Adrenergic Receptor Agonists and Sympathomimetic Drugs Flashcards
What do Sympathomimetic/Adrenergic Drugs do?
Mimic actions of epinephrine or norepinephrine at adrenergic receptors.
How are Sympathomimetic/Adrenergic classified?
• Direct Agonists:
- Act directly on adrenergic receptors
• Indirect Agonists:
- Displace stored catecholamines from nerve
ending/varicosities or…
- Inhibit reuptake of catecholamines released from the nerve ending
What determines the effects of direct agonists?
1) Route of administration
2) Relative affinity for adrenergic receptor subtypes
3) Relative expression of receptor subtypes in the target tissue
What determines the effects of indirect agonists?
exhibit greater adrenergic effects in conditions of increased sympathetic tone and NE storage and release
Mechanism of Action:
- Pharmacological Actions mediated by G protein- coupled, adrenergic receptors (adrenoceptors)
- Notable G Proteins for Adrenergic Receptor Function:
* Gs – stimulatory G protein of adenylyl cyclase
* Gi & Go – inhibitory G protein of adenylyl cyclase
* Gq & G11 – couple α receptors to phospholipase C
Comparative Catecholamine Potencie /Relative Affinities at Adrenoceptors:
- α-receptors:
- epinephrine ≥ norepinephrine»_space; isoproterenol
- β-receptors:
- isoproterenol > epinephrine ≥ norepinephrine
Dopamine Receptors:
- particular importance in the brain, splanchnic and renal vasculature
- D1 & D5 (D1–like)
- D2, D3 & D4 (D2–like)
Dopamine Receptors, cont:
- D1 receptors stimulate adenylyl cyclase
* D2 receptors inhibit adenylyl cyclase, open K+ channels, decrease Ca++ influx
Adrenergic Agonist Receptor Selectivity:
Agonists generally selective for major types (α1,α2, β) but not for subtypes
Sympathomimetics (adrenergic agonists)
(Chemistry):
• catecholamines exhibit maximal activity at α & β receptors:
• absence of catechol hydroxyls = much lower potency (phenylephrine)
• not orally active - metabolized by catechol-O-
methyltransferase (COMT)
• absence of either or both OH- groups increases bioavailability, distribution (including CNS) and duration of action
Sympathomimetics (Chemistry):
• increasing size of additions on the amino group increases β-receptor activity
• β2-selective require larger amino substitutions
• larger the substitution the lower the α-receptor
activity
Sympathomimetics (Chemistry):
- α-carbon substitutions can block oxidation via MAO
- indirectly acting sympathomimetics
- can displace endogenous catecholamines from storage sites in adrenergic nerves
Effects of Sympathomimetics - (Cardiovascular):
• Have prominent cardiovascular effects
• wide distribution of α and β adrenergic receptors – heart;
vessels; neural/hormonal systems
• effect dependent upon relative selectivity for α and β receptors and the types of receptors present in a given tissue
• BP effects related to specific individual effects on HR and myocardial function (e.g., force of contraction, stroke volume, etc), PVR, venous return
Effects of Sympathomimetics – (Cardiovascular), cont:
• α1 receptors widely distributed in the vascular bed
• vasoconstriction – both arterial & venous
• increase peripheral arterial resistance/decrease venous capacitance= increase BP
• increase BP countered by the baroreceptor reflex to slow HR
• impairment of autonomic function in patients exhibit exaggerated CV responses to sympathomimetics
Effects of Sympathomimetics – (Cardiovascular), cont:
- α2-receptor activation
- α2 receptor activation in vascular bed
- vasoconstriction
- ONLY when administered locally or with very high systemic doses
- central effects of α2-receptors predominate when given systemically
- decreased sympathetic tone and BP
- therefore, α2-agonists could be used in treatment of hypertension
- α2 receptor activation in vascular bed
Effects of Sympathomimetics (Cardiovascular), cont:
β receptor activation, Heart:
• increase contractility (+ inotropy) +  increase HR (+ chronotropy) =  increase cardiac output
• β1 predominate blood vessels
• β agonists act at β2 to dilate vessels in certain vascular beds (e.g., skeletal muscle and decrease PVR)
• isoproterenol non-specific β agonist activates both subtypes (primarily β1 – heart/ β2 vessels)
Effects of Sympathomimetics – (Cardiovascular), cont:
• Dopamine (DA) receptor activation
• D1 activation – vasodilation
• presynaptic D2 receptors inhibit NE release from the sympathetic nerve
• DA activates β1 receptors in heart
• DA
• low dose decrease PVR
• higher dose stimulates vascular α-receptors with
vasoconstriction
• therefore high dose DA can mimic actions of epinephrine
Non-CV actions of sympathetic agonists:
• Lung
• β2 activation results in relaxation of bronchial
smooth muscle
• Eye
• α-receptor activation
• mydriasis (dilation) - a1
• increased outflow of aqueous humor (decrease intraocular pressure) - a2
• β-agonists – no effect / β-antagonists decrease  production of aqueous humor
Non-CV actions of sympathetic agonists, cont:
- genitourinary
- α-receptors (α1) in base of bladder, urethral sphinchter, and prostate mediate contraction & urinary retention
- α-receptors (ductus deferens, seminal vesicles and prostate) involved in normal ejaculation and subsequent detumescence of erectile tissue as a result of sympathetic release of NE
- salivary glands – α-receptors regulating secretion of amylase & water
- sweat glands – adrenergic receptor activation = increased sweat production (sympathetic cholinergic)
Non-CV actions of sympathetic agonists, cont:
Metabolic effects of adrenergic receptor activation:
• fat cells
• β3 - receptor activation- increase lipolysis - increase FFA and glycerol in blood
• α2 decrease lipolysis via decrease cAMP
• liver
• β-receptor activation increase glycogenolysis - increase blood glucose
• pancreatic islet cells
• β-receptor activation increase insulin secretion
• α2-receptor activation decrease insulin
Non-CV actions of sympathetic agonists, cont:
• K+ regulation
• β2 receptors mediate cellular uptake of K+
• fall in blood K+ during stress & moderates rise in blood K+ during exercise (beta blockade may accentuate exercise-induced increase in blood K+)
• hormone secretion – e.g. insulin, renin
• β blockers may lower BP partially via decrease plasma
renin
• CNS – requires agonists to cross the bbb
Endogenous Catecholamines:
• epinephrine
• α & β agonist; potent vasoconstrictor & cardiac stimulant
• β1= + chronotropy & inotropy
• α = vasoconstriction
• β2 in skeletal muscle vessels = vasodilation
• physiologically functions primarily as a hormone
• norepinephrine
• α1 & α2 agonist; β1 agonist = epinephrine; little effect at β2 therefore increases systolic and diastolic pressure
• dopamine
• action on β1 in heart and α in the vasculature (at high doses) can mimic action of epinephrine
Sympathomimetic drugs (Direct Acting), phenylephrine:
- effectively pure α1-agonist
- not a COMT substrate – long duration of action relative to catecholamines
- mydriatic and decongestant; can increase bp
midodrine:
selective α1
• prodrug of desglymidodrine (α1-agonist)
• used in orthostatic hypotension related to impairment of ANS
methoxamine:
primarily α1
• activity similar to phenylephrine
• prolonged increase in bp (vasoconstriction) and vagally-mediated bradycardia
clonidine (Catapres); methyldopa; guanfacine; guanabenz:
- selective α2 agonists
* decrease bp through CNS effects
dexmedetomidine (Precedex):
- centrally acting α2 agonist
- sedation in intubated and ventilated ICU patients
- reduces opioid requirements for pain management
xylometazoline (Otrivin); oxymetazoline:
- α-agonists used as topical nasal decongestants (constriction of nasal mucosa)
- high doses may cause hypotension (central effect similar to clonidine)
isoproterenol (Isuprel):
- potent β receptor agonist (little α)
- chronotrope and inotrope & potent vasodilator (β receptor activation)
- increased cardiac output with fall in diastolic & mean bp/ slight increase in systolic (related to increased stroke volume & force of contraction)
beta1-selective agonists:
- beta1-selective
- dobutamine & prenalterol (partial agonist)
- increase cardiac output (β1) without decrease in bp (β2) minimizing reflex tachycardia (contrast with isoproterenol)
beta2 selective agonists:
- beta2 selective – important drugs in asthma
- albuterol (Ventolin)
- dilates bronchial smooth muscle via G-protein mediated increase in cAMP
beta3-selective agonists:
- beta3-selective – mirabegron
- bladder detrusor smooth muscle relaxes to allow for a larger bladder capacity.
- beta1 & beta2 activity at higher doses
Long-acting beta agonists (LABAs):
- Salmeterol
- Formoterol
- Bambuterol
- Indacaterol
- vilanterol
Mixed Acting sympathomimetics
- characteristics of direct acting (receptor binding and activating) and indirect acting (enhancing NE effects)
- ephedrine; pseudoephedrine
- phenylpropanolamine
Indirect Acting Sympathomimetics (amphetamine-like or “displacers”), amphetamine:
- racemic mix of phenylisopropylamine (D more potent than L)
- PK similar to ephedrine (highly bioavailable/long duration of action)
- readily distributes to CNS
- stimulates release of NE (& DA to lesser extent)
- marked stimulation of mood & alertness
- appetite depressant
methamphetamine:
• higher CNS to peripheral effects than amphetamine
phenmetrazine:
• anorexiant and drug of abuse
methylphenidate (Ritalin, Concerta):
- control symptoms of ADHD; narcolepsy
* effects and abuse potential similar to amphetamine
modanifil (Provigil):
- indicated for narcolepsy and excessive sleepiness
- inhibits NE & DA reuptake but also increases other transmitters associated with wakefulness serotonin, glutamate & GABA
tyramine:
- not readily bioavailable orally; metabolized by MAO in liver with a high first-pass clearance
- administered parentally; causes release of stored catecholamines with effects similar to NE
- blood pressure can be markedly increase in patients on MAO inhibitors
Catecholamine Reuptake Inhibitors:
atomoxetine, sibutramine, duloxetine, cocaine
atomoxetine (Strattera):
- selective NE reuptake inhibitor
- central clonidine-like affect to decrease central sympathetic outflow minimizes cardiovascular effects in most patients despite potentiating NE effects, peripherally
sibutramine:
• NE and DA reuptake inhibitor was approved as appetite suppressant for long term Rx of obesity – Removed from the Market due to increased incidence of heart attack and stroke
duloxetine (Cymbalta):
– depression/anxiety
• selective serotonin and norepinephrine reuptake inhibitor (SNRI)
• also indicted for pain of various etiologies (e.g., diabetic neuropathy)
cocaine:
- readily distributes to CNS
- shorter duration of action but more intense amphetamine-like psychological effect
- primary CNS action is to inhibit DA reuptake into neurons in the brain’s pleasure centers (e.g. nucleus accumbens, prefrontal cortex, amygdala)
Dopamine Agonists:
- levadopa
- converted to dopamine
- CNS actions important in treatment of Parkinson’s
- fenoldopam
- D1 receptor agonist
- peripheral vasodilation and used iv for treatment of severe hypertension
