Autonomic Nervous System, Adrenergic Antagonists Flashcards
What are adrenergic receptor antagonists?
drugs that inhibit the interactions of NE, EPI, and other sympathomimetics with α and β adrenergic receptors
How do α-antagonists receptor selectivity compare?
Prazosin, Terazosin, Doxasin - α1»»α2
Phenoxybenzamine - α1>α2
Phentolamine - α1=α2
Atipamezole, Yohimbine, Tolazoline - α2»α1
How does the mixed α- and β- antagonist receptor selectivity compare?
Carvedilol - β1=β2 >/= α1>α2
How do β-antagonists receptor selectivity compare?
Propranolol, Timolol - β1=β2
Metoprolol, Atenolol, Esmolol, Betaxolol - β1»>β2
What are the 3 categories of α-adrenoceptor antagonists? What kind of antagonists are they?
- β-haloethylamine alkylating agents: Phenoxybenzamine
- imidazoline analogs: Phentolamine, Tolazoline
- piperazinyl quinozolines: Prazosin
competitive antagonists
How are phenothiazine tranquilizers used? What selectivity do they demonstrate? What do they do?
potent α-adrenoceptor antagonist
substantial nonselective α-receptor clocking effects, leading to side effects
decrease peripheral vascular resistance secondary to antagonism of these receptors
What effect do α1-adrenergic receptor antagonists have on the cardiovascular system?
dilation of both arterial and venous vessels with an elimination of the increased peripheral vascular resistance to norepinephrine
What is the epinephrine reversal effect?
following pretreatment with an α1-adrenergic receptor agonist, administration of EPI may induce a reduction in peripheral vascular resistance and marked vasodilation mediated by the activation of β2-adrenergic receptors, resulting in a decrease in arterial blood pressure
What are some non-cardiovascular effects of α1, α2b, α2-adrenergic receptor antagonists?
α1 = decrease resistance to urine flow
α2b = antiaggregant in platelets,
α2 = stimulate insulin release from pancreatic islet cells, reverse sedation mediated by α2-adrenergic receptor agonists
How do α-adrenergic receptor antagonists affect the eye?
- protrusion of third eyelid
- miosis (constriction)
- nasal stuffiness
What is the main non-selective α1,α2 antagonist used in veterinary medicine? How does it bind to receptors? What does it do?
Phenoxybenzamine (α1>α2)
binds covalently to α-adrenergic receptors and produces and irreversible block
inhibits reuptake of NE at presynaptic nerve terminals
- can also antagonize at histamine, acetylcholine, and serotonin receptors
What is the predominant use of Phenoxybenzamine?
(non-selective α1>α2 antagonist)
manage the symptoms of catecholamine excess in the treatment of patients with a pheochromocytoma (tumor in adrenal medulla)
How do phenothiazine tranquilizers and the tetracyclic antidepressant trazodone work?
nonselective α1, α2 antagonists
What is Prazosin? What are 2 uses?
selective α1 antagonist
- treatment of hypertension - relaxes arterial and venous smooth muscle
- decrease resistance to urine flow in dogs with functional urethral obstructions, prostatic hyperplasia, and idiopathic vesicourethral reflext dyssynergia
What is thought to play a role in urethral obstruction recurrence? What is commonly used for postobstruction therapty?
urethral spasm
α1-receptor blockade (antagonists)
How does Prazosin compare to Phenoxybenzamine? What does administration to dogs result in?
higher α1-adrenergic receptor affinity
greater reduction of urethral pressure than phenoxybenzamine
- REMEMBER: α1 = sphincter contraction
Why is the efficacy of Prazosin in the treatment of urethral obstruction in cats debated?
antagonists usually acts on proximal urethra, and cats most commonly block at the distal portion
What is the most important limitation of α1-adrenergic receptor antagonists?
CARDIOVASCULAR EFFECTS:
- reduces vascular smooth muscle tone
- decreases systolic, diastolic, and mean arterial blood pressure
What is Tamsulosin? What receptor does it have the highest affinity for? Where are these receptors located?
second-generation α1-adrenergic receptor agonist
α1a (urethra/prostate in dogs) > α1b (vascular smooth muscle)
What is Silodosin?
third-generation α1-receptor antagonist
How does treatment of dogs with/without prostatic hyperplasia compare with Tamsulosin and Silodosin?
similar response on decreasing intraurethral pressure
(α1-antagonists)
What is Yohimbine? What is it most commonly used for?
α2-antagonist
reverse the sedative effects of α2-adrenergic agonists, like Xylazine, Medetomidine, Dexmedetomidine, Detomidine, and Romifidine
How does Yohimbine affect the CNS, cardiovascular system, and GI tract? What other receptors can it work at?
- CNS stimulation
- increased heart rate and blood pressure by increasing NE release
- increases GI motility by increasing parasympathetic tone
some antagonism at serotonin receptors
Why is Yohimbine less commonly used in small animal patients?
atipamezole (Antisedan) more commonly used
- efficacy of xylazine reversal in cattle is also variable
What is Tolazoline? What is approved for? In what 2 ways is it used off-label?
mixed sympathetic α2 and α1 adrenergic antagonist (imidazoline derivative)
used as an injection for reversing xylazine in horses
- reversal of other α2-adrenergic agonists in equids, such as detomidine
- less expensive alternative to atipamezole (Antisedan) and Yohimbine for reversing sedation in large animals and wildlife
What is Atipamezole? How does it compare to others of the same category of drugs?
selective α2-antagonist originally approved to reverse sedative and analgesic effect of medetomidine hydrochloride
more potent than Yohimbine and is able to reverse sedation induced by α2-agonists at 1/10 the dose
In what 2 ways is Atipamezole used off-label? In what species is it effective in?
- DOGS - treatment of imidazoline decongestant (oxymetazoline, tetrahydrozoline, xylometazoline) intoxication
- insecticide/acaricide (amitraz - α2 agonist) intoxication
all species, including ruminants
How are most β-adrenergic receptor antagonists available as? What effect do some exhibit?
pure (full) antagonists
- there are still inverse agonists favoring inactive conformations and partial antagonists
membrane-stabilizing activity (similar to local anesthetics)
What are the 2 main effects of partial β-adrenergic receptor antagonists? What does this result in?
- partial activation (not as much as a full agonist, like EPI)
- inhibit the activation of β-adrenergic receptors in the presence of high levels of EPI and NE
intrinsic sympathetic activity (ISA)
What are the 2 main cardiovascular effects of β-adrenergic antagonists? What does this result in?
- slows atrioventricular conduction
- produces negative ionotropic chronotropic effects
decreased cardiac output
What cardiovascular effect tends to happen when β-blocking drugs are administered chronically? What is a common acute effect observed?
decreased blood pressure in hypertensive patients
increased peripheral vascular resistance
What pulmonary effects are observed with nonselective β-adrenergic receptor antagonist usage?
blocks β2-receptors in bronchial smooth muscles, resulting in bronchoconstriction and increased airway resistance
- be careful with usage in asthmatic patients!
What 2 effects does the topical administration of β-adrenergic antagonists have on the eye?
- reduces intraocular pressure by blocking NE release from sympathetic nerves
- decreases in aqueous humor production
What 2 metabolic and endocrine effects are observed with β-adrenergic antagonist usage?
- inhibit the activation of lipolysis and glycogenolysis
- delay recovery from hypoglycemia (type-1>type-2 DM)
What are the 3 classifications of β-adrenergic receptor antagonists? What are the most common ones used in veterinary patients?
FIRST GENERATION: nonselective β-receptor antagonists
SECOND GENERATION: β1 selective receptor antagonists
THIRD GENERATION: nonselective β-receptor antagonists with additional cardiovascular actions (α-receptors)
FIRST GEN: Propanolol
SECOND GEN: Atenolol, Esmolol, Metoprolol
THIRD GEN: Carvedilol
What 4 treatments if Propranolol used for?
(FIRST GEN)
1. tachyarrythmias
2. hypertension
3. hypertrophic and obstructive cardiomyopathies
4. cardiovascular consequences of thyrotoxicosis or pheochromocytoma
What are 2 side effects of Propranolol? What is its usage contraindicated in?
(FIRST GEN)
1. upregulation of β-receptors occur with long-term therapy
2. abrupt cessation leads to excessive stimulation of β-receptors
asthmatic patients —> causes bronchospam
What β-antagonists have no intrinsic sympathetic activity (ISA)?
Metoprolol and Atenolol (SECOND GEN)
Carvedilol (THIRD GEN)
- no membrane-stabilizing activity
What can happen with high-dose administration of Metoprolol? What are 5 common pharmacological effects?
(SECOND GEN)
blocks β2 receptors
- decreased sinus heart rate and slowed AV conduction
- diminished cardiac output
- decreased myocardial oxygen demand
- reduced blood pressure
- inhibition of β-agonist-induced tachycardia
What are 5 uses of oral Metoprolol? Is it safe to use in patients with bronchospastic disease?
- supraventricular tachyarrythmias
- premature ventricular contractions
- systemic hypertension
- hypertrophic cardiomyopathy
- thyrotoxicosis in cats
YES
What is the main use of Atenolol? What 3 things can it be given orally to treat?
(SECOND GEN)
decreases heart rate, cardiac output, and systolic/diastolic pressure
- supraventricular arrhythmias
- systemic hypertension
- hypertrophic cardiomyopathies in cats
What are 4 possible side effects of Atenolol usage?
- can block β2 receptors at high doses - use carefully in patients with asthma or history of bronchospasm
- excessive β1 blockade can greatly reduce cardiac output
- must be used carefully in patients with CHF and renal failure
- lethargy, hypotension, diarrhea
What are 2 characteristics of Esmolol? What is a therapeutic use? A possible side effect?
(SECOND GEN)
1. little membrane-stabilizing activity
2. ultrashort acting β1-selective receptor agonist (~20mins)
- ventricular outflow obstruction in cats
- excessive β1 blockade greatly reduces cardiac outflow
What are the 2 IV drugs of choice for tachyarrhythmias?
- Esmolol
- Propranolol
What is Carvedilol? What does it demonstrate?
THIRD GEN nonselective β-receptor agonist with modest α1-receptor antagonism
- vasodilation, reduce afterload
- reduces effects of sympathetic stimulation
membrane-stabilizing activity without intrinsic activity
What is a unique effect that Carvedilol has? What are 2 common therapeutic uses?
free radical scavenging and antidysrhythmic effects
- anti-arrhythmic
- long-term management of dilated cardiomyopathy and chronic valve disease
What is the drug of choice for reducing mortality and increasing the quality of life in heart failure patients? What are the 2 most common causes of heart disease and CHF in dogs?
β-adrenergic antagonists with selective β1 antagonists or third-generation antagonists
- selectivity is key
- chronic mitral valvular disease (CMVD)
- dilated cardiomyopathy (DCM)
How were dogs with mitral valve disease treated?
oral administration of carvedilol imprtoved life scores and reduced systolic blood pressure
What are the 2 most common cardiac disease in cats? What are they characterized by?
- hypertrophic cardiomyopathy leading to…
- dynamic obstruction of the left ventricular outflow tract (HOCM)
concentric ventricular hypertrophy
What is the most commonly prescribed medications to reduce dynamic obstructions of the left ventricular outflow tract (LVOT)?
β-receptor antagonist - Atenolol
What is a congenital abnormality that causes varying degrees of obstructions of the left ventricular outflow tract (LVOT) in dogs? How has it been treated?
subaortic stenosis (SAS)
β-receptor antagonist - Atenolol
Pharmacodynamic characteristics of adrenergic receptor agonists?
