Adrenergic Receptor Agonists and Sympathomimetic Drugs

Question 1

What do Sympathomimetic/Adrenergic Drugs do?

Answer 1

Mimic actions of epinephrine or norepinephrine at adrenergic receptors.

Question 2

How are Sympathomimetic/Adrenergic classified?

Answer 2

• 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

Question 3

What determines the effects of direct agonists?

Answer 3

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

Question 4

What determines the effects of indirect agonists?

Answer 4

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

Question 5

Mechanism of Action:

Answer 5

• 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

Question 6

Comparative Catecholamine Potencie /Relative Affinities at Adrenoceptors:

Answer 6

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

Question 7

Dopamine Receptors:

Answer 7

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

Question 8

Dopamine Receptors, cont:

Answer 8

• D1 receptors stimulate adenylyl cyclase

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

Question 9

Adrenergic Agonist Receptor Selectivity:

Answer 9

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

Question 10

Sympathomimetics (adrenergic agonists)

(Chemistry):

Answer 10

• 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

Question 11

Sympathomimetics (Chemistry):

Answer 11

• 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

Question 12

Sympathomimetics (Chemistry):

Answer 12

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

Question 13

Effects of Sympathomimetics - (Cardiovascular):

Answer 13

• 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

Question 14

Effects of Sympathomimetics – (Cardiovascular), cont:

Answer 14

• 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

Question 15

Effects of Sympathomimetics – (Cardiovascular), cont:

Answer 15

• 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

Question 16

Effects of Sympathomimetics (Cardiovascular), cont:

Answer 16

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)

Question 17

Effects of Sympathomimetics – (Cardiovascular), cont:

Answer 17

• 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

Question 18

Non-CV actions of sympathetic agonists:

Answer 18

• 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

Question 19

Non-CV actions of sympathetic agonists, cont:

Answer 19

• 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)

Question 20

Non-CV actions of sympathetic agonists, cont:

Answer 20

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

Question 21

Non-CV actions of sympathetic agonists, cont:

Answer 21

• 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

Question 22

Endogenous Catecholamines:

Answer 22

• 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

Question 23

Sympathomimetic drugs (Direct Acting), phenylephrine:

Answer 23

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

Question 24

midodrine:

Answer 24

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

Question 25

methoxamine:

Answer 25

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

Question 26

clonidine (Catapres); methyldopa; guanfacine; guanabenz:

Answer 26

* selective α2 agonists | * decrease bp through CNS effects

Question 27

dexmedetomidine (Precedex):

Answer 27

* centrally acting α2 agonist * sedation in intubated and ventilated ICU patients * reduces opioid requirements for pain management

Question 28

xylometazoline (Otrivin); oxymetazoline:

Answer 28

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

Question 29

isoproterenol (Isuprel):

Answer 29

* 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)

Question 30

beta1-selective agonists:

Answer 30

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

Question 31

beta2 selective agonists:

Answer 31

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

Question 32

beta3-selective agonists:

Answer 32

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

Question 33

Long-acting beta agonists (LABAs):

Answer 33

* Salmeterol * Formoterol * Bambuterol * Indacaterol * vilanterol

Question 34

Mixed Acting sympathomimetics

Answer 34

* characteristics of direct acting (receptor binding and activating) and indirect acting (enhancing NE effects) * ephedrine; pseudoephedrine * phenylpropanolamine

Question 35

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

Answer 35

* 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

Question 36

methamphetamine:

Answer 36

• higher CNS to peripheral effects than amphetamine

Question 37

phenmetrazine:

Answer 37

• anorexiant and drug of abuse

Question 38

methylphenidate (Ritalin, Concerta):

Answer 38

* control symptoms of ADHD; narcolepsy | * effects and abuse potential similar to amphetamine

Question 39

modanifil (Provigil):

Answer 39

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

Question 40

tyramine:

Answer 40

* 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

Question 41

Catecholamine Reuptake Inhibitors:

Answer 41

atomoxetine, sibutramine, duloxetine, cocaine

Question 42

atomoxetine (Strattera):

Answer 42

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

Question 43

sibutramine:

Answer 43

• 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

Question 44

duloxetine (Cymbalta):

Answer 44

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

Question 45

cocaine:

Answer 45

* 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)

Question 46

Dopamine Agonists:

Answer 46

* 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