Sympathomimetics Flashcards
Name the 3 direct acting endogenous catecholamines
1) Epinephrine
2) Norepinephrine
3) Dopamine
Name 2 nonselective direct acting beta agonists
1) Isoproterenol
2) Dobutamine
Name the short acting direct Beta 2-selective agonist
Albuterol
Name 2 direct, long acting Beta-2 selective agonists
1) Salmeterol
2) Formoterol
Name the Beta 3-selective direct agonist
Mirabegron
Name the direct acting alpha 1-selective agonist
Phenylephrine
What’s the mixed acting andrenergic agonist
Pseudoephedrine
Name 3 indirect acting adrenergic agonists
1) Amphetamine
2) Dextroamphetamine
3) Methylphenidate
Where are Alpha 1 receptors widely expressed? What does their activation lead to? Compare Alpha 2 to alpha 1.
Widely expressed in vascular beds
Vasoconstriction
Alpha 2 plays a minor role in vasoconstriction compared to alpha 1
Where are beta 2 receptors expressed and their roles?
Expressed in certain vascular beds (ie. skeletal muscle)
Activation leads to vasodilation
What is predominant cardiac adrenergic receptor. Which becomes more important during heart failure?
Beta 1 is the predominant cardiac
receptor
- Beta 2 receptors become functionally
more important in heart failure
What does beta adrenergic activation accomplish in the heart.
SA node / AV node / mycardium / physiologic effect
- Sinoatrial node: increased pacemaker
activity and heart rate (positive chronotropic effect) - Atrioventricular node: increased conduction velocity (positive dromotropic effect)
- Myocardium: increased intrinsic contractility (positive inotropic effect)
- Physiologic response: Increased cardiac output
Where are alpha 1 receptors primarily expressed in the heart? What does their activation lead to?
- Alpha 1 receptors are expressed in the myocardium
- Minor role in normal physiology
- May become functionally more important in heart failure
- Activation leads to: Minor increase in contractility (positive inotropic effect)
Epinephrine Mechanism of Action
Potent agonist of both alpha and beta receptors
- stimulates all alpha and beta receptors comparably
- Complex effects on target organs
- Most prominent actions are on the cardiovascular
system
- Most prominent actions are on the cardiovascular
- Potent vasopressor
What are the effects of epinephrine on the cardiovascular system
BP / Heart / Vasculature
Blood pressure
* Increased systolic pressure
* Decreased diastolic pressure (dose-dependent)
* MAP is largely unchanged: Thus, no compensatory
baroreceptor reflex
Heart
* Increased heart rate (chronotropic), contractile force
(inotropic), and cardiac output
Vasculature
* Constriction of most vascular beds
* Dilation of skeletal muscle blood vessels (dose-dependent)
* Net effect is a decrease in peripheral vascular resistance
What are some respiratory and metabolic effects of epinephrine
Respiratory effects
* Bronchodilation
Metabolic effects
* Hyperglycemia
* Stimulates gluconeogenesis and glycogenolysis
* Inhibits insulin release
* Lipolysis: Increased free fatty acids
Adverse effects of epinephrine
Minor and serios
Minor:
* Restlessness, throbbing headache, tremor, and palpitations
Serious:
* Cerebral hemorrhage: With large doses or rapid IV
injections
- Due to sharp rise in blood pressure
–NOTE: rapid IV administration
during pulseless arrest is necessary
- Cardiac arrhythmias
- Angina: In patients with coronary
artery disease
Contraindications for epinephrine
Patients on nonselective beta blockers
* Result in unopposed activation of vascular alpha 1
receptors
* May lead to severe hypertension and cerebral
hemorrhage
Epinephrine therapeutic uses
allergic reaction / heart / eyes / anesthesiology
Hypersensitive reactions
* Provides rapid emergency relief to anaphylaxis
Bradyarrhythmias
* Restore rhythm in patients with cardiac arrest
Asystole/pulseless cardiac arrest
Ophthalmic uses
* Mydriatic agent for ocular surgery
* Glaucoma
- Mechanism is complex
- No longer commonly used for this purpose
Co-administered with local anesthetics
* Increases duration of action by decreasing local blood flow
Mechanism of action of norepinephrine
Similar to epinephrine:
- Differs in receptor selectivity
- Relatively little action on beta 2 receptors
Effect of norepinephrine on cardiovascular system.
BP / Heart / Vasculature
Blood pressure
* Increased systolic and diastolic pressure
- Initiates compensatory baroreflex response
Heart
* Decreased heart rate
- Increased vagal reflex activity
* Increased contractile force (inotropic)
- Unaffected by vagal reflex
* Cardiac output is unchanged or decreased
Vasculature
* Constriction of vascular beds
* Increased peripheral vascular
resistance
Adverse effects of norepinephrine
Some similarities with epinephrine but greater elevation in BP results in some unique adverse effects
- Severe hypertension
- Necrosis at injection site
- Impaired circulation, with or without extravasation
- Can be improved with infiltration of phentolamine (alpha receptor antagonist)
- Peripheral vascular insufficiency
- Reduced blood flow to organs (e.g. kidney, intestines)
Therapeutic uses of norepinephrine
- Raise or support blood pressure
- Cardiogenic shock
- Vasopressor of choice for initial management in patients
with hemodynamic instability (systolic blood pressure
<90 mm Hg or evidence of end organ hypoperfusion)
- Vasopressor of choice for initial management in patients
- Septic shock
- First-choice vasopressor for management of septic shock
- Spinal anesthesia
What is Dopamine and its mechanism of action
- Metabolic precursor of NE and epinephrine
- Central neurotransmitter
- Particularly important in the regulation of movement
Mechanism of action
* Low concentrations: Agonist of D1 receptors
* High concentrations: Agonist of beta 1 and alpha 1 receptors
Cardiovascular effects of dopamine
Low dose - receptor / medium dose - receptor / high dose - receptor
Low dose (D1 receptors)
* Vasodilation of renal, mesenteric, and coronary vasculature
(D1 receptors)
* Increases glomerular filtration rate, renal blood flow, and
natriuresis
Intermediate dose (beta 1)
* Increased heart rate and contractility
* Increased systolic pressure
* Little to no effect on diastolic pressure
High dose (alpha 1)
* Vasoconstriction and increased peripheral vascular resistance
Adverse effects of dopamine
minor / serious
Some overlap with epinephrine
Minor
* Anxiety, headache, palpitations
Serious
* Angina pectoris
* Arrhythmias
- May cause increases in heart rate, increasing the risk of
tachycardia and other tachyarrhythmias including ventricular
arrhythmias
Dopamine: Therapeutic uses
Severe decompensated heart failure
* Inotropic support
Cardiogenic shock
* Norepinephrine is preferred over dopamine for most
etiologies - lower likelihood for causing arrhythmias
* cardiogenic shock associated with bradycardia or aortic regurgitation, then dopamine is preferred
Sepsis and septic shock
* An alternative vasopressor to norepinephrine only in highly
selected patients
2 nonselective beta agonists
- Isoproterenol (Isuprel)
- Dobutamine
One Beta 2-selective agonist
(short-acting)
Albuterol
Two Beta 2-selective agonists
(long-acting)
Salmeterol
Formoterol
One Beta 3-selective agonist
Mirabegron
Isoproterenol mechanism of action
- Potent, nonselective beta agonist
- Very low affinity for alpha receptors
Isoproterenol: Cardiovascular and Respiratory effects
BP / Heart / Vasculature / Respiratory
Cardiovascular:
Blood pressure
* Decrease in diastolic pressure
* Systolic pressure may remain
unchanged or increase
* Typically, MAP will decrease
Heart
* Increase heart rate, contractile force,
and cardiac output
Vasculature
* Decreased peripheral resistance
* Primarily in skeletal muscle
vasculatur
Respiratory: Bronchodilation
Isoproterenol: Adverse effects
- Palpitations
- Tachycardia
- Headache
- Flushing
- Cardiac ischemia and arrhythmias: More common in patients with underlying coronary artery disease
Isoproterenol: Therapeutic uses
- Emergency stimulation of heart rate
- Patients with bradycardia or heart block
- NOTE: The use of isoproterenol in advanced cardiac life support (ACLS) has largely been supplanted by the use of other adrenergic agents (e.g. epinephrine and dopamine)
Dobutamine Mechanism
Two enantiomers
* (-) isomer is an alpha 1 agonist
* (+) isomer is an alpha 1 antagonist
- Both are agonists of beta receptors
- (+) isomer has 10-fold more beta activity than (-) isomer
Racemic mixture is used clinically: Net effect is a beta agonist
Dobutamine: Cardiovascular effects
BP / Heart / Vasculature
Blood pressure
* Minor effect on blood pressure
Heart
* Increases contractility and cardiac output
* Modest effect on heart rate
* More prominent inotropic effect than chronotropic
Vasculature
* Minimal effect on peripheral resistance
- Counterbalancing of:
– Alpha 1 receptor-mediated
vasoconstriction
– Beta 2 receptor-mediated
vasodilation
Dobutamine Adverse Effects
BP / AFIB
Blood pressure and heart rate may increase significantly
* Requiring reduction of infusion rate
* Hypertensive patients may have an exaggerated pressor response
Patients with atrial fibrillation are at risk of marked
increases in ventricular response rates (ventricular
tachycardia)
* Due to facilitation of AV conduction
* May require digoxin or other agent as a preventative
Dobutamine:
Therapeutic uses
Short-term management of patients with cardiac decompensation
* After cardiac surgery
* Congestive heart failure
* Acute myocardial infarction
Beta 2-selective adrenergic
receptor agonists:
Mechanism of action
(Systemic conc? / heart effects)
Selective agonist of beta 2 receptors
* Not absolute
* Selectivity is lost at high concentrations
* Developed for the treatment of asthma and COPD
- Avoids adverse effects in the heart (beta 1)
- Administered by inhalation
– Targeted delivery to pulmonary tissue
– Very low systemic drug concentrations
- Pulmonary effects:
- Bronchodilation
- Reduced airway inflammation: Suppression of leukotriene and histamine release from mast cells
Beta 2-selective adrenergic
receptor agonists:
Adverse effects
- Tremor: Tolerance generally develops
- Anxiety
- Tachycardia
- Arrhythmias, myocardial ischemia: Rare in patients without cardiac disease
- Greater risk in patients with underlying coronary artery disease or preexisting arrhythmia
- Increased in patients receiving MAO inhibitors
Note: Likelihood of adverse effects can be greatly reduced by
inhalational administration
Short-acting beta 2-selective agonists: Albuterol: Pharmacokinetics and Therapeutic use
Pharmacokinetics
* Duration of action: 3-6 hours (inhaled)
* Onset of action: Bronchodilation within 15 min
Therapeutic use
* Asthma: Symptomatic relief of
bronchospasm
Pharmacokinetics and Therapeutic uses of Long-acting beta 2-selective agonists: Salmeterol, Formoterol
Pharmacokinetics
* Duration of action: >12 hours (inhaled)
Onset of action
* Salmeterol: Relatively slow
- Not suitable for treatment of acute asthma symptoms
* Formoterol
- Bronchodilation within minutes
Therapeutic use
* Chronic obstructive pulmonary disease (COPD)
* Asthma
- Nocturnal and persistent
Mirabegron: Type of receptors and where are they expressed, mechanism of action, adverse effects and therapeutic use
- Beta 3 receptors are expressed in
brown fat, GI, and bladder
Mechanism of action
* Relaxation of the detrusor muscle of
the bladder
- Increased bladder capacity
Adverse effects
* Hypertension (9-11%)
* Urinary tract infections (3-6%)
* Headache (2-4%)
Therapeutic use
* Urinary incontinence
Mechanism of action of Phenylephrine
Mechanism of action
* Potent, direct-acting alpha 1 adrenergic agonist
* Virtually no beta-adrenergic activity
* Direct acting vasoconstrictor
Cardiovascular effects of Phenylephrine
BP / Heart / Vasculature
Blood Pressure
* Increases systolic and diastolic pressure
Heart
* Decreased heart rate: Due to reflex bradycardia
Vasculature
* Vasoconstriction
* Decreased blood flow
Therapeutic uses of Phenylephrine
Hypotension
* Orthostatic hypotension (Midodrine)
* Shock
Nasal decongestant
Ophthalmic: Mydriatic agent
What reflex blunts the alpha-1 agonist blood pressure effect
Compensatory autonomic baroreflex response
Pseudoephedrine: Mechanism of action and Therapeutic use
Mechanism of Action: Mixed acting sympathomimetic like ephedrine
However, receptor selectivity differs from ephedrine
* Direct alpha 1 agonist
- Little direct beta 2 agonist activity
Therapeutic use
* Nasal decongestant
Amphetamine Mechanism of Action
- Powerful CNS stimulant with peripheral sympathomimetic actions
Mechanism of action
* Releases biogenic amines from storage vesicles in CNS and peripheral sympathetic nerve terminals
- Inhibits vesicular monoamine transporter (VMAT)
Amphetamine: Cardiovascular, smooth muscle and CNS effects
Cardiovascular effects
* Increases systolic and diastolic pressure
* Heart rate is often reflexively slowed
Other smooth muscle effects
* Contraction of the urinary sphincter
* GI effects are unpredictable
CNS effects
* One of the most potent sympathomimetic amines in stimulating the CNS
* CNS effects will be discussed in
future lectures
Amphetamine: Therapeutic use
Used for the treatment of:
* Narcolepsy
* ADHD
Dextroamphetamine: Mechanism of action and therapeutic uses
- Same as amphetamine except greater CNS and less peripheral
action - Same therapeutic uses as amphetamine
Methylphenidate: Mechanims of Action and Therapeutic Uses
- Piperidine derivative, structurally similar to amphetamine
- Mild CNS stimulant
- More prominent effects on mental than on motor activities
Therapeutic use:
Both methamphetamine and methylphenidate are approved for the treatment of narcolepsy and ADHD
Note: Amphetamine, methamphetamine, and methylphenidate are Schedule II drugs due to a high potential for abuse
