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IMCP I > Adrenergic Receptor Agonists and Sympathomimetic Drugs > Flashcards

Adrenergic Receptor Agonists and Sympathomimetic Drugs Flashcards

1
Q

What do Sympathomimetic/Adrenergic Drugs do?

A

Mimic actions of epinephrine or norepinephrine at adrenergic receptors.

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2
Q

How are Sympathomimetic/Adrenergic classified?

A

• 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

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3
Q

What determines the effects of direct agonists?

A

1) Route of administration
2) Relative affinity for adrenergic receptor subtypes
3) Relative expression of receptor subtypes in the target tissue

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4
Q

What determines the effects of indirect agonists?

A

exhibit greater adrenergic effects in conditions of increased sympathetic tone and NE storage and release

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5
Q

Mechanism of Action:

A
  • 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
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6
Q

Comparative Catecholamine Potencie /Relative Affinities at Adrenoceptors:

A
  • α-receptors:
    • epinephrine ≥ norepinephrine&raquo_space; isoproterenol
  • β-receptors:
    • isoproterenol > epinephrine ≥ norepinephrine
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7
Q

Dopamine Receptors:

A
  • particular importance in the brain, splanchnic and renal vasculature
  • D1 & D5 (D1–like)
  • D2, D3 & D4 (D2–like)
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8
Q

Dopamine Receptors, cont:

A
  • D1 receptors stimulate adenylyl cyclase

* D2 receptors inhibit adenylyl cyclase, open K+ channels, decrease Ca++ influx

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9
Q

Adrenergic Agonist Receptor Selectivity:

A

Agonists generally selective for major types (α1,α2, β) but not for subtypes

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10
Q

Sympathomimetics (adrenergic agonists)

(Chemistry):

A

• 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

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11
Q

Sympathomimetics (Chemistry):

A

• 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

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12
Q

Sympathomimetics (Chemistry):

A
  • α-carbon substitutions can block oxidation via MAO
  • indirectly acting sympathomimetics
    • can displace endogenous catecholamines from storage sites in adrenergic nerves
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13
Q

Effects of Sympathomimetics - (Cardiovascular):

A

• 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

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14
Q

Effects of Sympathomimetics – (Cardiovascular), cont:

A

• 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

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15
Q

Effects of Sympathomimetics – (Cardiovascular), cont:

A
  • 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
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16
Q

Effects of Sympathomimetics (Cardiovascular), cont:

A

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)

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17
Q

Effects of Sympathomimetics – (Cardiovascular), cont:

A

• 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

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18
Q

Non-CV actions of sympathetic agonists:

A

• 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

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19
Q

Non-CV actions of sympathetic agonists, cont:

A
  • 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)
20
Q

Non-CV actions of sympathetic agonists, cont:

A

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

21
Q

Non-CV actions of sympathetic agonists, cont:

A

• 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

22
Q

Endogenous Catecholamines:

A

• 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

23
Q

Sympathomimetic drugs (Direct Acting), phenylephrine:

A
  • effectively pure α1-agonist
    • not a COMT substrate – long duration of action relative to catecholamines
    • mydriatic and decongestant; can increase bp
24
Q

midodrine:

A

selective α1
• prodrug of desglymidodrine (α1-agonist)
• used in orthostatic hypotension related to impairment of ANS

25
Q

methoxamine:

A

primarily α1
• activity similar to phenylephrine
• prolonged increase in bp (vasoconstriction) and vagally-mediated bradycardia

26
Q

clonidine (Catapres); methyldopa; guanfacine; guanabenz:

A
  • selective α2 agonists

* decrease bp through CNS effects

27
Q

dexmedetomidine (Precedex):

A
  • centrally acting α2 agonist
  • sedation in intubated and ventilated ICU patients
  • reduces opioid requirements for pain management
28
Q

xylometazoline (Otrivin); oxymetazoline:

A
  • α-agonists used as topical nasal decongestants (constriction of nasal mucosa)
  • high doses may cause hypotension (central effect similar to clonidine)
29
Q

isoproterenol (Isuprel):

A
  • 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)
30
Q

beta1-selective agonists:

A
  • beta1-selective
    • dobutamine & prenalterol (partial agonist)
    • increase cardiac output (β1) without decrease in bp (β2) minimizing reflex tachycardia (contrast with isoproterenol)
31
Q

beta2 selective agonists:

A
  • beta2 selective – important drugs in asthma
    • albuterol (Ventolin)
    • dilates bronchial smooth muscle via G-protein mediated increase in cAMP
32
Q

beta3-selective agonists:

A
  • beta3-selective – mirabegron
    • bladder detrusor smooth muscle relaxes to allow for a larger bladder capacity.
    • beta1 & beta2 activity at higher doses
33
Q

Long-acting beta agonists (LABAs):

A
  • Salmeterol
  • Formoterol
  • Bambuterol
  • Indacaterol
  • vilanterol
34
Q

Mixed Acting sympathomimetics

A
  • characteristics of direct acting (receptor binding and activating) and indirect acting (enhancing NE effects)
  • ephedrine; pseudoephedrine
  • phenylpropanolamine
35
Q

Indirect Acting Sympathomimetics (amphetamine-like or “displacers”), amphetamine:

A
  • 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
36
Q

methamphetamine:

A

• higher CNS to peripheral effects than amphetamine

37
Q

phenmetrazine:

A

• anorexiant and drug of abuse

38
Q

methylphenidate (Ritalin, Concerta):

A
  • control symptoms of ADHD; narcolepsy

* effects and abuse potential similar to amphetamine

39
Q

modanifil (Provigil):

A
  • indicated for narcolepsy and excessive sleepiness
  • inhibits NE & DA reuptake but also increases other transmitters associated with wakefulness serotonin, glutamate & GABA
40
Q

tyramine:

A
  • 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
41
Q

Catecholamine Reuptake Inhibitors:

A

atomoxetine, sibutramine, duloxetine, cocaine

42
Q

atomoxetine (Strattera):

A
  • selective NE reuptake inhibitor
  • central clonidine-like affect to decrease central sympathetic outflow minimizes cardiovascular effects in most patients despite potentiating NE effects, peripherally
43
Q

sibutramine:

A

• 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

44
Q

duloxetine (Cymbalta):

A

– depression/anxiety
• selective serotonin and norepinephrine reuptake inhibitor (SNRI)
• also indicted for pain of various etiologies (e.g., diabetic neuropathy)

45
Q

cocaine:

A
  • 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)
46
Q

Dopamine Agonists:

A
  • 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

IMCP I (32 decks)

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