Adrenergic Drugs Flashcards
What do adrenergic drugs do?
Modulate adrenergic transmission and primarily control function of sympathetic nervous system
Contrast adrenomimetics vs sympatholytics
- Adrenomimetics/sympathomimetics/drugs activating adrenergic transmission: mimic or promote effects of norepinephrin/epinephrine/dopamine at adrenergic receptors in sympathetic NS
- Sympatholytics/antiadrenergic/drugs inhibiting adrenergic transmission: prevent effects of norepinephrine/epinephrine/dopamine at adrenergic receptors in sympathetic NS
Describe types of adrenergic receptors
Alpha1: Gq: Increase IP3, DAG Alpha2: Gi: decrease cAMP Beta: Gs: increase cAMP D1 and D5: Gs: Increase cAMP D2-4: Gi: decrease cAMP
Describe alpha1 receptor activation, tissue, and actions
IP3 leads to increase in cytosolic Ca2+.
DAG activates PKC
Most vascular smooth muscle = contraction
Pupillary dilator muslce = contraction (dilates)
Pilomotor smooth muscle = erects hair
Prostate = contraction
Heart = increases force of contraction
Describe alpha2 receptor activation, tissue, and actions
Decrease in cAMP and inhibition of PKA
Postsynaptic CNS neurons = multiple actions
Platelets = aggregation
Adrenergic and cholinergic nerve terminals = inhibits transmitter release
Some vascular smooth muscle = contraction
Fat cells = inhibits lipolysis
Beta receptor activation?
Accumulation of cAMP
Activation of PKA
Beta1 tissue and actions
Heart, juxtaglomerular cells = increases force and rate of contraction. Increases renin release
Beta2 tissue and actions
Respiratory, uterine, vascular smooth muscle = relaxation
Skeletal muscle = promote potassium uptake
Liver = activates glycogenolysis
Beta3 tissue and actions
Bladder = relaxes detrusor muscle
Fat cells = activates glycogenolysis
D1 and D2 tissue and actions
D1 = smooth muscle = dilates renal blood vessels D2 = nerve endings = modulates transmitter release
Compare direct-acting adrenergic drugs with indirect-acting
Direct-acting: interaction with adrenergic receptors: agonists and antagonists
Indirect-acting: increase or reduce concentration of NE at target receptors
List alpha agonist drugs and receptor affinities
Phenylephrine, methoxamine: a1>a2»>B
Clonidine: a2>a1»>B
List mixed alpha and beta agonists and receptor affinities
Norepinephrine: a1=a2; B1»B2
Epinephrine: a1=a2; B1 = B2
List beta agonists and receptor affinities
Dobutamine: b1>b2»>a
Isoproterenol: b1 = b2»>a
Albuterol, terbutaline: b2»b1»>a
List dopamine agonists and receptor affinities
Dopamine: D1 = D2»b»a
Fenoldopam: D1»D2
Describe epinephrine effects on cardiac function
Beta1
Increases force of contraction: positive inotropic effect
Increases heart rate
Increases conduction velocity at AV node
Epinephrine effects on vascular tone
Beta2 and alpha1
Increases systolic BP
May decrease diastolic BP and total peripheral vascular resistance
Mean arterial pressure often remains unchanged
Significant differences in receptor types found in vascular beds
-skin vessels and mucous membranes: mostly alpha1
-skeletal muscle: alpha1 and beta2
-renal, cerebral: D1 and alpha1
Epinephrine effects on respiratory system
Relaxes bronchial muscle: beta2
Decreases bronchial secretion and congestion within bronchial mucosa: alpha1
Epinephrine effects on skeletal muscle, blood glucose, free fatty acids, renin
Skeletal muscle
causes muscle tremor: b2
Increases K+ uptake by skeletal muscle: b2
-promotes hypokalemia and decreases K+ excretion by kidneys
Elevates blood glucose levels
- enhances liver glycogenolysis: b2
- inhibits insulin release: a2
Increases free fatty acid levels in blood: beta
Increases renin release: b1
Describe norepinephrine effects
A1=a2; B1»B2
Potent cardiac stimulant but reduces heart rate
Potent vasoconstrictor
Lacks B2 agonist effects: no bronchodilation and vasodilation
Increases peripheral vascular resistance and blood pressure
Role of baroreflex
Describe effects of dopamine
D1=D2»B1»a1
D1 stimulation causes vasodilation
-high density of D1 receptors in renal, cerebral, mesenteric and coronary vessels
Activation of presynaptic D2: suppresses norepinephrine release
Activates B1 in heart at higher doses
At still higher doses stimulates vascular alpha1 AR to cause vasoconstriction
Effects of phenylephrine
Alpha agonist. a1>a2»>B
Not a catecholamine, not inactivated by COMT
-longer duration of action
Effective mydriatic and decongestant
Causes severe vasoconstriction and blood pressure elevation
Role of baroreflex in response to phenylephrine
Effects of Clonidine
Selective alpha2 agonist. a2>a1»»b
Central effect on alpha2 receptors in lower brainstem area
-decreasing sympathetic outflow
-reduction in blood pressure
-bradycardia (reduces peripheral vascular resistance, decrease heart rate and cardiac output)
Local application produces vasoconstriction
Effects of isoproterenol
B1=B2»>A
Nonselective beta agonist
Positive inotropic and chronotropic action, increases cardiac output: B1
Vasodilator, decreases arterial pressure: B2
Causes bronchodilation: B2
Effects of dobutamine
B1>B2, a1
Selective B1 agonist
A1 receptor activity (-)isomer agonist at these receptors, while +isomer is a1 antagonist
Potent inotropic action
Less prominent chronotropic action as compared to isoproterenol
Effects of terbutaline, albuterol
B2>B1»>a
Selective B2 agonists
Cause bronchodilation and relaxation of uterus
Describe indirect adrenergic agonists
Usually more lipophilic compounds (not catecholamines)
Easily penetrate BBB: have significant central effects: CNS system stimulants
Effects of amphetamine, methamphetamine, methylphenidate
Mild alerting effects
Improved attention
Effects of cocaine
Inhibits transmitter reuptake at adrenergic synapses
Peripheral and intense central adrenomimetic action
Local anesthetic properties
Effects of ephedrine
Releases stored catecholamines with some direct adrenomimetic action
Plant constituent
Non-catechol
-long duration of action
-effective after oral administration
Nonselective: similar to epinephrine in actions
Mild stimulant enter CNS
Effects of tyramine
Accumulates in protein-rich foods during fermentation
Readily metabolized by MAO in liver (very high first-pass effect)
If administered parenterally, affords indirect sympathomimetic action caused by release of stored catecholamines (norepinephrine-like effect)
Use of adrenergic agonists on CV conditions to increase blood pressure
Hypotensive emergencies: hemorrhagic shock, overdose of antihypertensives, CNS depressants
-Norepinephrine, phenylephrine, methoxamine
Chronic hypotension: ephedrine
Cardiogenic shock (due to massive acute MI): dopamine, dobutamine
Use of adrenergic agonists on CV conditions: heart failure
Short-term use of dobutamine in acute HF
Dopamine in congestive severe HF with reduced renal perfusion
Use of adrenergic agonists on CV conditions: hypertension
Alpha-2 agonists for long-term treatment
Fenoldopam in hypertensive emergencies
Use of adrenergic agonists on CV conditions: emergency therapy for complete AV block and cardiac arrest
Epinephrine, isoproterenol
Use of adrenergic agonists on CV conditions: decongestion of mucous membranes
Phenylephrine, ephedrine, pseudoephedrine
Use of adrenergic agonists for bronchial asthma
Beta-2 selective agonists:
Albuterol, terbutaline
Use of adrenergic agonists for anaphylaxis (immediate type 1 allergic reaction characterized by respiratory and CV components)
Respiratory component: bronchospasm and upper airway congestion
CV component: severe hypotension, cardiac depression
Ephinephrine: effective at both components
Use of adrenergic agonist for ophthalmic applications
Exam of retina: induction of mydriasis: phenylephrine
Glaucoma: alpha-2 selective agonists: apraclonidine, brimonidine
Use of adrenergic agonist for GU applications
Suppression of premature labor: beta-2 agonists: terbutaline
Stress urinary incontinence: ephedrine
Priapism: alpha-1 agonists (phenylephrine) via injection into penis
Use of adrenergic agonist on CNS conditions
Narcolepsy (sudden brief sleep attacks): amphetamines, methylphenidate
ADHD (short attention span, learning problems, and hyperkinetic physical behavior): methylphenidate
Obesity (central inhibition of appetite and increased energy expenditure): phentermine, ephedrine, amphetamines
Cardiovascular adverse effects of adrenergic agonists
Elevation in blood pressure
Increased cardiac work may precipitate myocardial ischemia and heart failure: special attention given to elderly pts and pts with hypertension, coronary artery disease, and chronic heart failure
Sinus tachycardia and serious ventricular arrhythmias
Direct myocardial damage leading to cardiomyopathy
May induce sudden cardiac death
Central nervous system toxicity of adrenergic agonists
Most of agonist drugs (catecholamines and other polar drugs that do not cross BBB) do not cause CNS toxicity
Amphetamine and amphetamine-like compounds cause: insomnia, lack of appetite, anxiety, restlessness, psychoses (paranoid state, hallucinations)
Cocaine may cause: convulsions, arrhythmias, hemorrhagic stroke
Direct vs indirect adrenomimetic drugs at synapse
Monoamine oxidase (MAO) inhibitors: Selegiline, phenelzine (indirect)
Reuptake blockers: Cocaine (indirect)
Releasing agents: amphetamines, methylphenidate (indirect)
Mixed acting: ephedrine (direct and indirect)
Adrenergic receptor agonists (direct)
Describe common sites of action for antiadrenergic drugs (direct vs indirect)
Inhibits NE synthesis: metyrosine (indirect)
Deplete NE: guanethidine (indirect)
Adrenergic receptor antagonists (direct)
What are the nonselective alpha receptor antagonists?
Phentolamine
Phenoxybenzamine
What are the alpha1 receptor selective antagonists?
All end in -osin Prazosin Terazosin Tamsulosin Doxazosin Alfuzosin Silodosin
Compare competitive alpha antagonist with irreversible alpha antagonist
Competitive alpha antagonist: Noncovalent binding to receptor Shorter acting Effect antagonized by high concentration of agonist Ex: phentolamine
Irreversible alpha antagonist: Covalent binding to a receptor Longer acting Effect is not antagonized by alpha agonist Ex: phenoxybenzamine
Alpha antagonist effects on CV system
Decreased peripheral vascular resistance and blood pressure
Reflex tachycardia
Postural hypotension
Alpha antagonist effects on GU system
Relaxation of smooth muscle in prostate
Decreased resistance to flow of urine
Alpha antagonist effects on
Relaxation of pupillary dilator muscle (miosis)
Alpha antagonist effects on pheochromocytoma
Tumor of adrenal medulla producing catecholamines
Excess causes tachycardia, arrhythmias, hypertension
Treatment: phentolamine, phenoxybenzamine
Alpha antagonist effects on chronic hypertension
Prazosin, terazosin, doxazosin: alpha1 selective
Work well in moderate hypertension
Generally well tolerated
Nonselective alpha-blockers not used
Alpha antagonist effects on erectile dysfunction
Combination of phentolamine and nonspecific vasodilator papaverine (injected into penis)
Alpha antagonist effects on benign prostate hyperplasia (BPH) to treat chronic urinary obstruction
Tamsulosin
Silodosin
-greater selectivity for alpha1a than alpha1b
-alpha1a most important alpha subtype mediating prostate smooth muscle contraction
-effectively relieves urinary obstruction and pain with little effect on blood pressure
Prazosin, doxazosin, terazosin also effective
Adverse effects of alpha antagonists
Most significant effects are on CVS
Seen less with alpha1 selective antagonists
Postural hypotension: antagonism of alpha1 in venous smooth muscle
Tachycardia
Retention of fluid and salt
Impaired ejaculation
Nasal stuffiness
What are the mixed antagonists?
Labetalol (beta and alpha1 antagonist)
Carvedilol (beta and alpha1 antagonist)
What are the beta1 and beta2 antagonists?
Propranolol
Pindolol
Nadolol
Penbutolol
What are the beta1 selective antagonists?
Metoprolol
Betaxolol
Acebutolol
Atenolol
Which beta-blockers are antagonists, partial agonists, inverse agonists?
Antagonists: atenolol, nadolol, propranolol, betaxolol
Partial agonists: acebutolol, labetalol, penbutolol, pindolol
Inverse agonists: carvedilol, metoprolol
Effects of beta-blockers on CV system
Heart Negative inotropic effect Negative chronotropic effect Block AV node -slowed atrioventricular conduction -increased PR interval
Blood vessels
Initially: rise in peripheral vascular resistance
Chronic use: decrease in PVR (lowers blood pressure in hypertensive individuals)
RAS
Inhibit renin release
Effects of beta-blockers on respiratory system
Increase in airway resistance
Effects of beta-blockers on eye
Reduce production of aqueous humor: reduce intraocular pressure
Effects of beta-blockers on metabolic effects
Inhibit lypolysis
Increase VLDL and decrease HDL, reduce HDL cholesterol/LDL cholesterol ratio
Inhibit glycogenolysis in the liver
Effects of beta-blockers on hypertension
Antihypertensive effect is delayed
Both beta-blockers and mixed alpha and beta blockers (Labetaolol, alpha1 and beta blocker) are used
Effects of beta-blockers on angina pectoris
Blocking cardiac beta-receptors decreases cardiac work and reduces oxygen consumption
Beta-blockers reduce the frequency of anginal episodes and improve exercise tolerance
Effects of beta-blockers on myocardial infarction
Long-term use in postinfarction period: prolong surivival
Timolol, propranolol, metoprolol
Acute phase of myocardial infarction
Contraindications: bradycardia, hypotension, acute heart failure, AV block, active airway disease
Effects of beta-blockers on cardiac arrhythmias
Effective in ventricular and supraventricular arrhythmias
- atrial flutter and atrial fibrillation
- ventricular ectopic beats
Effects of beta-blockers on heart failure
Effective for treatment of chronic heart failure in selected pts
Metoprolol, bisoprolol, carvedilol
Contraindicated in acute congestive heart failure
Effects of beta-blockers on glaucoma
Mech involves reduction in production of aqueous humor by ciliary body
Timolol, betaxolol: blockers w/o local anesthetic activity (propranolol not used)
Effects of beta-blockers on hyperthyroidism
Important aspect: excessive catecholamine action on heart
Thyroid storm: severe form of hyperthyroidism
Tachycardia, supraventricular and ventricular ectopic arrhythmias
Propranolol
Adverse effects of beta-blockers on CNS
(Switch to more hydrophilic drug)
Sedation
Sleep disturbances
Depression
Adverse effects of beta-blockers on respiratory system
(Switch to beta-1 selective)
Increase airway resistance
Trigger bronchospasm and asthma attack in susceptible indivduals (chronic asthma, COPD, chronic bronchitis)
Adverse effects of beta-blockers on CV system
Depression of heart rate, cardiac contractility and excitability (switch to partial agonist)
Exacerbation of peripheral vascular disease (switch to beta1 selective)
Adverse effects of beta-blockers on lipid profile
(Switch to a partial agonist drug)
Chronic use: increase VLDL and decrease HDL (LDL usually not changed, but ratio HDL/LDL cholesterol decreases)
Seen with both selective and non-selective B-blockers
Adverse effects of beta-blockers on hypoglycemic episodes
(Switch to beta1-selective)
May delay recovery form insulin-induced hypoglycemia by inhibiting glucose output by liver
Blunt perception of hypoglycemia by these pts (tremor, tachycardia, and nervousness are caused by B-AR activation)
Increased incidence and severity of hypoglycemic episodes in pts with diabetes type 1 on insulin
Much safer in diabetes type 2 pts who usually do not have hypoglycemic reactions
Adverse effects of beta-blockers on abrupt discontinuation of beta-blocker therapy
Increased risk in pts with ischemic heart disease
Gradually taper beta blocker dosing to prevent sympathetic hyper-responsiveness and potential toxicity
What is the norepinephrine release inhibitor?
Guanethidine
Taken up by reuptake mech
Replace norepinephrine in vesciles
Causes a gradual depletion of norepinephrine stores
Inhibition of norepinephrine release via local anesthetic properties
What is the inhibitor of tyrosine hydroxylase
Metyrosine
Clinical use of indirect acting antiadrenergic drugs
Chronic hypertension: guanethidine
Pheochromocytoma: metyrosine
