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Sympathomimetics: indirect & direct
  • direct: bind directly to and activate adrenergic receptors
  • indirect: depend on release of endogenous cathecolamine
Adrenergic receptors
α1, α2 and β
  • α: epi>NE>>isoproterenol
  • β: isoproterenol>Epi> NE
  • (isoproterenol is β selective)
α1 adrenergic receptors

  • 3 subtypes: 1A, 1B, 1D
  • coupled to Gq
  • stimulate phospholipase C, which produces IP3 and DAG
  • IP3 stimulates release of IC Ca+2, activates kinases, muscle contraction
α2 adrenergic receptors
  • 3 subtypes: 2A, 2B, 2C
  • coupled to Gi, decrease in adenylyl cyclase
  • reduction of cAMP
β adrenergic receptors
  • 3 subtypes: 1, 2, 3
  • activation of all three leads to increased adenylyl cyclase and rise in IC cAMP
  • coupled to Gs regulatory proteins
Dopamine receptors
  • D1 and D2
  • D1 coupled to increased AC activity, and increased cAMP
  • D2 have opposite effect, reduce cAMP levels
α agonists

  • Phenylephrine & methoxamine (α12>>>>>β)
  • Clonidine (α21>>>>>β)
Mixed α and β agonists

  • NE (α12, β1>>β2)
  • Epi (α12, β1= β2)

β agonists
  • Dobutamine (β1 > β2>>>>>α)
  • Isoproterenol (β1 = β2>>>>>α)
  • Terbutaline, metaproterenol, albuterol, ritodrine (β2>>β1 >>>>>α)
Dopamine agonists
  • D1 = D2 >> β>>α
  • D1 >>D2
Structure of catecholamines and sympathomimetics
  • substitutions on amino group
  • increased size of alkyl subst increases β activity
  • ex: isoproterenol has isopropyl group on amino terminal: highly selective for β activity
Structure of catecholamines and sympathomimetics 
  • substitutions on benzene ring
  • OH groups on position 3 and 4 have max activity at α and β receptors.  removal reduces potency. (epi >>>phenylephrine)
  • sensitive to metab by COMT; removal of hydroxyl groups reduces COMT activity, increases bioavailability and duration of action
  • absence of OH group on ring increases distribution in CNS
Structure of catecholamines and sympathomimetics 
  • substitutions on Alpha C
  • blocks oxidation by MAO, prolongs action (esp non catecholamines)
  • enhances ability to displace catecholamines from storage sites
Structure of catecholamines and sympathomimetics 
  • substitutions on Beta C
  • Direct agonists usually have  -hydroxyl group (NE)
Adrenergic activation - organ system effects
  • CV system: BV's
  • Skin/splanchnic vessels: α r's contstrict - ↑ arterial R
  • Smooth muscle: β2 relaxes
  • Skeletal muscle: β2 vasodilation
  • Renal, splanchnic, coronary, cerebral arteries: D1 vasodilation
Adrenergic activation - organ system effects
  • CV System: heart

β1 activation:
  • Ca+2 influx, ↑pacemaker activity (SAnode), ↑contraction rate.
  • pacemaker activity inc →arrhythmias
  • CV in AV node ↑, refrac period ↓
  • ↑Contractility
  • shorter, more powerful systole
  • work and CO↑, O2 consump ↑
  • may be in absence of reflex (gang blockade).  normal reflex can change pressure by increased vagal discharge.
Adrenergic activation - organ system effects
  • Blood Pressure - Pure α agonist
  • ↑vasc R, ↓venous C, dose dep rise in BP
  • ↑BP→ reflex ↑ vagal tone, ↓HR
  • may not result in ↓CO, since inc venous return increases SV and stim α receptors again (↑contractility!)
  • normal pt: reflex. hypotensive pt might not get reflex bc BP rise doesn't exceed normal!

Adrenergic activation - organ system effects
  • Blood Pressure - β selective agonist
  • Isoproterenol
  • ↑CO
  • peripheral β2 activation → ↓peripheral R (dilation of skeletal muscle vessels!)
Adrenergic activation - organ system effects
  • Blood Pressure - mixed receptor agonist
  • epi/NE
  • more complex response
Adrenergic activation - organ system effects
  • Eye
  • α1 - mydriasis d/t radial pupillary dilator muscle
  • α2 agonist ↓ aq humor production
  • β agonist ↑ prod aq humor and ↑ aq outflow
  • α & β agonist ↓IOP (ex: epi, but has systemic SE!)
Adrenergic activation - organ system effects
  • Respiratory tract
  • β2 - bronchial smooth muscle relaxation (most pronounced in diseases like asthma)
  • α recep in BV's of URT mucosa results in decongestant effect.
Adrenergic activation - organ system effects
  • GI tract
  • α & β receptor agonists cause relaxation of GI smooth muscle
  • Pyloric & ileocecal sphincters are contracted
Adrenergic activation - organ system effects
  • GU tract
-pregnant: useful for preterm labor
  • α1 - contraction of uterus
  • β2 - relaxation of uterus
-Urinary continenceα1 bladder base, urethral phincter, prostate
-β2 in bladder wall - relaxation
-Ejac - depends on normal α recept function
Adrenergic activation - organ system effects 
  • Exocrine glands
  • sweat glands secrete in response to stress, not T, activated by adrenergic stimulation
Adrenergic activation - organ system effects 
  • Metabolic effects
  • β3 activation - ↑lipolysis, FA and glycerol release into circulation
  • Sympathomimetics ↑glycogenolysis & gluconeogenesis in liver
  • K+ uptake in cells ↑
  • Pancreas:
α2 stim ↓insulin secr
β2 stim ↑insulin secr
**epi is a good inhibitor**
Adrenergic activation - organ system effects 
  • Endocrine & leukocytosis
Kidney: Renin secretion
  • stim by β1
  • inhib by α2
Adrenergic activation - organ system effects 
  • CNS
depends on ability to X BBB (no OH's on benzene ring)
  • α2 activation in brain stem ↓symp outflow - causes hypotension
  • catecholamines don't x BBB unless high rates of infusion
  • non-cat's (amphetamine, methylphenidate) enter readily, basically uppers, appetite suppressant, high dose makes you crazy.  Long term use leads to damage of DA receptors, since effects are d/t ↑ DA rather than α or β stimulation.
  • vasoconstrictor, cardiac stimulant, with variable physio consequences depending on method of administration and dose
  • rapid IV infusion, small dose, slow IV infusion/subQ doses
Sympathomimetic agents
  • Epinephrine: Rapid IV infusion
  • β1 receptors inc HR and F of contraction: BP ↑ rapidly, proprtional to dose
  • Systolic↑ > diastolic ↑
  • α1: ↑ Peripheral resistance - induces arterial constriction in skin & viscera
  • HR may decr due to reflex vagal discharge on heart
Sympathomimetic agents
  • Epinephrine: Small doses
  • β2 vasodilation in skeletal muscle: ↓ diastolic BP
Sympathomimetic agents 
  • Epinephrine: Slow IV infusion/SubQ
  • Subq: absorption reduced d/t local vasoconstriction: ↑ systolic P
  • β2: vasodilation - ↓diastolic P
  • MAP doesn't change, no baroreceptor reflex
  • ↑: HR, CO, SV, F of contraction, O2 consump
Non CV effects of Epinephrine
  • ↑blood glucose, lactate
  • glucagon secretion enhanced
  • circulating FA's inc
  • β2 stim in bronchial smooth muscle - bronchodilation
  • exercise: epi released from adrenal medulla; body adapts to demands of exercise (↑ blood to muscles, lungs, bronchodilation, inc metabolism)
Epinephrine: Therapeutic uses
  • Metab rapidly by MAO, COMT, brief duration if IV
  • emergency asthma subQ/IV (better agents available)
  • prolongs actions of local anesthetics (local vasoconstriction)
  • tx open angle glaucoma (inc ouflow, decr prod of aq humor)
  • Emergency cardiac arrest/heart block, used to revert to normal rhythm by IV into central line
  • DOC anaphylactic shock, hypersensitivity rxn
Sympathomimetic agents 
  • Norepinephrine
  • α & β1: ↑HR, F of contrac, peripheral Rreflex response slows HR, but BP, F still increase.
  • β2 - little effect
  • therapeutic use: ↑BP in acute hypotensive state - short half life, metab by MAO, COMT
Sympathomimetic agents 
  • Isoproterenol
  • β selective, little α activity
  • β1: ↑HR, F contraction
  • β2(vascular): ↓Peripheral R
  • net: ↑CO, ↓diastolic & MAP, slight systolic P
  • lead to palpitations, sinus tachy, arrhythmias

Therapeutic uses of Isoproterenol
  • rel resistant to MAO, but metab by COMT in liver.  half life longer than epi, NE, DA
  • used as bronchodilator, but better agents for that
  • emergency bradycardia, heart block, ventricular arrhythmia (pacemakers better
Sympathomimetic agents 
  • Dopamine
  • activates D1 & D2 receptors
  • low dose D1: dilation: renal, coronary, mesenteric arteries; GFR, renal BF, Na+ excretion inc
  • Presyn D2 at adrenergic n. terminals inhibit NE release
  • higher doses activate β1, on heart - +inotropic effect.
  • activate α recep in high doses: inc peripheral R
  • can stim inc NE release, heart actions.  Can't x BBB.
Therapeutic uses of Dopamine
  • only given IV! titration necessary
  • vasodilatory, & at high doses, vasopressor; used to tx severe congestive heart failure (esp in pt with oliguria & normal peripheral vasc R)
  • beneficial for septic/cardiogenic shock
  • monitor pt for chg in urine flow, tachy, arrhythmias - slowing or termination of infusion is necessary
  • used to tx/prevent acute renal failure, no longer.
  • brief duration of action, intensity correlated with rate of infusion
Sympathomimetic agents 
  • Fenoldopam
  • D1 DA receptor selective agonist
  • short duration of action
  • ↓BP in severe HTN
  • no affinity for D2, alpha1 or beta
  • some affinity for α2
Sympathomimetic agents 
  • Dobutamine
  • synthetic catecholamine
  • β1 selective, some α activity
  • no dopaminergic activity
  • full agonist on β1
  • different isomer activates or antagonizes α1
  • racemic mix on heart ↑ F of contraction more than isoproterenol
Therapeutic uses of Dobutamine
  • ST tx of cardiac decompensation after heart surgery, in CHF or acute MI
  • ↑ CO & SV in these pts without effect on HR
  • half life 2min
Sympathomimetics: α1 selective agents
  • Phenylephrine
  • diff from epi: missing one OH on benzene
  • resists COMT metab (not MAO)
  • ↑ oral availability, ↓potency
  • vasoconstriction, ↑BP w/ sinus bradycardia
Therapeutic uses of Phenylephrine
  • IV - vasopressor w/ no ino/chrono-tropic effects on heart
  • α1 mediated vasoconstriction leads to reflex ↓HR - tx paroxysmal ventricular tachy.
  • ↓splanchnic blood flow in septic shock (DA, NE better)
  • advantage in treating shock w/ assoc tachy
  • cold remedies: decongestant (vasoconstriction in nasal mucosa)
  • mydriatic in eye drops
Sympathomimetics: α1 selective agents
  • Metaraminol
  • Direct:agonist at α receptors
  • Indirect: increases NE release from adrenergic terminals
Therapeutic uses of Metaraminol
  • Reverse/prevent hypotension assoc with spinal anesthesia
  • adjunct for hemorrhagic hypotension,
  • hypotension assoc w/medication/surgical complication
  • shock assoc with brain damage d/t trauma, tumor
Sympathomimetics: α1 selective agents
  • Midodrine
  • converted to desgymidodrine, an α1 selective agonist
  • causes ↑ BP through stimulating arterial and venous contraction
Therapeutic uses of Midodrine
  • for autonomic insufficiency and postural hypotension
  • cancels fall in P when pt is standing, may cause HTN if pt is supine...dosing should be avoided prior to bedtime
Sympathomimetics: α2 selective agents
  • Clonidine
  • activates α2 receptors in brain stem - depresses sympathetic outflow: ↓ periph R, renal vasc R, HR, BP
  • IV of high dosecaues acute rise in BP (d/t postsyn α2 recep) on vasc smooth muscle - quickly followed by longer lasting hypotensive effect)
  • rise in BP does not occur with oral administration!
Therapeutic uses of Clonidine
  • **antihypertensive** oral
  • dx of phaeochromocytoma
  • epidurally - analgesic for CA pt refractive to opioid tx
  • ADHD
  • ↓symp nervous activity assoc with opiate, nicotine, alcohol withdrawal
  • vasc headaches, diabetic dia, glaucoma, ulcerative colitis, tourette's syndrome, hot flashes.
Sympathomimetics: α2 selective agents
  • Guanfacine
  • more selective α2 agonist than clonidine
  • same mechanism, same applications
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