sympathomimetics Flashcards
what are the sympathetic neurotransmitters?
adrenergic: norepinephrine and epinephrine
derivative of tryptophan
serotonin
monoamine
-contain one amino group connected to aromatic ring by two-carbon chain
-serotonin, dopamine, norepinephrine, epinephrine, (histamine)
derivatives of tyrosine
dopamine, epinephrine, and norepinephrine
cathecholamine
-monoamine with catechol group (benzene with two hydroxyl groups)
-dopamine, norepinephrine, epinephrine
two types of metabolic enzymes
COMT: catechol-o-methyltranferase
MAO: monoamine oxidase
COMT
Highest activity in liver, important for metabolism of
circulating and administered catecholamines. Also at
nerve terminals.
MAO
Surface membrane protein of mitochondria
High concentrations in nerve terminals, liver, kidney, gut
receptor selectivity of albuterol
Beta2-selective
receptor selectivity of dobutamine
beta1-selectivity
receptor selectivity of isoproterenol
nonselective beta
receptor selectivity of clonidine
alpha2-selective
receptor selectivity of phenylephrine
alpha1-selective
receptor selectivity of norepinephrine
nonselective alpha
direct acting adrenergic receptor agonist
-norepinephrine (levophed)
-epinephrine (adrenalin)
adrenergic receptor summary alpha 1
-Gq
-vasoconstriction (innervated)
-pupillary dilation
-ejaculation
-inhibition of micturition
-GI inhibition
adrenergic receptor summary alpha 2
-GI
-vasoconstriction (innervated)
-prejunctional inhibition of NE release
-in CNS: decrease CV and SNS input
adrenergic receptor summary beta 1
-Gs
-cardiac stimulation (innervated)
-secretion of renin
adrenergic receptor summary beta 2
-Gs
-cardiac stimulation (uninnervated, minor)
-bronchodilation
-uterine relaxation
-GI inhibition
-vasodilation (uninnervated)
norepinephrine (NE)
-activates alpha and beta receptors little afinity got beta 2
-alpha 1 agonist: vasoconstriction leading to a rise in blood pressure)
-Beta 1 agonist: cardiac stimulation by increase in force and conduction
epinephrine (E)
-activates alpha and beta receptors
-α1 agonist: Vasoconstriction leading to a rise in blood pressure
-β1 agonist: Cardiac stimulation by increasing in force, rate and conduction
-β2 agonist: Vasodilation leading to a fall in blood pressure and bronchodilation
dopamine (D)
*Lower doses
-D1 agonist (Vasodilation in renal, mesenteric and coronary arteries increasing blood flow)
-β1 agonist (Cardiac stimulation by increasing force, rate and conduction)
*High doses
-α1 agonist (Vasoconstriction leading to a rise in blood pressure)
direct acting adrenergic receptor agonist: norepinephrine
-potent alpha anf beta 1 receptor agonist
-substrate for MAO and COMT
-parenteral administration
-used as a pressor
-sodium bisulfite used in preparations to prevent oxidation
direct acting adrenergic receptor agonist: epinephrine
-potent alpha, beta 1, and beta 2 receptor agonist
-substrate for MAO and COMT
-parental administration
-sodium bisulfite used in preparation to prevent oxidation
-available as many salt: hydrochloride, nitrate, bitartrate
-uses: anaphylaxis, in combination with local anesthesics
actions of epinephrine
-Lower concentrations: effects at b 1 and b 2 predominate
-higher concentrations: effects at a 1 predominate
clinical use of epinephrine
Treatment of acute anaphylaxis or cardiac arrest; adjunct with local anesthetics
problems of epinephrine
-not orally active due to COMT and MAO breakdown in liver (first-pass metabolism)
epinephrine counters hypoglycemia
beta 2: glycogenolysis, glyconeogenesis —> increased glucose
alpha 2: inhibits insulin secretion
dipiveferin
-epinephrine dipivalate, propine
-infant glaucoma (not in US)
-lipophilic
-activated by esterase
actions of D1 agonist dopamine (intropin)
-Renal D1-receptor agonist, renal vessel dilation
-Direct and indirect b1-agonist, a1-agonist (high dose):
Sympathomimetic activity
-Cardio stimulate & systemic vasoconstrictor outside the kidney
clinical use of D1 agonsit dopamine
-shock
-acute congestive heart failure
-must be given IV
adrenergic receptor subtype -alpha 1 signal pathway
-signal via Gq pathway
-mobilize Ca++ from intracellular stores
-activate PKC
-found on: vascular smooth muscles, genitourinary smooth muscles, intestinal smooth muscles, heart, liver
-mediates vasoconstriction
alpha 1 receptors are clinically manipulated for
-agonist: nasal decongestion, vascular failure in shock and supra-ventricular tachycardia
-antagonist: hypertension, benign prostatic hyperplasia, pheochromocytoma
clinical use of phenylephrine
-nasal decongestant
-Mydriasis without cycloplegia
-Pressor
-Vasoconstrictor in regional anesthesia
administration of phenylephrine
-parenteral, oral, local
-substrate for MAO
direct alpha 1 agonist
phenylephrine
problems of phenylephrine
few: although not a very effective decongestant
direct acting adrenergic receptor agonst: a 1 receptor agonists: 2-aralkylimidazolines
-partial agonist at alpha receptors
-administered locally/topically to promote vasoconstriction
-basic nature of imidazoline ring causes compounds to exist in ionized form at physiologic pH
-tachyphylaxix/ desensitization
uses: nasal and ophthalmic decongestants
adrenergic receptor subtypes: beta 1,2,3
signal
-signal through Gs
-activate adenylyl cyclase
-increase cAMP
-increase cAMP dependent protein kinase activity
-results in phosphorylation
-ion channels and other proteins
Beta 1 receptor found in
heart:
-Increases force of contraction (inotropy)
-Increases heart rate (chronotropy)
-increases conduction velocity in AV node
kidney:
-increases renin release
clinical manipulated for beta 1 receptors
-agonist: shock, congestive heart failure
-antagonist: hypertension, angima, arrhythmias, congestive heart failure
beta 2 receptors are found in
smooth muscles: relaxation, especially bronchial smooth muscle
vasodilation
beta 2 receptors are clinically manipulated for
-agonist: asthma, premature labor
-antagonist: glaucoma
beta 3 receptor are found in
-urinary bladder: relaxation, prevention of urination
beta 3 receptors are clinically manipulated for
agonist: overactive bladder
direct acting adrenergic receptor agonist: beta receptor agonist: isoproterenol
-non-selective beta receptor agonist
-bronchodilation
-increased cardiac output
-metabolized by conjugation reactions (phase II) and by COMT
-not sensitive to MAO
-administration: oral, parenteral, local
-uses: asthma, chronic obstructive pulmonary disease (COPD), cardiostimulant
action of isoproterenol
b 1 and b 2 receptor agonist;
*Positive inotropic & chronotropic effects, thereby increasing CO
*In peripheral vessels, stimulation of β 2 -receptors results in vasodilation &
reduced peripheral resistance (may cause blood pressure to fall)
clinical use of isoproterenol
*Emergency use to increase the heart rate in patients with bradycardia or heart
block before pacemaker implantation
*Patients with systolic dysfunction & slow heart rates with high systemic vascular
resistance: after cardiac surgery in patients who previously used β-blockers
*Asthma and COPD
selective beta 2 receptor agonist: resorcinol derivatives
-selective beta 2 receptor agonist
-bronchodilation
-cardiac effects observed only at high doses
-not metabolized by MAO and COMT
-longer duration of actionn than isoproternol
-administration: oral, parenteral, local
-uses: asthma, COPD, terbutaline used as tocolytic(prevent premature labor)
selective Beta 2 receptor agonist: meta hydroxymethyl derivatives
-selective beta 2 receptor agonist
-bronchodilation
-cardiac effects observed only at high doses
-not metabolized by MAO and COMT
-longer duration of action than isoproterenol
-administration: oral, local
-uses: asthma, COPD
mirabegron
direct acting beta 3 receptor agonist
long acting beta 2 receptor agonsit
-Selective b2 receptor agonists
-Bronchodilation
-Not metabolized by MAO or COMT
-Onset of action:
Salmeterol 10-20 min
Formoterol < 5 min
-Longer duration of action
-Administration: inhaled (metered-
dose inhaler and powder)
-Uses: Long-term Asthma, COPD
-Not recommended for acute
treatment of asthma symptoms
action of albuterol and terbutaline
beta 2 agonist
clinical use of mirabegron
overactive bladder
mixed beta 1 and alpha 1 receptor agonist
-Dopamine derivative
-Available as a racemic mixture
-(+)-enantiomer: potent b1 receptor agonist
-(-)-enantiomer: potent a1 receptor
agonist, potency for b receptors reduced 10X
-racemic exerts a much stronger inotropic than chronotropic effect
-Metabolized by COMT and conjugation, not sensitive to MAO
-Short half-life (~2 min)
-Administered: i.v. infusion (why?)
-Use: Acute heart failure, shock, Labaoratory “stress test”
clinical use of albuterol and terbutaline
-Asthma: albuterol and terbutaline
-Tocolytic: terbutaline (to relax uterus during premature labor)
problems of albuterol and terbutaline
minor cardiac stimulation
problems of mirabegron
-slow onset (8 weeks)
-hypertension
alpha 2 receptor clonidine
-imidazolidine
-selective alpha 2 receptor agonist
-basicity of the guanidine group (pKa 13.6) is decreased to Pka 8 because of the attachment to the dichlorophenyl ring
-activation of alpha 2 receptors in CNS decreases SNS activity and presynapes
action of clonidine
-a 2 receptor agonist; in the CNS (brainstem) to decrease sympathetic nervous
system activity to the heart and blood vessels
- presynaptic a 2 receptor, decrease cAMP, inhibit certain calcium channels
(decrease vesicular release), activate certain potassium channels
(hyperpolarize)
clinical use of clonidine
-hypertension
-neuropathic pain/ opiate withdraw
-ADHD
administration of clonidine
oral, parenteral, transdermal
problems with clonidine
hypotension, sedation, dry mouth – withdrawal syndrome sometimes seen after prolonged use (hypertension, tachycardia, angina or myocardial infarction)
methyldopa analpha 2 receptor agonist
-A prodrug metabolized to active a2 receptor agonist, (1R, 2S)-a- methylnorepinephrine
-Act at CNS a2 receptors to decrease sympathetic outflow
-Water soluble, ester hydrochloride salt Methyldopate is used for parenteral solutions
-Administration: Methyldopa, oral; Methyldopate; parenteral
-Uses: Hypertension (especially during pregnancy)
alpha 2 adrenergic agonist reduce blood pressure by reducing sympathetic output from the brain
-inhibition of NE release
-decreased sympathetic tone in CNS
-decr HR
-decr contractility
-decr renin release
-decr vasoconstriction
alpha 2 receptor agonist guanabenbz and guanfacine
-“Open-ring” imidazolidines
-Two atom bridge to the guanidine group decreases the pKa so that the drug is mostly non-ionized at physiological pH
-Guanabenz has the shortest t-1/2 at ~ 6 hours. Half-life of clonidine and guanfacine is 12-16 hours
-Administration: oral
-Uses: Hypertension, ADHD (guanfacine)
action of brimonidine
-a2 receptor agonist
-Inhibits aqueous humor production (acute effect) and stimulate
aqueous humor outflow (chronic effect)
clinical use of brimonidine
glaucoma
problems ofbrimonidine
allergic conjunctivitis
indirect acting sympathomimetics
-amphetamine, pseudoephrine ephedrine, tyramine
-promotes release of NE via reverse action of plasma membrane transporter
-clinical uses: amphetamines, ADHD, narcolepay, anorexiant, nasal decongestants
what is one of the most potent stimulators
amphetamine
clinical use of amphetamine and methamphetamine
-Narcolepsy
-ADHD (first-line: low doses increase wakefulness, alertness, ability to concentrate)
-also used as appetite suppressants but not approved for this use
problems of Indirect Sympathomimetics:
Ephedrine and Pseudoephedrine
Increased blood pressure, increased heart rate via enhanced NE signaling
from SNS
ephedrine and pseudoephedrine are ____- active
orally
problems of amphetamine and methamphetamine
-At therapeutic doses: anorexia, poor growth, sleep disturbances, jitteriness
-At toxic dose
-Increased blood pressure, increased heart rate via enhanced NE signaling:
Potential for stroke, cardiac arrhythmias, myocardial infarction, and sudden death
-From CNS: agitation, confusion, addiction (Schedule II drug). Amphetamine group
of drugs release dopamine which lead to CNS effects
ADHA
characterized by excessive
motor activity, difficulty in sustaining attention, and impulsiveness. (low DA)
Indirect-acting sympathomimetics:
D-(-)-Ephedrine vs. L-(+)-Pseudoephedrine
-Alkaloid obtained from the stemsof Ephedra. Also found in mahuang.
-D-(-)-Ephedrine has desired ( R) configuration at b-OH and (S)- configuration at the a carbon, so has direct alpha and beta agonist activity at adrenergic receptors
-L-(+)-Pseudoephedrine is the (S,S)-diastereoisomer; (S)- configuration of b-OH reduces agonist activity-major mechanism is via reversal of the transporter
clinical use of Indirect Sympathomimetics:
Ephedrine and Pseudoephedrine
-Pseudoephedrine (Sudafed): nasal decongestion
-Ephedrine (Ephedra): has direct alpha and beta effects. has been used as a “natural product” for weight loss and to increase muscle strength– has led to increased blood pressure, strokes, deaths. Banned in dietary supplements in US in 2004
norepinephrine transporter inhibitors
cocaine, methyphenidate, atomoxetine
action of cocaine
-Block NET, DAT
-Decrease uptake
-Enhance NE signaling by keep more transmitter in synaptic cleft
important take away from indirect acting sympathomimetics
co-administration with other indirect acting drugs can lead to a hypertensive crisis
wine/cheese effect
-tyramine high levels in beer, cheese, wine, and many processed meat or sausage
-Tyramine is an indirect sympathomimetic
agent and can produce strong effects if it
reaches sympathetic nerve terminals.
-Normally, almost all ingested tyramine is
rapidly broken down by MAO in the liver.
-MAO inhibitors decrease the breakdown of
tyramine resulting in a bolus release of NE
potentially resulting in a hypertensive crisis
clinical use of cocaine
Local anesthetic (sodium channel blocker) for nasal mucosa and vasoconstriction
side effects of cocaine
Peripheral
-Increased blood pressure and heart rate
-Potential for stroke, cardiac arrhythmias, myocardial infarction and sudden death
(Len Bias 1986, 2 nd overall pick)
Central: Euphoria, Increase alertness, Arousal, Addictive
action of methylphenidate
- Blocks NE and DA reuptake transporters that transport monoamines from synaptic cleft
back to presynaptic terminal
-Overall effect: enhance NE and DA signaling
clinical use of methylphenidate
ADHD, narcolepsy (similar to amphetamine)
Recommended for preschool children with ADHD
problems with methylphenidate
- (similar to amphetamine)
- Priapism (prolonged penile erection): rare but serious
- Also addictive potential (C-II drug) via enhanced DA signaling
clinical use of atomoxetine
attention deficit hyperactivity disorder (ADHD)
-note: not a controlled substance and stimulants so isnt associates with agitation or sleeplessness
action of atomoxetine
selective inhibitor of NET and thus enhances NE levels
problems of atomoxetine
-Black-box warning for suicidal ideation
-Priapism (prolonged penile erection): rare but serious
-May take longer than stimulants for effect
-May be less effective than stimulants
other non stimulants for ADHD
Guanfacine (Intuniv): alpha2 agonist
Clonidine (Kapvay): alpha2 agonist
stimulants for ADHD
Amphetamine/methamphetamine
Methylphenidate
