Adrenergic agonists and antagonists
clonidine is an __________.
alpha 2(a2) agonist
EPI is an example of a __________ agonist
alpha and beta agonist
adrenergic receptors are subdivided into ________ and _________. Most receptors on the post synaptic membrane are what type? Most presynaptic receptors are what type?
alpha and beta. alpha. a2
What are the types of antagonists?
alpha blockers, beta blockers: nonselective, selective beta 1 blockers, BB with ISA, alpha and beta blockers, neuronal blockers
Because NE is the NT of adrenergic nerves, it should, theoretically, stimulate all types of adrenergic receptors. However, when administered in therapeutic doses, the ___________ is most affected.
alpha-adrenergic receptor
norepinephrine(NE) is an ________.
alpha1 agonist
What receptors are found in the heart?
b1 * and b2 receptors
What receptors are found in the kidney? What occurs when they are stimulated?
b1 receptors release renin increasing angiotensin II(vasoconstrictor) which will stimulate aldosterone and increase BP.
_____________ are usually located in blood vessels of skeletal muscle. When they are stimulated, the blood vessel is dilated.
b2
"-terol" drugs are usually ________.
b2 agonists
what are the two major adrenergic receptors located in the vascular smooth muscle of blood vessels?
b2 and a1
What receptors are found in the bronchiole? What occurs when they are stimulated? What is the clinical significance of this?
b2 receptor. When they are stimulated, bronchioles are dilated. b2 agonist is used as asthma treatment
What receptors are found in the uterine lining? What occurs when they are stimulated?
b2. When stimulated, dilation occurs- premature labor
what are the effects of clonidine?
-stimulates α2 receptors in CNS to decrease NE release Clonidine enters CNS, reduces NE release and inhibits post synaptic α2 receptors—SNS reduced BV dilation, reduction of BP
What are the ADRs of phenylephrine, naphazoline, and oxymetazoline?
(SAME AS NE)-increase BP, cardiac failure and arrhythmia -Reflex bradycardia -Infiltration necrosis after parenteral admin. -Rebound nasal congestion
adrenergic antagonist
(sympatholytic) the drug that binds to the receptor cannot activate the receptor. Inhibits or prevents the cellular responses induced by NE or circulating catecholamines
what are the clinical uses of clonidine?
-Hypertension -Withdrawal symptoms from opiates, tobacco smoking, and benzodiazepines
what are the clinical uses of phenylephrine, naphazoline, and oxymetazoline(ALPHA 1 AGONISTS)?
-IV to increase BP (stimulates α1 = vasoconstriction) -P.O. or intranasal as nasal decongestant -Ophthalmic drops for mydriasis—pupil dilation, -reduce eye redness
What are the clinical uses of isoproterenol? What metabolizes it?
-IV, metabolized by COMT not MAO -longer half-life than EPI o Treatments heart block, bradycardia, ventricular arrhythmia due to the slow HR. o **NOT used for treating asthma
what are the ADRs of NE?
-Increase BP hypertensive crisis/hemorrhage -Reflex bradycardia -nasal dryness -Blurred vision—pupils dilated -IV infiltration (NE out of blood vessel) tissue necrosis (vasoconstriction by NE in tissue) **must administer α1 ANTagonist to counteract that agonist effect.
timolol and nadolol
-More potent than propranolol -long duration of action -use for hypertension, angina, and migraine prophylaxis and chronic open-angle glaucoma
isoproterenol is a ___________. What does it bind to? What is the result of binding?
-Nonselective β adrenergic receptor agonist Binds mainly to β1 or β2 receptor o β1 binding = stimulation of the heart o β2 binding = relaxation of smooth muscle
dobutamine
-Selective β1 agonist -Increases force and HR Clinical use: parenterally for acute CHF as an inotropic drug ADRs: develop ventricular arrhythmia; tolerance
albuterol/terbutaline is a _____________. It functions how?
-Selective β2 agonist: -relaxes smooth muscle (bronchodilation, relax uterus) -vasodilation in skeletal muscle -Selective: usually requires lower dose
What are the effects of NE?
-Vasoconstriction > heart stimulation, increases peripheral resistance = increased BP -Reflex bradycardia
What are the clinical uses and ADRs of EPI?
-asthma (bronchodilation via stimulation of β2) -anaphylaxis shock (IM--epipen) and angioedema -prolongation of local anesthetics -cardiac arrest, bradycardia, complete heart block in emergency • ADRs: ventricular arrhythmias, headache and restlessness
MOA inhibitors & COMT inhibitors
-can prolong the circulating catecholamines, MOA degrades catecholamines and is located in nerve terminal so inhibitors can reduce degradation of NE so more can be stored in the vesicle and released.
what are the clinical uses of dopamine
-circulatory shock -acute heart failure
What are the ADRs of selective a1 blockers?
-excessive/postural hypotension -headache and dizziness, nasal congestion, blurred vision -reflex tachycardia -sexual dysfunction -EPI reversal
what are the characteristics of the catecholamines?
-high potency - rapid inactivation: MAO, COMT - poor CNS penetration
What do selective a1 blockers treat?
-hypertension block α1 and prevent NE from stimulating α1, prevents vasoconstriction—blood vessel will be more dilated -Benign prostate hyperplasia reduces urine hesitancy, block α1 receptors relax for passing urine
Phenoxybenzamine
-irreversible non-selective a-agonist, long-acting; used for preoperative management of pheochromocytoma
what are the characteristics of the non-catecholamines(amphetamine, phenylphrine, ephedrine)?
-longer t1/2 and duration -less polar -greater CNS penetration
propranolol
-most lipid soluble BB, highest membrane stabilizing effect.
phentolamine
-non-selective a agonist -reversible (competitive), short-acting; used to diagnose and treat pheochromocytoma -Can be used to treat hypertension
esmolol
-short HL- IV for hypertensive crisis and acute SVT usually used to treat acute or emergent conditions
What are the three types of adrenergic agonists?
1. Direct action 2. Indirect action 3. Mixed Action
What are the three types of Indirect action agonists?
1. MOA inhibitors & COMT inhibitors 2. Uptake Inhibitor 3. Releasing agents
Describe the mechanism of action of a1 receptors. What occurs when they are stimulated in muscle? In pupil?
1. agonist binds to α1 receptor, (Gq protein coupled) 2. IP3 and DAG are generated and increase intracellular Ca In smooth muscle, this causes muscle contraction (This is why when α1 receptors are stimulated in a blood vessel, vasoconstriction occurs. α 1 stimulation in the pupil causes the muscles to contract causing pupillary dilation).
What occurs in a low, medium and high dose of dopamine?
1. low= dopaminergic (dopamine receptor in renal and mesenteric—vasodilation, more blood to kidney= generate more urine and maintain kidney function) 2. medium= β1 vasoconstriction (force (contractility) > heart rate) 3. high dose = α1 (vasoconstriction)
How do neuronal blockers function?
Adrenergic neuronal blocker by general reduction of SNS activity (storage, release); Reserpine also depletes serotonin and dopamine in CNS and reduces NE release
what is a beta blocker with ISA
BB with intrinsic sympathomimetic activity
What are the ADRs of beta blockers(BB)?
Common: weakness, dizziness, tiredness, minor GI disturbances, sexual dysfunction CV - bradycardia, AV block, exacerbate acute HF, hypotension, chest pain, aggravation of peripheral vascular disease
What is the major use of b agonists?
CV maintanence and function. • Nonselective drugs: ISOP & EPI stimulate β1 and β2 and increase cAMP • Main Use: cardiac stimulants during resuscitation and bronchodilators, mostly in acute asthma and allergic reactions • ADRs: tachycardia, palpitations, arrhythmias, headache, hyperactivity, increased BP, insomnia, nausea, tremors; CNS stimulation/anxiety in overdoses
Not only do adrenergic receptors respond to NE, but they also respond to what else?
EPI and dopamine in systemic circulation(circulating catecholamines) from adrenal medulla
At a lower dose where would EPI bind? At a higher dose?
EPI has a higher affinity to β2 than α1 in blood vessels—a lower dose would cause it to bind to β2 and cause vasodilation; at a higher dose, it binds to more α1 and causes vasoconstriction.
describe the pulse rate, BP, and peripheral resistance of EPI
EPI stimulates all adrenergic receptors. In the BVs, EPI stimulates α1 and β2. At a lower dose, EPI binds to β2 and dilates BVs in skeletal muscle; when this effect goes to skin BVs or splanchnic BV, it will stimulate α1 and cause vasoconstriction. The net effect is a reduction in peripheral resistance in lower dose. This will cause a drop in diastolic BP and meanwhile, EPI will stimulate HR (increase) and contractility. When you increase contractility the SV, CO and sys. BP will increase. So diastolic BP drops and systolic BP increases—mean arterial pressure has no change. Baroreflex will maintain the basal level; HR is increased because EPI can directly stimulate the heart β1 receptor.
EPI reversal
EPI stimulates all adrenergic receptors; no change in BP unless you give very high dose.
What are the different effects of EPI, NE and Isoproterenol in stimulating α and β adrenergic receptors?
EPI: higher affinity for α1 receptors, than Isoproterenol because EPI non-selectively stimulates all of the receptors. NE is α1 agonist. Isoproterenol is nonselective β agonist—has a much higher affinity for β receptor than NE and EPI **Because of these differences, peripheral resistance, BP and pulse rate are also different.
Why shouldn't non selective BB be given to patients with COPD or ASTHMA?
If nonselective, do not administer these to patients with COPD or asthma(blocks b2 which will prevent vasodilation from occurring)
what is reflex bradycardia?
In blood vessels, activation of α1 receptor causes vasoconstriction (increased peripheral resistance = increased BP = baroreceptor more activated). This REDUCES ACTIVITY of the SNS, slowing HR.
What are the clinical uses of labetalol and carvedilol?
L: IV for hypertension and pheocromocytoma C: used for heart failure
describe the pulse rate, BP, and peripheral resistance of NE. How does it cause reflex bradycardia?
NE stimulates α1 receptor, causing vasoconstriction(This is why peripheral resistance(BP) is increased) An increase in peripheral resistance is why diastolic and systolic BP increase as well as MABP. Increased MABP will activate the baroreceptor and reduce SNS activity—causes HR/ pulse rate to reduce: reflex bradycardia.
how does isoproterenol differ from EPI?
No stimulation of α1 receptor in BV
describe the pulse rate, BP, and peripheral resistance of Isoproterenol
Nonselective -stimulates β1 and β2. When β2 receptor is stimulated in blood vessels of skeletal muscle it will cause dilation, reducing peripheral resistance(BP) more so than EPI. Diastolic BP will drop more and heart stimulation will be similar so systolic BP increase but since diastolic BP drops more, mean arterial blood pressure will drop—baroreceptor will be less activated. This means SNS will be more active (release the brake) and will stimulate the heart. Thus, the HR will increase more than it did with EPI because there is direct stimulation of isoproterenol on the β1 and because baroreceptor leads to tachycardia.
what are the selective a1 blockers?
Prazosin, Terazosin, Tamsulosin, Alfuzosin, Doxazosin
what occurs when a b1 receptor is stimulated? if it is blocked?
S: cardiac stimulation; renin release B: cardiac depressant
what occurs when a b2 receptor is stimulated? blocked?
S: relaxation smooth muscle - bronchiolar, uterine, GI, skeletal muscle blood vessels B: COPD/asthma; pregnancy
adrenergic agonist
SNS-mimicking. mimics the effect of circulating catecholamines or neurotransmitter NE -increase BP, HR, and contractility
releasing agents
Tyramines and amphetamines have very similar structure as NE; they will be taken up into the neural terminal depleting NE from vesicle.allowing it to leak out
___________ are located in the spleen, splanchnic vessels, and kidney as well as BV in skeletal muscle. When they are stimulated, vasoconstriction occurs.
a1
What is used to dilate pupil in eye exam?
a1 agonist
What receptors are found in the sphincter muscles of the bladder? What occurs when they are stimulated?
a1 receptors Stimulation causes constriction of sphincter muscles to reduce urine incontinence.
What receptors are found in the eye? What occurs when they are stimulated? What is the clinical significance of this?
a1 receptors. When stimulated, contraction of muscle and pupil dilated(mydriasis).
Where does EPI bind?
a1, b1, b2
most presynaptic drug receptors are __________.
a2
stimulating ________ reduces insulin secretion. This is a presynaptic adrenergic receptor.
a2.
___________is a BB with membrane stabilizing activity and ISA
acebutenolol
What are the BB with ISA?
acebutolol, pindolol
Direct Action agonists
binds to adrenoceptors: NE, EPI, Isoproterenol (ISOP) and activates cellular response. May be Selective or Nonselective
what results from the use of trimethapan?
blocks reflex bradycardia from occurring with phenylphrine. BP still increases but no HR change
nebivolol
can stimulate NO release causing vasodilation, use for hypertension
Uptake inhibitor
cocaine mainly inhibits NET(NE transporter) and lets NE stay in synapse longer
what are the ADRs of labetalol/cervedilol?
combination of alpha/beta blockade, hepatic injury
Why is dopamine used in acute heart failure but not NE or EPI?
doesn't cause kidney shutdown like others
Indirect action agonists
drug is not bound to receptor; influence release, reuptake and degradation of NE and EPI to potentiate sympathetic activity
__________ is a BB with a very short half life and can only be given via IV.
esmolol
___________ is a neuronal blocker which reduces the fusion of vesicles to nerve terminal and reduces NE release
guanethidine
What are the clinical uses of a b-blocker(b receptor blocker)
hypertension, angina, arrhythmias, myocardial infarction, chronic heart failure, hyperthyroidism, tremor, glaucoma, and prophylaxis of migraine
In smooth muscle, activating b2 receptors will have what effects?
increase cAMP concentration resulting in inactivation of Myosin-LC Kinase causes dissociation of actin and myosin and smooth MUSCLE RELAXATION
What occurs when b1 receptors are stimulated?
increase contractility and HR
What is the result of increased cAMP(during b2 activation) in heart?
increased Ca increasing contractility and HR
What are the alpha and beta blockers?
labetolol/ carvedilol(alpha-1 and NS BB)
what are the cardioselective beta 1 blockers MEAAN
metoprolol, acebutolol, atenolol, esmolol, nebivolol
___________ is a BB with membrane stabilizing effects
metropolol
___________ is a non-selective BB with a very long half-life
nadolol
pindolol
non-selective BB with ISA and membrane stabilizing effect, used as an antihypertensive in people with diminished cardiac reserve (cardiac β1 stimulation is low, need to stimulate the heart so it can respond to a need for more cardiac output).
What are the nonselective a1 and a2 blockers?
phentolamine and phenoxybenzamine
What are some other alpha1 agonists?
phenylephrine, naphazoline, oxymetazoline(non-selective a agonist)
___________ is a non-selective BB with ISA
pindolol
a2 receptors are most commonly located ___________- negatively regulate NE release.
presynaptically.
___________ is a non-selective BB; has membrane-stabilizing activity which lets it be used to treat arrhythmia
propanolol
what are the nonselective BB?
propranolol, timolol, nadolol
__________occurs when a patient abruptly discontinues their clonidine.
rebound hypertension
reflex tachycardia
reduced BP causes reflex tachycardia, nonselective has more severe reflex tachycardia because it also blocks α2 presynaptically causing an increase in NE release in the heart which will stimulate β1.
What are the clinical uses for albuterol/terbutaline?
relieves acute bronchospasm in asthma via inhaler or nebulizer -inhibits uterine contractions in premature labor (terbutaline)
what are the neuronal blockers?
reserpine/ guanethidine
______________ are much safer to be used for COPD or asthma patients
selective beta 1 blockers(won't bind b2 and prevent bronchodilation)
acebutolol
selective β1 blocker, active metabolite (diacetolol), membrane stabilizing effect, also has ISA, used to treat ventricular arrhythmias
What are the distinguishing features of BB?
selective, Lipid soluble,membrane stabilizer intrinsic sympathomimetic activity (ISA)- partial agonist activity
___________is a non-selective BB; does not have membrane-stabilizing activity which is why is can be used for glaucoma
timolol
What are the ADRs of albuterol/terbutaline?
tremor, tachycardia(at higher doses can cause some b1 stimulation on the heart)
pheochromocytoma
tumor cell in adrenal gland medulla that can synthesize a large amount of catecholamines (dramatically increase BP)
metoprolol and atenolol
use for hypertension, angina, acute myocardial infarction, heart failure, and tachycardia
describe the clinical use of NE
used in shock (IV) -monitored very closely to prevent too high of a BP
what are the clinical uses and ADRs of the neuronal blockers?
used to treat hypertension ADRs: hypotension, reflex tachycardia, increased GI & CNS depression
NE causes greater __________than EPI, because it doesn't bind b2 receptors inducing vasodilation in blood vessels supplying skeletal muscles.
vasoconstriction
describe how beta receptors are activated.
β1 is Gs protein coupled; adenylyl cyclase is activated and cAMP concentration is increased.
