adrenergic agonists and antagonists Flashcards
Epinephrine
Agonist
Receptor- alpha and Beta 2
Low dose beta effects
high dose alpha effects
Indications/ effects- high doses, potent vasopression, increase in blood pressure (systolic more than diastolic. positive chornoropic and inotropic effects ( beta 1), vasoconstriction(alpha1) increase in cardiac output and increase in O2 demand from heart
- bronchodilation (Beta2)
- relaxation GI smooth muscle with contracted sphincters( alpha1)
- relaxed detrusor ( Beta2)
- Metabolic hyperglycemia due to increase in glycogenolysis and glucagon release (Beta2). There is a net inhibition of insulin secretion(alpha2) while beta 2 enhances secretion)
- increase in lipolysis through Beta2(increase incAMp and HSL)
DOC for patients in anaphylactic shock- cardiac arrest, asthma(combined with local anesthetics to increase duratino) glaucoma ( decreased production of aqueous humor)
Pharmacokinetics- rapid onset, brief duration, administered IV in emergences. can also be administered SC, ET tube, inhalation, and topically on eye.
Adverse/contra ( CNS disturbances) restlessness, fear, apprehension, headache, tremor(secondary effects outside the CNS), ICH due to increased BP, Cardiac arrhythmias, especially in patients on digitalis, pulmoary edema
synthesized from tyrosine in the adrenal medulla.
- it is a polar molecule and doesn’t cross CNS
- metabolized by COMT and MAO into VMA and meanephrime
- hyperthyroid may enhance CV actions likely due to upregulation of receptors
- cocaine prevents reuptake
- beta blockers cause predominate alpha effects such as incerease in TPR and BP
NE
alpha and Beta1 more than Beta 2- agonist
Indications/effects-Vasoconstriction (alpha 1)- increased PVR which causes increased systolic and diastolic pressure along wiht mean areterila pressure
-bradycardia due to decreased sympathetic outflow following the baroreceptor response (indirect effect throughM2). induces hyperglycemia(less potent than epi)
-Limited therapeutic vaule but can treat shock, but dopamine is better due to preservation of renal blood flow.
Adverse/contra- may cause kidney shutdown
Baroreceptor reflex counteracts local action which can be blcoked by pretreatment with atropine reveals direct effect of tachycardia
Dopamine
Dopamine, alpha, beta agonist
Effects/indications
-central regulator of movement
-CVS: low doses vasodilate through D1 receptor (cAMP) especially at renal, mesenteric and coronary
- ionotropic effect at intermediat concentration (beta1) and increasing release of NE
-increase in Systolic BP
-High concentration- alpha1 mediated vasoconstriction,
DOCfor cardiogenic and hypovolemic shot. it increases GFR, renal blood flow and Na excretion which preserves renal function.
Pharmacokinetics:Ineffective when given orally due to metabolism by MAO and COMT
Adverse/contra: overdose causes sympathomimetic symptoms
-can cause nausea, HTN and arrhythmia but it is short lived due to rapid metabolism to HVA
doesn’t cross BBB
Fenoldopam
D1 agonist- Peripheral vasodilation- used in short term management of HTN
give continuosly via IV not bolus
Isoproterenol
drect acting beta1,2 agonist
effects/indications
CVS- increases CO through rate and force of contraction, used in AV block or cardiac arrest. decrease in TPR due to no alpha 1 opposing it.
-slight increase in Systolic blood pressure, decrease in mean arterial pressure and diastolic blood pressure, tachycardia
pharmacokinects. most reliable when given parenterally or inhaled
similar adverse effects compared to epi
Dobutamine
direct acting beta 1 agonist
used in acute managment of congestive heartfailure. increases contractility. increase in cardiac output with little change in heart rate. O2 demands of the myocardium are not significantly affected. it gives it an advantage over other sympathomimetics.
Pharmacokinetics: can build up a tolerance with long term use
racemic mixture: negative is an alpha 1 and weak Beta 1 agonist, positive is an alpha 1 antagonist and a potent beta 1 agonist which makes it a selective beta agonist.
Terbutaline
direct acting beta 2 agonist
bronchodilator, used for emergency treatmetn of status asthmatics, reduces uterine contractions in premature labor.
resorcinol ring is no metabolized by COMT giving it a longer duration . Oral, inhalation or SC
Selectively is lost at high concentrations, used in treatment of asthma without having effects on heart
Albuterol
direct acting beta 1 agonist
Selectively is lost at high concentrations, used in treatment of asthma without having effects on heart
Salmetrol/Formeterol
beta 2 direct acting agnoist
bronchodilator- long acting not used for prompt relief of bronchospasm
slow onset, but prolonged action (12 hours) after inhalation
Selectively is lost at high concentrations, used in treatment of asthma without having effects on heart
Phenylephrine
Direct acting alpha 1 agonist
causes peripheral vasoconstriction
indications/effects Vasoconstrictor: ↑ SBP and DBP Nasal decongestant Mydriasis Tx of supraventricular tachycardia
oral or topical.
NO direct effect on heart, but does cause reflex bradycardia after parenteral administration
Clonidine
alpha2 direct acting partial agonist. activation of CENTRAL ALPHA 2 RECEPTORS which suppresses sympathetic outflow
antihypertensive
Acute rise in BP due to transient vasoconstriction when given IV, but not when given orally
Adverse/Contra: Centrally acting antiadrenergic drugs:Sedation, mental lassitude, impaired concentration
Methyldopa
direct acting alpha 2 agonist
Indications/effects
Metabolized to α-methylnorepinephrine which causes effects similar to clonidine: ↓ TPR and BP… prodrug
DOC in pregnant patients with HTN [safety]
adverse/contra:Centrally acting antiadrenergic drugs:Sedation, mental lassitude, impaired concentration
Brimonidine
direct acting alpha 2 agonist
↓ aqueous humor production along with increased outflow
↓ intraocular pressure in glaucoma
Amphetamine
Indirect acting adrenergic agonist
Displaces catechol from storage vesicle
Weak inhibitor of MAO
Blocks catechol reuptake
↑ BP through α1 and β effects
Central stimulatory action: alertness, ↓ fatigue & appetite, insomnia,
Tx of depression, narcolepsy and appetite suppression [in the past]
adverse/contra:Fatigue and depression following stimulation
Releasing Agents
Potentiate actions of endogenous NE by causing release from presynaptic vesicles
Methylphenidate
indirect acting adrenergic agonist,
structural analog of amphetamine,
used in treatment of ADHD in children
Releasing Agents
Potentiate actions of endogenous NE by causing release from presynaptic vesicles
Tyramine
Not clinically useful, but is found in fermented foods [cheese and wine]
Byproduct of tyrosine metabolism, normally oxidized by MAO
Serious vasopressor episodes in patients on MAO-I’s after release of NE
Releasing Agents
Potentiate actions of endogenous NE by causing release from presynaptic vesicles
Cocaine
Drug acting presynaptically on DAT, SERT, NET receptor
Blocks dopamine [major effect], serotonin and NE transporters → potentiation and prolonged effects
Sympathomimetic
Therapeutic use: blockage of voltage gated Na+ channels → local anesthetic
Intense euphoria from blockage of dopamine reuptake in the limbic system
Monoamine reuptake inhibitors
Atomoxetine
Drug acting presynaptically on NET receptor
Selective NET inhibitor
Tx of ADHD
Monoamine reuptake inhibitors
Ephedrine
alpha and beta mixed acting agonist
INDICATIONS EFFECTS:
Vasoconstriction and cardiac stimulation → ↑ BP
Bronchodilation [prophylactic Tx of asthma because it is slower onset and less potent than epi or isoproterenol]
Synergistic effect with Anti-AChE in treatment of myasthenia gravis
Mild CNS stimulation [alertness] and increased athletic performance
PK:
NOT a catecholamine → poor substrate for COMT and MAO → longer duration of action
Excellent oral absorption, enters CNS
Eliminated unchanged in urine
ADVERSE/CONTRA: herbal supp, banned due to life threatening CV reactions
Induces release of NE and activates adrenergic receptors
Use declining due to better drugs with fewer side effects
Pseudoephedrine
alpha and beta mixed acting agonist
Nasal decongestant with an H1 histamine antagonist
alpha 1 antagonists
Primary effect on blood pressure: vasculature is under tonic sympathetic control so blockade of these receptors reduces tone and decreases TPR
Epinephrine Reversal: all α-blockers inhibit Epi induced vasoconstriction, but not the β effect of vasodilation → ↓ BP in response to Epi in the presence of phenoxybenzamine [NE is only diminished]
Selective α1 blockers can cause dizziness, lack of energy, nasal decongestant, HA, drowsiness, orthostatic hypotension; tendency to retain Na+ and fluid → give with a diuretic
phenoxybenzamine
Nonselective α
Alkylation irreversibly blocks receptor
Slightly α1 selective
Also blocks H1, M and 5-HT receptors; inhibits NET
EFFECTS:
-CVS: prevents vasoconstriction of peripheral blood vessels →
reflex tachycardia
-Presynaptic α2 block → ↑ CO
INDICATIONS
- Pheochromocytoma [DOC]: blocks effects of excess catecholamines [may require a β blocker to control tachycardia after α blockade is established]
- Historically used to lower BP, but was unsuccessful [block presynaptic α2]
ADVERSE: Postural hypotension Nasal stuffiness Nausea and vomiting Inhibit ejaculation
CONTRA-in pt’s with decreased coronary perfusion due to reflex tachycardia
Phentolamine
Nonselective α
Reversible α blocker
Serotonin blocker
Muscarinic, H1 and H2 agonist
INDICATIONS:
- Dx & control hypertensive episodes of pheochromocytoma
- Prevents dermal necrosis when NE extravasates
- Antihypertensive in stimulant OD, sudden withdrawal of sympatholytics [clonidine], interaction between MAO-Is and tyramine
ADVERSE
Postural hypotension –baroreceptor reflex and α2 blockade on cardiac nerves
Arrhythmia & angina
CONTRAINDICATED in pt’s with decreased coronary perfusion
Prazosin
Selective α1 -
Useful in treatment of HTN
↓ TPR through relaxation of arterial and venous smooth muscle
EFFECTS:
↓ BP without reflex tachycardia […α2]
↓ LDL/TAG, ↑ HDL
I-mproves urinary blood flow
INDICATIONS:
- Suppress sympathetic outflow from CNS
- Tx of HTN, BPH
ADVERSE
- Not the DOC for primary HTN
- First dose effect may cause exaggerated hypotensive response and syncope [adjust 1st dose ¼ of normal]
Terazosin/doxazosin
Selective α1 -
Useful in treatment of HTN
Structural analog of prazosin → longer t1/2 → Less frequent dosing
the rest is the same as prozosin
Tamsulosin
Selective α1 -
Useful in treatment of HTN
ADVERSE
- Not the DOC for primary HTN
- First dose effect may cause exaggerated hypotensive response and syncope [adjust 1st dose ¼ of normal]
Yohimbine
α2 blocker → indirect adrenergic agonist
Effects;↑ NE release → ↑ BP
Tx of erectile dysfunction, but has been replaced by PDE-5 inhibitors
Can reverse effects of α2 agonists i.e. clonidine [bad]
Propranolol
[prototype]
β1 & 2 antagonist
MECHANISM:
-CVS: ↓ HR and contractility
↑ TPR [β2]
-Metabolic: ↓ glycogenolysis and glucagon secretion → severe hypoglycemia in pt’s on insulin
Effects/INDICATIONS
- Used in treatment of:HTN [through ↓ CO, not the DOC]
- Migraine [blocks vasodilation]
- Hyperthyroidism
- Chronic angina [↓ O2 requirement]
- A-fib, MI [protective]
- Performance anxiety/stage fright [DOC]
- Essential tremor
ADVERSE/CONTRA
-Bronchoconstriction →
Contraindicated in patients with COPD or asthma; variant angina
-Impair recovery from hypoglycemia in insulin dependent patients → syncope
Mask signs i.e. tachycardia seen in such episodes
-CNS: sedation, dizziness, lethargy, fatigue, depression
Does not induce postural hypotension because α1 receptors remain active
Reduce HDL and increase LDL and TAGs [block activation of HSL] – β1 selective actually improve the lipid profile
Abrupt withdrawal → HTN
Nadalol
Beta 1 and 2 blocker
longer duration of action, used in long term treatmetn of angina and HTN
TImool
used in HTN, prophylaxis for migraine’s glaucoma(open angle)
Atenolol/metroprolol
beta1 cardioselectiveblocker
Management of HTN in pt’s with impaired pulmonary function or IDDM
Less likely to induce bronchospasm
Long term management of angina; s/p MI reduces mortality
Esmolol
Beta1 cardioselective blocker
indications/effects:
Useful in controlling arrhythmia [supraventricular or thyrotoxicosis], perioperative HTN, and MI in acutely ill pt’s
Safer in critically ill patients
PK: Ultra short acting: t1/2 is about 10 minutes
Administered IV
Labetalol
Combined α-1 and β-antagonists
Mechanism:/Effects/indications
Decrease in BP:
α1 → relaxation of arterial smooth muscle
β1 → blocks sympathetic reflex
β2 → sympathomimetic action contributes to vasodilation
PK:
More potent β antagonist
Oral: chronic HTN
IV: emergencies
Adverse Effects:
Orthostatic hypotension and dizziness [α1]
Carvedilol
Combined α-1 and β-antagonists
Used on pt’s with CHF and HTN
More potent β antagonist
Antioxidant properties
Pindolol
β partial agonist- beta blocker with intrinsiic sympathomimetic activity helps manage HTN
Causes a smaller reduction in resting HR and BP
Preferred in pt’s with diminished cardiac reserve or propensity to bradycardia
α-methyltyrosine
aka: metyrosine
Mechanism:Blocks NE [& E] synthesis through competitive inhibition of tyrosine hydroxylase
Indications/Effects:
Used in adjuvant therapy with phenoxybenzamine in treatment of malignant pheochromocytoma [when surgery is not possible]
Reserpine:obsolete
Irreversible damage to VMAT → ↓ NE and dopamine availability → sympatholytic response
Unable to concentrate and store NE and dopamine in the vesicle → continuous breakdown by MAO
↓ BP and HR
Historical Tx of HTN
PK: Slow onset and long duration
Guanethidine
Uptake into nerve terminal via NET → storage in vesicle and displacement of NE → NE depletion
Anti-hypertensive that was used in the early 1970’s
Orthostatic HTN and male sexual dysfunction
Also disrupts the release of NE from the nerve terminal
Autocoids
Autocoids have diverse physiologic and pharmacologic activities; site of action is near their synthesis and their lifetime is brief
Formed by decarboxylation of L-histidine
Most found in mast cells and basophils; also in ECL cells in the fundus of the stomach → activates parietal cells
Found in the brain as a neurotransmitter
HIstamine agonists
