Adrenergics Flashcards
Sympathomimetics
Adrenergic Agonists
Sympatholytics
Adrengergic antagonists
a1 in Eye
Contraction of the radial muscle of iris (mydriasis)
a1 in Arteries, Vein
Vasoconstriction
a1 in urinary tract of male
Constriction of sphincter
a1 in vas deferens
Ejaculation
a2 in pre-syaptic nerve terminals
inhibits NT release
a2 in CNS
Sympathetic outflow to vessel inhibition
Classes of Adrenergic Agonists
Direct-acting -Catecholamines -Non-catecholamines Indirect acting -Indirect only -Mixed activity
Base structure of agonist
Phenylethylamine
Importance of catecholamine structure
3,4 hydroxylation of phenyl group (catechol group) improves affinity for maximal alpha, beta receptors
Factors affecting affinity for agonists
2 carbons b/w aromatic ring and amino group affords greatest sympathomimetic activity
Substitution of alkyl group on the amino group tends to increase beta activity
Features influence bioavailability/metabolism
Absence of one or both -OH on phenyl increases oral effectiveness
Substitution on alpha-carbon makes the compound more resistant to MAO
Substitution of -OH group on beta carbon decreases lipid solubility and decreases CNS actions, increases peripheral activity
Metabolism of catecholamines
Metabolized by MAO and catechol-O-methyltransferase
Not effective by oral administration
Must be given parenterally to avoid liver
Short half life (minutes)
Predominant role of catecholamines
CV actions
Norepinephrine - Receptor selectivity
Alpha1/2,Beta1
Norepinephrine - CV Effects
Alpha-1 primarily
Increases peripheral vascular restriction (PVR)
Increases mean BP
Reflex towards bradycardia (Decreased HR)
Norepinephrine - Therapeutic uses
Vasoconstrictor in certain acute care situations (shock)
Elevate BP during reduced sympathetic tone (examples: neurological injury, spinal anesthesia)
Epinephrine - Receptor selectivity
All major receptors (alpha-1/2,beta-1/2)
Epinephrine - CV Effects
Increase HR, contractile force, cardiac output
Increase systolic BP, decrease diastolic BP
Vasoconstriction except in skeletal muscle beds so net PVR decrease (Beta-2)
Epinephrine - Respiratory effects
Bronchodilation
Epinephrine - Metabolic effects
Hyperglycemia
Increase free fatty acids
Epinephrine - Therapeutic uses
Hypersensitivity reaction - Allergies, bronchoconstriction
Increase duration of action of local anesthetics
Bradyarrhythmias
Opthalmic uses - Mydriatic so decreases hemorrhage and conjunctival congestion
Dose dependence of Epi on PVR
Low concentration of epi results in B2 vasodilation
High concentration of epi, B2 is saturated so binds to A1 resulting in vasoconstriction
At high concentration CV effects becomes the same as norepi
Isoproterenol - Receptor selectivity
B1/2
Isoproternol - CV Effects
Decrease PVR
Increase HR, contractile force, CO
Decrease mean BP
Isoproternol - Respratory effects
Bronchodilation
Isoproternol - Therapeutic uses
Emergency use for treatment of bradycardia or heart block
Dopamine - CV effects
Low dose (0.5 ug/kg/min) Renal dose - Dilation of renal and mesenteric arteries, decreasing PVR, increase renal flow (D1 receptor) Intermediate dose (5-10 ug/kg/min) Cardiac dose - Increases HR, contractile force, CO (D1 + B1) High dose (10-20 ug/kg/min) Pressor dose - Vasoconstriction and increased PVR (D1 + B1 + A1)Used in coronary care settings
Dobutamine racemic effects
(-) : A1 agonist, B agonist
(+) : A1 antagonist, B agonist
Net result: B1 agonist
Dobutamine CV effects
Increased HR, contractility, CO
Minimal change in PVR and BP
Dobutamine Therapeutic uses
Short-term treatment of cardiac decompensation (cardiac surgery, heart failure, MI)
Cardiac stress testing
B1 - Heart response
Increased HR, contractile force, AV nodal conduction velocity
B1 - Kidney response
Renin release
B2 - Artery (Skeletal, cardiac muscle) response
Dilation
B2 - Bronchi response
Dilation
B2 - Skeletal muscle response
Glycogenolysis
B2 - Liver response
Glycogenolysis, gluconeogenesis
D1 Receptor response
Arteries (kidney, mesentery) - Dlation
Methyldopa - Metabolism and receptors
Orally active pro-durg (Catecholamine Agonist)
Metabolized in nerve terminals to alpha-methyldopamine, alpha-methylnorepi, which are stored and released with nerve stimulation
A2 receptor agonists, and stimulate central A2 receptors to reduce sympathetic outflow
Methyldopa - Major therapeutic use
HTN
Especially gestational HTN, has no effect on fetus
Methyldopa - Side effects
From CNS penetration
Sedation, dry mouth, edema, rebound HTN if discontinued
Where does methyldopa target for decreased sympathetic outflow?
CNS
PNS would not have the CV effects
Phenylephrine - Target and CV effects
A1 adrenergic recepetor agonist
Increase systolic and diastolic BP, PVR
Reflex decrease in HR
Decrease flow in most vascular beds
Phenylephrine - Therapeutic uses
Opthalmic: Mydriatic
Nasal decongestant: Oral or nasal spray
Adminster with local anesthetics to increase duration of action
Treatment of HTN
Similar drug to phenylephrine
Midodrine
Clonidine - Target
A2 adrenergic receptor Orally active
Clonide - Therapeutic Use, CV effect
Anti-HTN by CNS: Activates central A2 receptors decreasing sympathetic outflow (Hypothalamus and medulla)
Prolonged BP lowering
Decreases PVR, HR, CO
Clonide - Adverse effects
Dry mouth, sedation (50% of patients), edema, rebound HTN
Albuterol - Therapeutic use
Bronchodilator - Asthma
Albuterol - Adverse effects
Tremor, anxiety, tachycardia
Salmeterol - Target and kinetics
B2 adrenergic receptor agonist
Long duration of action: 12h
Aryl alkyl (11 carbons) substitution makes the compound lipophilic
Salmetrol - Therapeutic use
COPD, nocturnal or persistent asthma
Too slow for acute bronchospasm (asthma attack)
Tyramine - Function
Indirect only agonist in presence of MAO inhibitors - Metabolized in liver, no effect
In presence of MAO inhibitors - Reaches axon synapse and encourages monoamine release (dopamine, norepi, epi), can lead to HTN
Example of mixed acting sympathomimetics
Amphetamine
Methamphetamine
Ephedrine/Pseudoephdrine
Amphetamine - Target and effects
CNS stimulant in addition to peripheral alpha/beta action
Depresses appetite
Effective after oral administration (long half-life)
Releases NE from adrenergic nerves, weak direct alpha/beta agonist, competes with NET
Amphetamine - Therapeutic uses
Narcolepsy
ADD
Ephedrine - Targets and metabolism
Direct agonist of alpha/beta receptors, release NE
Orally active
CNS stimulation
Ephedrine - Usage
Previously for asthma
Found in some herbal supplements but now banned by FDA
Pseudoephedrine - Targets
Direct A1 agonist, minor B2 activity
Less CNS stimulation
Pseudoephedrine - Therapeutic use
OTC Nasal Decongestant (Oral, Spray)
Sale is now limited due to illegal use in synthesis of methamphetamine
General Side Effects/Toxicity of Sympathomimetics and Receptor cause
Throbbing headache - Alpha (vasoconstriction)
Increased heart rate, palpitations - Beta
Pericardial pain - Beta (Angina due to increased HR)
Cardiac arrhythmias - Beta
Cerebral hemorrhage - Alpha (Increased BP)
Restlessness, anxiety - Both
Definition of Adrenergic Neuron Blockers
Agents that block the synthesis, storage or release of norepinephrine
Guanethidine and Guanadrel - Target and Kinetics
Orally active, long acting
Taken up into adrenergic nerves via NET
Inhibit NE relase and deplete neuronal amine stores
Guanethidine and Guanadrel - Therapeutic use and side effects
Therapeutic for severe HTN
Can cause orthostatic hypotension, male sexual dysfunction, diarrhea, muscle weakness, edema
Reserpine - Target and Kinetics
Diffuses into adrenergic neurons and depletes NE stores by inhibiting VMAT2
Reserpine - Therapeutic use and side effects
Therapeutic: essential HTN
Can cause sedation, depression (suicidal tendencies), Diarrhea, Orthostatic hypotension, Increased gastric acid secretion
Definition of Adrenergic Receptor Antagoinists
Agents whose effects are produced by inhibiting either alpha and/or beta receptors
Blocks both endogenous and exogenous catecholamines
Targets specific receptor response
May affect NE release from adrenergic neurons
Non-selective Alpha Adrenergic Receptor Antagonist
Both alpha receptors
Overview of phenoxybenzamine
Irreversible non-selective alpha antagonist
Orally active, long duration
Produces vasodilation proportional to degree of sympathetic tone
Overview of phentolamine
Competitive, reversible non-selective alpha agonist
Orally active, shorter duration (2-4 h)
Block can be overcome (competitive kinetics)
Therapeutic use of non-selective alpha antagonist
HTN (phentolamine only) - Cases refractory to other treatments, an only in combination with other agents
HTN with pheochromocytoma (Both)
Reverse or shorten duration of anesthesia produced by a combination of local anesthetic and sympathomimetic (phentolamine)
Side effects of non-selective alpha antagonist
Tachycardia
Edema
Orthostatic hypotension
Prazosin - Overview
A1 Competitive Adrenergic Antagonist
Orally active
Little blockade of pre-synaptic A2 receptors so minimal tachycardia, CO increase
Decrease vascular tone in resistance (aa.) and capacitance (vv.) beds
Produces favorable effects on lipid profile
Prazosin - Therapeutic uses
HTN
Short-term treatment of CHF
Urination problems with benign prostatic hyperplasia (BPH)
Prazosin - Side effects
First dose phenomenon - hypotension and syncope 30-90 mins after 1st dose
Orthostatic hypotension
Edema
Tamsulosin - Overview
Orally active A1 adrenergic receptor antagonist (favors A1A in prostate over A1B in blood vessels)
Tamsulosin - Therapeutic use
Urination problems with BPH
Little effect on BP or HTN
Overview of beta-blockers
Beta-blocking selectivity
Minor actions: Partial agonists, local anesthetic or quinidine-like activity, some A1 selective as well, can be vasodilating
Location of clinically relevant beta receptors
Heart Bronchial Smooth Muscles Kidney (renin) Skeletal muscle Blood vessels supplying skeletal muscle Liver
Propranolol - Overview
Non-selective beta competitive, reversible antagonist
Orally active - substantial first-pass metabolism
Propranolol - Therapeutic uses
HTN Angina pectoris Cardiac arrhythmias Acute MI Pheochromocytoma Migraine prophylaxis
Propranolol - Side effects
Cardiac depression, bradycardia/heart block
Bronchoconstriction
Sedation, impotence, nightmares
Mask hypoglycemia
Propranolol - Careful in patients with
Asthma CHF Bradyarrhythmias, AV block Insulin-dependent diabetes: hypoglycemic episodes Hypotension Vasospastic angina
Timolol - Overview
Non-selective beta adrenergic receptor antagonist
Orally active
Timolol - Therapeutic uses
Similar to propranolol
Also widely used in the treatment of wide-angle glaucoma
Decreases aqueous humor formation by the ciliary epithelium, leading to decreased intraocular pressure
Does not affect pupil size or accomodation
Administered as eye drops
Small amounts can be absorbed into sytemic circulation
Metoprolol - Overview
B1-selective competitive, reversible antagonist
10-fold selectivity for B1 at low doses
Cardioselective, 2nd generation beta-blocker
Metoprolol - Therapeutic usesH
Similar to propranolol
Also used for CHF
Metoprolol - Side effects
Similar to propranolol
Less bronchoconstriction
Atenolol - Overview
B1-selective, orally active, once per day dosing
Does not penetrate into CNS, less side effects
Therapeutic similar to propranolol except for migraine prophylaxis
3rd Generation Beta Blockers
Antagonists with additional CV effects due to A1 selectivity
Labetolol
Competitive, reversible antagonist of a1, beta
Therapeutic use for essential HTN (orally) and HTN crisis (IV)
Carvedilol
Competitive, reversible antagonist of a1, beta
Therapeutic use for CHF, acute MI
Albuterol - Target and Kinetics
B2 adrenergic receptor agonist
Short acting: 3-6 h after inhalation
Primarily taken as inhalant, but also available as oral tablet
