptors.
What is their relative efficacy at their preferred receptors related to?
NE slightly prefers to stimulate alpha receptors more so than beta-
- Thus, NE is more alpha selective. Epi is slightly more beta than alpha and thus beta selective. However, the relative efficacy at each agonist at its receptor is a function of dose (i.e., relative level of SANS activation), and neither NE nor Epi are specific for alpha or beta receptors at high levels of SANS activation. It is also important to note that there is distribution of function based on innervation. Thus, there is little innervation of vascular beds in striated muscle so that the beta-2 effects of increasing vascular flow is a consequence of Epi circulating as a hormone and not NE mediated effects.
Define homologous desensitization.
What is the function of G-protein coupled receptor kinases (GRK)?
What are beta arrestins? What is their function?
Desensitization refers to reduced function in response to an agonist and underlies the phenomena of tolerance or refractoriness. It occurs over weeks of continuous stimulation. Tachyphylaxis is a form of desensitization that is often used to describe abrupt desensitization that would occur over of a period of hours.
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Homologous desensitization is a form of Pharmacodynamic tolerance and refers to desensitization of the receptor to which the agonist or natural ligand binds.
a. G-protein-coupled receptor kinase (GRK) involves phosphorylation of a G protein receptor when it is bound to its ligand. Phosphorylation enhances affinities for beta-arrestins which is a family of proteins that when bound, interferes with the ability of the receptor to bind with its G-protein counterpart.
(1) binding of the arrestins allows ligation with clathrin and clathrin adaptor proteins leading to internalization of the receptor and down-regulation of the receptor (i.e., receptor is internalized and not available to bind an extracellular neurotransmitter).
Define heterologous desensitization.
Heterologous desensitization is a form of Physiological tolerance and refers to the effect of an agonist or natural ligand that acts through its receptor to affect the function of another receptor or system
a. binding of a ligand to a heteroreceptor can lead to phosphorylation of a receptor via PKC which can alter the sensitivity of a different receptor.
b. Although we tend to use these terms to describe regular receptors, it is important to note that activation of auto-receptors can also affect the sensitivity of other functional receptors as well as reuptake pumps. Thus, prolonged alpha-2 stimulation can reduce function of NET.
What receptor(s) is phenylephrine specific for?
State the MOA, effects, clinical uses, and toxicities for phenylephrine.
What is responsible for the metabolism of phenylephrine? How does this affect how it is adminstered?
Direct acting Receptor Agonists
A. Alpha-1 selective drugs:
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Phenylephrine is the prototypical drug of this class
a. MOA: Direct-acting competitive agonist at alpha-1 receptors which is specific for alpha-1 (i.e., > 1000 fold)
b. Effects: smooth muscle contraction and other alpha-1 effects
c. Clinical:
(1) most widely used decongestant.
(2) hypertensive to reverse anesthetic hypotension because it has mild ino- and chronotropic effect. HR is decreased due to baroreceptor reflex, however.
* The mild alpha-1 chronotropic effects are offset by the baroreceptor response which, mediated by ACh (increased vagal tone) actually reduces HR.*
(3) priapism (direct injection—ouch!!) to reverse effects of drugs used to treat erectile dysfunction through NO increases. Epi can also be used.
(4) to induce mydriasis (NARROW ANGLE GLAUCOMA IS A CONTRAINDICATION due to further pinching off the angle secondary to mydriasis). However, contraction of the pupillary dilator muscle of the iris by alpha-1 agonists facilitate outflow of aqueous humor and can be used in open angle glaucoma.
(5) Enters CNS and enhances alertness. Used in several cold formulations to reduce drowsiness. Thus, its vasoconstrictive effects reduce congestion while its NE effects in the CNS activate the ventral arousal system to reduce sleepiness.
d. Toxicity: issues related to hypertension (dissecting aneurysm is thus a problem in individuals predisposed) and very high dose use can lead to increased seizures (CNS effects).
e. Pharmacokinetic considerations: it is a substrate for MAO-A and therefore has significant first pass effect. Is often used locally (as in nasal sprays).
How are shock and hypotension managed? Explain the efffects of the drugs used and which are used depending upon the cause of shock.
What are drugs used for hypotension and shock called? What are drawbacks to these medications in the management of hypotension and shock?
Management of shock and hypotension primarily employs phenylephrine and methoxamine although DA drip can be used as well. These pressor agents primarily cause arteriolar vasoconstriction via alpha-1 receptors although they also slightly constrict venules as well.
There overall effect is to increase TPR, which can increase work by the heart (could produce angina). There would be compensatory reductions in HR due to baroreceptor responses which would be partly offset by the direct actions of these drugs on the heart. If the shock is due to fluid loss, DA is preferred (want to maintain kidney function).
What receptor is clonidine specific for?
State the MOA, effects, clinical uses, and toxicities for clonidine.
How does the route of administration determine the effects of clonidine?
What is the bioavailability of drugs of this class? Explain the distribution.
Alpha-2 selective drugs:
- Clonidine is the prototypical drug in this class and is specific for alpha-2 receptors. It is primarily used for its sympatholytic effects. Other drugs in this class include methyldopa, guanfacine and guanabenz.
a. MOA: direct-acting competitive agonist at alpha-2 receptors and is specific. Methyldopa is also an aromatic amino acid decarboxylase inhibitor.
b. Effects: activates alpha-2 receptors and reduces NE release. This would normally lead to hypotension, but the effects are dependent upon the route of injection. Oral administration leads to mild reductions in SANS outflow from CNS and mild direct alpha-2 effects reduce NE release that together produce a hypotensive response. However, IV or topical administration will produce mild vasoconstriction due to the direct effects on alpha-2 receptors located post-synaptically. There are post-synaptic alpha-2 receptors in the periphery as well as CNS. The magnitude of the effect will be dependent upon the degree of SANS activation.
Generally used in patients with high SANS activity where its hypotensive effects can produce clinically relevant reductions in BP.
c. Clinical:
(1) primarily used for CNS effects associated with ADHD although it is a third line drug. Also used to treat the CNS anxiety effects of opiate withdrawal (discussed later in the drugs of abuse lectures) since opioid withdrawal is associated with rebound increases in NE release in the amygdala which produces anxiety
(2) Less used as an anti-hypertensive by reducing NE release and SANS outflow
(3) mild sedation associated with reductions in activity in the ventral alertness system
d. Toxicity: orthostatic hypotension (secondary to inadequate release of NE due to continued alpha-2 stimulation), dizziness, palpitations, and tachycardia. Headache, depression, loss of appetite, fatigue, and nasal congestion (opposite effect as that of phenylephrine which increases NE tone) can also occur. Based on its mechanism of action, the reduced release of NE produced by clonidine when a patient stands up is readily predictable. Indeed, as a general rule, anything that interferes with NE will produce orthostasis.
e. Pharmacokinetic considerations: Members of this class are all highly orally bioavailable and readily enter CNS. Methyldopa is also an aromatic amino acid decarboxylase inhibitor which would reduce synthesis of DA, NE and Epi. Several of the drugs are available in sustained release formulations.
What receptors does isoproterenol bind to?
State the MOA, effects, clinical applications, and toxicities of isoproterenol.
Non-specific beta receptor agonist: Affect all beta receptors.
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Isoproterenol
a. MOA: direct-acting, competitive beta-1, 2 and 3 agonist.
b. Effects: activates all beta receptors directly with very little, if any alpha activation. See table below.
c. Clinical: Was used at one time for asthma, but beta-1 actions caused cardiac issues (positive inotropy and chronotropy) that led to problems in asthmatics who also had cardiac problems. First aid: Used for electrophysiologic evaluation of tachyarrhythmias. Can worsen ischemia.
Toxicity: High doses cause significant initial increase in BP with concomitant marked reductions in heart rate that can be problematic and can produce fatal arrhythmias.
