Chapter 14 Morgan: Adrenergic Agonist and Antagonist Flashcards
What is the primary mechanism of action of adrenergic agonists and antagonists?
- They interact with adrenergic receptors (adrenoceptors)
- To produce clinical effects.
How can the clinical effects of adrenergic drugs be understood?
- By understanding adrenoceptor physiology
- Knowing which receptors each drug activates or blocks
What are adrenoceptors?
Specific receptors that interact with adrenergic agonists and antagonists to mediate their effects.
Why is knowledge of adrenoceptor physiology important in pharmacology?
It helps deduce the clinical effects of adrenergic drugs.
What determines the specificity of adrenergic drugs?
They activate or block the specific adrenergic receptors.
What is the primary neurotransmitter for adrenergic activity in the sympathetic nervous system?
Norepinephrine (noradrenaline).
Where is norepinephrine released in the body, and what are the exceptions?
Released by postganglionic sympathetic fibers at end-organ tissues, except in eccrine sweat glands and some blood vessels.
How is norepinephrine synthesized and stored?
- Synthesized in the cytoplasm of sympathetic postganglionic nerve endings.
- Stored in vesicles.
What terminates norepinephrine’s actions?
Primarily terminated by reuptake into the postganglionic nerve ending.
How do tricyclic antidepressants, cocaine, and amphetamines affect adrenergic activity?
- They inhibit transporters that facilitate the removal of norepinephrine from the synapse.
What happens to norepinephrine after it diffuses from receptor sites?
- Is taken up by nonneuronal cells
- Metabolized by catechol-O-methyltransferase or
- Metabolized in neurons by monoamine oxidase.
What is the effect of prolonged adrenergic activation?
- Leads to desensitization
- Reduce responses to subsequent stimulation.
What are the two general categories of adrenergic receptors?
1. α (alpha) receptors
2. β (beta) receptors.
How are α and β adrenergic receptors subdivided?
- α receptors into α1and α2
- β receptors into β1, β2, and β3.
What are the further divisions of α-receptors identified through molecular cloning?
α1A, α1B, α1D, α2A, α2B, and α2C.
What is the role of G proteins in adrenergic receptors?
- Are heterotrimeric receptors
- Linked to different adrenoceptors
- Each with a unique effector
Which G protein is linked to α1 receptors, and what does it activate?
- Linked to Gq
- Activates phospholipases
What G protein is α2 receptors linked to?
- Linked to Gi
- Inhibits adenylate cyclase.
Which G protein is linked with β receptors, and what is its function?
- β is linked to Gs
- Activates adenylate cyclase.
Includes: β2 β1
Where are α1-Receptors located and what is their primary function?
- Postsynaptic adrenoceptors in smooth muscle throughout the body
- Increase intracellular calcium ion concentration, causing smooth muscle contraction.
What are the effects of α1-agonists in the body?
- Mydriasis (pupillary dilation)
- Bronchoconstriction
- Vasoconstriction
- Uterine contraction
- Increase salivation
- Constriction of gastrointestinal and Genitourinary sphincters.
How does stimulation of α1-receptors affect insulin secretion and lipolysis?
Inhibits insulin secretion and lipolysis.
What role do α1-receptors play in the myocardium?
- Possess a positive inotropic effect
- Might contribute to catecholamine-induced arrhythmia.
How does α1-receptor stimulation affect the cardiovascular system, especially during myocardial ischemia?
- Enhances vasoconstriction
- Increases peripheral vascular resistance
- Increases left ventricular afterload
- Increases arterial blood pressure
- Enhanced receptor coupling with agonists during myocardial ischemia.
Where are α2-Receptors primarily located, and what is their main function?
- Located on presynaptic nerve terminals
- It inhibits adenylyl cyclase
- Reduces calcium ion entry
- Limits norepinephrine release.
How do α2-Receptors regulate norepinephrine release?
- Create a negative feedback loop
- Inhibits further norepinephrine release from neurons.
What is the role of postsynaptic α2-Receptors in vascular smooth muscle?
Produce vasoconstriction.
How does stimulation of CNS α2-Receptors affect the body?
- Causes sedation
- Reduces sympathetic outflow
- Leads to peripheral vasodilation
- Lower blood pressure.
What are the classifications of β-Adrenergic receptors?
- β1, β2, and β3 receptors.
How do norepinephrine and epinephrine compare in their potency on β1 and β2 receptors?
- Both Equipotent on β1 receptors
- Epinephrine is more potent on β2 receptors
- Norepinephrine on β1 receptors.
Where are β1-receptors primarily located, and what is their role in the heart?
- Located on postsynaptic membranes in the heart
- Stimulate adenylyl cyclase, leading to increased heart rate, conduction, and contractility.
What is the effect of β1-receptor stimulation on cardiac function?
- Activates a kinase phosphorylation cascade
- Cause positive chronotropic, dromotropic, and inotropic effects.
Where are β2-Receptors primarily located?
- Primarily in smooth muscles
- Gland cells
- Ventricular myocytes.
What is the role of β2-Receptors in patients with chronic heart failure?
Their contribution to the response to intravenous catecholamines increases in chronic heart failure.
What is the common mechanism of action shared by β2 and β1-Receptors?
Both activate adenylyl cyclase.
What are the effects of β2-Receptor stimulation?
- Bronchodilation
- Vasodilation
- Relaxation of the uterus, bladder and gut
- Stimulates glycogenolysis, lipolysis, gluconeogenesis
- Insulin release
Where are β3-Receptors located?
- Gallbladder.
- Brain.
- Adipose tissue.
What is the known role of β3-Receptors in gallbladder physiology?
- Is currently unknown.
What functions are associated with β3-Receptors?
- Play a role in lipolysis
- Thermogenesis in brown fat
- Bladder relaxation.
What are Dopamine (DA) receptors?
- A group of dopamine-activated adrenergic receptors
- Classified as D1 and D2 receptors.
What is the function of D1 receptors?
Mediates vasodilation in the kidney, intestine, and heart.
What role do D2 receptors play in medication?
- Involved in the antiemetic action of drugs
- Like droperidol and haloperidol.
What complicates the prediction of clinical effects of adrenergic agonists?
- Overlapping receptor activity,
- As epinephrine stimulates α1-, α2-, β1-, and β2-adrenoceptors
How does epinephrine’s net effect on blood pressure vary?
- Depends on dose-dependent balance between
- α1-vasoconstriction
- α2- and β2-vasodilation
- β1-inotropic influences.
What is the distinction between direct and indirect adrenergic agonists?
- Direct agonists bind to receptors.
- Indirect agonists increase endogenous neurotransmitter activity.
Why is it important to distinguish between direct and indirect agonists?
- Particularly crucial in patients with abnormal endogenous norepinephrine stores
- Those on some antihypertensive medications
- Monoamine oxidase inhibitors.
What is unique about the chemical structure of catecholamine adrenergic agonists?
- They have a 3,4-dihydroxybenzene structure
- Include epinephrine, norepinephrine, and dopamine.
How does the modification of side-chain structures in catecholamines affect them?
- Leads to development of synthetic catecholamines
- Ex: isoproterenol, dobutamine with more receptor specificity.
What should be considered when using adrenergic agonist dosing recommendations?
- Recommendations are guidelines only
- Individual responses to these drugs can vary significantly
What is Phenylephrine’s primary effect?
- Peripheral vasoconstriction
- Increasing systemic vascular resistance
- Increase blood pressure.
How does Phenylephrine affect heart rate?
- Can cause reflex bradycardia
- Potentially reduce cardiac output.
What are some topical uses of Phenylephrine?
- Used as a decongestant
- Mydriatic agent.
How is Phenylephrine administered for reversing hypotension?
Intravenous boluses of 50 to 100 mcg (0.5 to 1 mcg/kg).
What is the duration of Phenylephrine’s action?
Approximately 15 minutes after a single dose.
Can tachyphylaxis occur with Phenylephrine infusions?
Yes, it may require upward titration of the infusion.
How should Phenylephrine be prepared for administration?
Diluted from a 1% solution (10 mg/1-mL ampule) to a 100 mcg/mL solution and titrated to effect.
10 mg/mL vial in 100 mL NS bag to get 0.1 mg/mL or 100 mcg/mL
What are the effects of Clonidine?
- Decreases anesthetic and analgesic requirements
- Provides sedation
- Prolongs the duration of regional anesthesia blocks.
What are α2-Agonists commonly used for?
- Antihypertensive effects
- Negative chronotropic effects
- Sedation.
How does Clonidine affect intraoperative and postoperative management?
- It enhances circulatory stability during surgery
- Reduces postoperative shivering
- Helps manage acute pain.
What are the side effects of α2-Agonists like Clonidine?
- Bradycardia
- Hypotension
- Sedation
- respiratory depression
- Dry mouth.
How does Dexmedetomidine compare to Clonidine?
- Higher α2-receptor affinity
- Shorter half-life
- Stronger α2:α1 receptor specificity ratio.
What are the clinical applications of Dexmedetomidine?
- Sedation during awake fiberoptic intubation
- Postoperative sedation without significant respiratory depression
- Potential renal protection in ischemic kidney injury.
What is the recommended dosing for Dexmedetomidine?
- Loading dose: 1 mcg/kg over 10 minutes,
- Followed by an infusion of 0.2 to 0.7 mcg/kg/h.
What happens upon abrupt discontinuation of long-term α2-Agonists?
- Risk of acute withdrawal syndrome
- Including hypertensive crisis
What is Epinephrine, and where is it synthesized?
- An endogenous catecholamine.
- Synthesized in the adrenal medulla.
How does Epinephrine affect the myocardium?
- Stimulates β1-receptors
- Raise blood pressure, cardiac output, and myocardial oxygen demand.
What is the effect of Epinephrine on α1 and β2 receptors?
- α1: Decreases splanchnic and renal blood flow; increases coronary perfusion.
- β2: Causes vasodilation in skeletal muscle and relaxes bronchial smooth muscle.
What are the primary clinical uses of Epinephrine?
- Treating anaphylaxis.
- Increasing coronary perfusion pressure during ventricular fibrillation.
What are the complications associated with Epinephrine?
- Cerebral hemorrhage
- Myocardial ischemia
- Ventricular arrhythmias.
How is Epinephrine administered in emergencies?
- Intravenous bolus of 0.5 to 1 mg
- Anaphylaxis, 100 to 500 mcg followed by infusion.
What concentrations of Epinephrine are available?
- 1:1000 (1 mg/mL) vials
- 1:10,000 (0.1 mg/mL) prefilled syringes.
What are the cardiovascular effects of Ephedrine?
- Increases blood pressure
- Increases heart rate
- Increases contractility
- Increases cardiac output
- Acts a bronchodilator.
How does Ephedrine differ from Epinephrine?
- Longer duration
- Less potency
- Indirect and direct actions stimulation of CNS
- Raising of minimum alveolar concentration.
What are Ephedrine’s mechanisms of action?
- Peripheral postsynaptic norepinephrine release
- Inhibition of norepinephrine reuptake.
What is Ephedrine’s common use in anesthesia?
- As a vasopressor
- Especially during hypotension in anesthesia.
Why is Ephedrine preferred in obstetric anesthesia?
- It doesn’t decrease uterine blood flow.
- Now, phenylephrine is often used due to faster onset and fewer fetal pH effects.
How is Ephedrine administered?
- Adults: 2.5 to 10 mg bolus.
- Children: 0.1 mg/kg bolus.
What is the cause of Ephedrine’s tachyphylaxis?
Likely due to depletion of norepinephrine stores.
What are the primary actions of Norepinephrine?
- Direct α1 stimulation
- Intense vasoconstriction
- Increased myocardial contractility from β1 effects.
What are the effects of Norepinephrine on blood pressure?
- Increases both systolic and diastolic pressures
- May increase afterload.
How does Norepinephrine affect cardiac output?
- Increase afterload
- Reflex bradycardia
- May prevent elevation in cardiac output.
What concerns are associated with Norepinephrine use?
- Decreased renal and splanchnic blood flow.
- Increased myocardial oxygen requirements.
What is the clinical use of Norepinephrine?
- Management of refractory shock
- Especially septic shock.
How is Norepinephrine administered?
- Continuous infusion
- Rate of 2 to 20 mcg/min.
What is a potential side effect of Norepinephrine infusion?
- Extravasation
- Tissue necrosis at the infusion site.
What are the effects of low doses of Dopamine?
- Activates dopaminergic receptors
- Dilates renal vasculature
- Promotes diuresis and natriuresis.
How does Dopamine function at moderate doses?
- Stimulates β1 receptors
- Increases myocardial contractility
- Increases heart rate
- Increases systolic blood pressure
- Increases cardiac output.
What occurs at high doses of Dopamine?
- Prominent α1 effects
- Increased peripheral vascular resistance
- Decreased renal blood flow.
What are Dopamine’s indirect effects?
Due to release of norepinephrine from presynaptic sympathetic nerve ganglion.
What are the limitations of Dopamine in clinical use?
- Chronotropic and proarrhythmic effects limit its use
- It has replaced by other drugs in critical illness scenarios.
How is Dopamine administered?
- As a continuous infusion
- Rate of 1 to 20 mcg/kg/min.
What type of agonist is Isoproterenol?
Is a pure β-agonist.
What are the primary effects of β1 stimulation by Isoproterenol?
- Increases heart rate
- Increase contractility
- Increase cardiac output.
How does Isoproterenol affect systolic and diastolic blood pressure?
- Systolic blood pressure may increase or remain unchanged.
- β2 stimulation decreases peripheral vascular resistance and lowers diastolic blood pressure.
Why is Isoproterenol often not the preferred inotropic choice?
- It increases myocardial oxygen demand
- Potentially reduce oxygen supply.
What receptors does Dobutamine primarily affect?
- Affinity for both β1- and β2-receptors
- Greater selectivity for β1-receptors.
What is the primary cardiovascular effect of Dobutamine?
- Increases cardiac output
- Due to enhanced myocardial contractility.
How does Dobutamine affect peripheral vascular resistance and arterial blood pressure?
- β2 activation leads to decreased PVR
- Preventing increases in arterial blood pressure.
How does Dobutamine impact left ventricular filling pressure and coronary blood flow?
- Decreases LV filling pressure
- Increases coronary blood flow.
Should Dobutamine be used routinely for myocardial oxygen consumption?
- No, it increases myocardial oxygen consumption
- Is not recommended for routine use without specific indications.
In what clinical scenario is Dobutamine commonly used?
It is often employed in pharmacological stress testing.
How is Dobutamine typically administered?
- Administered as an infusion
- Rate of 2 to 20 mcg/kg/min.
What type of receptor agonist is Fenoldopam, and what is its primary action?
- Selective D1-receptor agonist
- Decreases PVR
- Increases renal blood flow.
In which surgical scenarios is Fenoldopam commonly used?
- Used in cardiac surgery
- Aortic aneurysm repair
- Potential risk of perioperative kidney impairment.
What are the key clinical indications of Fenoldopam?
- Severe hypertension
- Particularly in patients with renal impairment
- PreventS contrast media-induced nephropathy.
How is Fenoldopam administered and titrated?
- Continuous infusion of 0.1 mcg/kg/min
- Increments of 0.1 mcg/kg/min at 15- to 20-minute intervals
- Until the target blood pressure is achieved.
What are the effects of Fenoldopam on renal function and blood pressure?
- It reduces blood pressure
- Helps to maintain renal blood flow.
Is there strong evidence supporting Fenoldopam’s renal protection efficacy?
- The efficacy of Fenoldopam in “protecting” the kidney perioperatively remains debated
- No strong evidence for efficacy.
What is a notable side effect of lower doses of Fenoldopam?
- Associated with less reflex tachycardia.
The term adrenergic originally referred to:
- The effects of Epinephrine
(adrenaline)
What is the primary neurotransmitter responsible for most of the adrenergic activity of the sympathetic nervous system?
Norepinephrine (Noradrenaline)
Where can Dopamine be converted into Epinephrine?
In the Adrenal Medulla
Monoamine oxidase (MAO) And catechol-O-methyltransferase (COMT) produces a common end product known as:
Vanillylmandelic acid (VMA).
What are the naturally
occurring catecholamines?
Think about END
- Epinephrine
- Norepinephrine
- Dopamine (DA)
Adrenergic Agonists that have a 3,4-
dihydroxybenzene structure and are known as:
- catecholamines.
- These drugs are typically short-acting because of their metabolism by monoamine oxidase and catechol-O-methyltransferase
Which drugs are synthetic catecholamines?
- Isoproterenol
- Dobutamine
Tend to be more receptor-specific
