Adrenergic Agonists and Antagonists Flashcards
Epinephrine’s dose dependent effect on different adrenoceptors
Functions as a hormone - acts on distant cells after release from adrenal medulla
Agonist at both a and b receptors
At low concentrations: epinephrine activates mainly b1 and b2 receptors
At higher concentrations, a1 effects become more pronounced
Effects of epinephrine at physiological doses
Increases heart rate and force of contradiction (b1). Cardiac output increases = oxygen demand of the myocardium increases
Increased renin release (b1)
Increased lipolysis (b1 and b2 effect)
Constricts arterioles in skin and viscera (a1)
Dilates blood vessels of skeletal muscle (b2)
Relaxes bronchial smooth muscle (b2)
Increases liver glycogenolysis
Increased glucagon release from a cells of pancreas (b2)
Effect of epinephrine on blood pressure when given IV in large doses vs low doses
Large dose: increase in MAP
- Increased ventricular contraction (b1) –> increased systolic
- Increased heart rate (b1) –> this may be opposed by the baroreceptor reflex
- Vasoconstriction (a1) –> increased diastolic
Small dose: no change in MAP
- Peripheral vascular resistance decreases due to vasodilation as b2 receptors are more sensitive to epinephrine than a1 –> fall in diastolic
- Increased contractility due to b1 –> systolic increases
- Heart rate increases (b1 effect) –> no change in blood pressure so baroreceptor reflex does not kick in
Uses of epinephrine
DOC for anaphylactic shock
Acute asthmatic attacks
Cardiac arrest
In local anesthetics: epinephrine increases duration of local anesthesia by producing vasoconstriction at teh site of injection
Norepinephrine specificity to adrenoceptors
Agonist at a1, a2 and b1 receptors
Little action on b2 receptors
Cardiovascular effects of IV infusion of norepinephrine
Peripheral vasoconstriction (a1)
Increases cardiac contractility (b1)
Increases PVR, systolic pressure and diastolic pressure –> increase in MAP –> triggers baroreceptor reflex –> reflex bradycardia
Cardiac output unchanged or decreases
Uses of norepinephrine
To treat shock because it increases vascular resistance and blood pressure
Baroreceptor reflex in response to increase in blood pressure
Baroreceptors in carotid sinus are mechanoreceptors that sense changes in blood pressure
1) Inhibits sympathetic activity at –> decrease force of contraction of heart (decreased activation of b1)
2) Stimulates parasympathetic activity –> Decreases heart rate (activation of m2 in atria)
Baroreceptor reflex in response to decrease in blood pressure
1) Stimulate sympathetic activity –> increase in force of contraction of heart
2) Inhibit parasympathetic activity –> increase in heart rate (inhibition of m2 receptors in atria)
Effect of atropine pre-treatment + norepinephrine on CVS
If atropine is given first, it will block the muscarinic receptors and block the baroreceptor reflex
So norepinephrine will cause increase in PVR, vasoconstriction and increased force of contraction which will increase MAP –> tachycardia
Dopamine selectivity for adrenoceptors
Dose dependent activation of a and b receptors. Physiologically activates D1 but in therapeutic doses can activate a1 and b1 too.
D1 > b1 > a1
Cardiovascular effects of low, intermediate and high rates of dopamine infusion
Low rate infusion: Activates D1 receptors in renal and other vascular beds leading to: - Vasodilation - Increased GFR - Increase in renal blood flow - Increase in sodium excretion
Intermediate rate of infusion Dopamine activates b1 receptors in heart and causes release of NE from nerve terminals which leads to: - Increased cardiac output - Increased systolic BP - Unchanged diastolic BP - Increased in MAP - PVR unchanged
High rate of infusion: Dopamine activates vascular a1 receptors: - Vasoconstriction - Increased PVR - Increased MAP
Dopamine uses (2)
Treatment of severe CHF
Treatment of cariogenic and septic shock
–> Intermediate to high rates of infusion are used to activate b1 and a1 receptors
Fenoldopam MOA and uses
D1-receptor selective agonist –> peripheral vasodilation in some vascular beds.
Indicated for in-hospital, short-term management of severe hypertension.
Fenoldopam should be administered by continuous intravenous infusion. A bolus dose should not be used.
Isoproterenol MOA and cardiovascular effects
Non-selective b-adrenergic agonist –> activates b1 and b2 receptors
Bronchodilation (b2)
Increases force of contraction and cardiac output (b1) –> systolic BP remains unchanged or rises
Dilates arterioles of skeletal muscle (b2) –> decrease in PVR –> diastolic BP falls
MAP typically falls –> increase in heart rate due to reflex tachycardia
Isoproterenol uses
Used in emergencies to stimulate heart rate in patients with bradycardia or heart block
Dobutamine MOA and cardiovascular effects
Predominantly b1 agonist
Increases force of contraction very well but has mild effect on heart rate.
Increases myocardial oxygen consumption therefore can be used for the dobutamine stress EKG
Causes mild vasodilation –> small decrease in PVR –> small increase in HR
Dobutamine uses (3)
Management of acute heart failure
Management of cardiogenic shock
Used in the dobutamine stress echocardiogram
Albuterol MOA and uses
Short acting b2 agonist –> bronchodilator
Management of acute asthma symptoms
Salmeterol and formoterol MOA and uses
Long acting b2 agonist –> bronchodilator
Prolonged duration of action (12 hours) due to very high lipid solubility –> slow onset of action
Used in asthma and COPD but cannot be used for prompt relief of acute symptoms
Albuterol, salmeterol and formoterol AE
b2 agonists
Tremor, restlessness, apprehension, anxiety
Yes are less likely with inhalation therapy than with parenteral or oral therapy
Phenylephrine MOA, cardiovascular effects
a1 agonist
Vasoconstriction –> large increase in PVR –> increased MAP –> reflex bradycardia
Decrease volume of nasal mucosa by decreasing resistance to airflow
Phenylephrine uses
a1 agonist
Nasal decongestant: given orally or topically
Mydriasis (but no cycloplegia)
Used to increase BP in hypotension resulting from vasodilation in septic shock or anaesthesia
Used to increase BP and terminate episodes of supra ventricular tachycardia
Clonidine MOA and cardiovascular effects of IV vs oral infusion, AE
Partial a2 agonist
Centrally acting antihypertensive
Activates central presynaptic a2 receptors –> reduces release of catecholamines –> reduces sympathetic outflow –> reduces blood pressure
IV infusion of clonidine causes an acute rise in blood pressure, because of activation of postsynaptic a2 adrenoceptors in vascular smooth muscle. This transient vasoconstriction is followed by a more prolonged hypotensive response which results from decreased sympathetic outflow from the CNS. The hypertensive response that follows IV administration is not seen when the drug is given orally.
AE: lethargy, sedation, xerostomia
Methyldopa MOA, effects, uses and AE
Taken up by noradrenergic neutrons –> converted to a-methynorepinephrine –> activates central a2 receptors
Decreases blood pressure
DOC for treatment of hypertension in pregnancy
AE: sedation, impaired mental concentration and xerostomia
Brimonidine MOA and uses
Highly selective a2 agonist
Given ocularly to lower intraocular pressure in glaucoma
Reduces aqueous humour production and increases outflow
Amphetemine MOA, effect and uses
Releasing agent –> displaces endogenous catecholamines from storage vesicles
Has central stimulatory action
Can increase blood pressure (a agonist action of vasculature) and b-stimulatory effects on heart
Marked behavioral effects including increased alertness, decreased fatigue, depressed appetite, and insomnia
Used to treat ADHD and narcolepsy
Methyphenidate MOA, effect and uses
Structural analog of amphetamine
Releasing agent –> displaces endogenous catecholamines from storage vesicles
Has central stimulatory action
Used to treat ADHD in children
Tyramine contraindications
Found in fermented foods such as ripe cheese and Chianti wine
Normally oxidised by MOA
If the patient is taking MAO inhibitors, it can precipitate serious vasopressor episodes.
Cocaine MOA
Blocks monoamine reuptake into presynaptic terminals. Most potent at blocking the dopamine transporter (DAT); higher concentrations block the serotonin transporter (SERT) and the norepinephrine transporter (NET).
This blockade leads to accumulation of the monoamines in the synaptic space resulting in potentiation and prolongation of their central and peripheral actions.
Cocaine effects
The sympathetic effects of cocaine include tachycardia, hypertension, pupillary dilation and peripheral vasoconstriction.
The major action of cocaine in the CNS is the inhibition of dopamine reuptake into neurons of the pleasure centers (the limbic system) of the brain –> this produces the intense euphoria
Atomoxetine MOA and use
Selective inhibitor of norepinephrine reuptake transporter
Used for treatment of ADHD
Modafinil MOA and use
Psychostimulant –> inhibitors norepinephrine and dopamine transporters –> increases synaptic concentrations of NE, dopamine, serotonin and glutamate and decreases GABA levels
Used for treatment of narcolepsy
Ephedrine MOA and PK
Mixed acting adrenergic agonists –> induce NE release and active adrenergic receptors
Not a catecholamine - poor substate for COMT and MOA –> long duration of action
Penetrates CNS and good oral absorption
Ephedrine uses
Mixed acting adrenergic agonist
Uses are pressor agent –> especially during spinal anesthesia
Used as adjunct in myasthenia gravis
Pseudoephredine MOA and uses
Mixed acting adrenergic agonists –> induce NE release and active adrenergic receptors
One of four ephedine enantiomers
Available OTC as a component of many decongestant mixtures
Non-selective a antagonists
Phenoxybenzamine - irreversible
Phentolamine - reversible
a1 selective antagonists
Prazosin
Terazosin
Doxazosin
Tamsulosin
Non-selective b blockers
Propanolol
Nadolol
Timolol
b1 selective antagonist
Atenolol
Metoprolol
Esmolol
a1 and b-antagonists
Labetalol
Carvedilol
Partial b-agonist
Pindolol
Inhibitor of NE synthesis
Metyrosine - competitive inhibitor of tyrosine hydroxylase
Inhibitors of NE storage
Reserpine –> Irreversibly blocks VMAT
Tetrabenazine –> Reversibly blocks VMAT
Phenoxybenzamine MOA, uses
Irreversible non-selective a-agonist
Unsuccessful for HTN: Blocks a2 which are found pre-synaptically –> increases catecholamine release.
Prevent vasoconstriction –> decreased PVR –> reflex tachycardia
Used in pheochromocytoma
- prior to surgical removal
- for chronic management of inoperable tumors
Phentolamine MOA and contraindications
Reversible non-selective a-agonist
Causes postural hypotension.
Phentolamine-induced reflex cardiac stimulation and tachycardia are mediated by the baroreceptor reflex and by blocking the a2-receptors of the cardiac sympathetic
nerves.
Contraindicated in patients with decreased coronary perfusion.
Phentolamine Uses (4)
Pheochromocytoma - control of hypertension during prep preparation and surgical excision
Diagnosis of pheochromocytoma - phentolamine blocking test
Prevention of dermal necrosis after extravasation of NE
Hypertensive crisis due to stimulant drug overdose (Cocaine, methamphetamines, MOA inhibitors + tyramine ingestion)
CVS effects of prazosin, terazosin, doxazaosin, tamsulosin
a1 selective blockers
Lower arterial BP by relaxing both arterial and venous smooth muscle
First dose produces an exaggerated hypotensive response that can result in syncope
First dose must be 1/3 or 1/4 of normal dose
a1 blockers uses
Hypertension –> but not DOC
DOC for symptom relief from BPH –> relaxation of smooth muscle in bladder neck, prostate capsule and prostatic urethra –> improved urinary flow
Tamsulosin MOA
Selective antagonist of a1A receptors that predominate in GU smooth muscle
Approved for BPH
Little effect on BP and less likely to cause orthostatic hypertension
Uses of b-adrenergic antagonists
Hypertension - lower BP by decreasing cardiac output
Glaucoma - Decrease aqueous humor secretion. Decreased IOP (Timolol)
Migraine - effective for prophylaxis of migraine
Hyperthyroidism
Angina Pectoris - decrease the O2 requirement of the heart muscle –> reduce chest main on exertion. Contraindicated in variant angina
Atrial Fibrillation - control ventricular rate
MI - protective effect on myocardium
Performance Anxiety
Essential tremor
Non-selective b-blockers effects on CVS, lungs and metabolism
Propanolol
Nadolol
Timolol
CVS:
- Slow heart rate and decrease myocardial contractility
- Reduction in cardiac output
- Reduction of renin release from the juxtaglomerular cells of the kidney
- A central action, reducing sympathetic activity
- b-blockers don’t induce postural hypotension because a1-adrenoceptors remain unblocked, therefore, normal sympathetic control of the vasculature is maintained
Lungs: blocking b2 can precipitate respiratory crisis in patients with COPD or asthma (causes bronchoconstriction)
Metabolic effects:
- Decreased glycogenolysis
- Decreased glucagon secretion
Contraindication of non-selective b-blockers
Asthma patients
If an insulin-dependent diabetic is to be given propranolol, very careful monitoring of glucose is essential, since pronounced hypoglycemia may occur after insulin injection and if it occurs, the symptoms of hypoglycemia will be masked
b1 selective antagonists uses
Atenolol
Metoprolol
- useful in hypertensive patients with impaired pulmonary function
- useful in diabetic hypertensive patients who are receiving insulin or oral hypoglycemic agents
Esmolol
- ultra-short acting
- given IV for rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter
Labetalol and carvedilol MOA and uses
Competitive a1 and b antagonists (more potent as a b-antagonist)
Labetalol - used in HTN
Carvedilol - used in HTN and CHF, has antioxidant properties
Pindolol MOA and uses
Partial b-agonist
B-blockers with partial agonist activity may produce smaller reductions in resting heart rate and blood pressure.
May be preferred as antihypertensive agents in individuals with diminished cardiac reserve or a propensity to bradycardia
b-blockers AE
Non-selective b-blockers:
- Bronchoconstriction
- Hypoglycemia
Lipid metabolism:
- Inhibits release of free FAs from adipose tissue
- Increase TG and reduce HDL
CNS effects:
- Sedation
- Dizziness
- Lethargy
- Fatigue
Precautions when giving b-blockers
Should not be withdrawn abruptly (especially in patients with CAD)
Gradually tapered to avoid acute tachycardia, hypertension and/or schema
AE are due to up regulation of b-receptors
a-methyltyrosine MOA and uses
Competitive inhibitor of tyrosine hydroxylase –> inhibitor of NE synthesis
Used for management of malignant pheochromocytoma
Used pre-op before resection of pheochromocytoma
Reserpine MOA and uses
Irreversible blocks VMAT –> vesicles cannot store NE or dopamine –> depletion of NE
Gradual decrease in blood pressure and decreased HR –> slow onset but long duration of action
Used in the past to treat HTN
Tetrabenazine MOA and use
Reversible inhibitor of VMAT –> vesicles cannot store NE or dopamine
Treatment of chorea associated with Huntington’s Disease
