Sympathomimetic Agents Flashcards
Alpha1 adrenergic Receptors
GPCR Gq -> activation of PLC/IP3/DAG pathway
alpha1A/B/D subtypes
found on postsynaptic membranes - predominantly in vascular beds of skin and splanchnic vessels, bladder, a pregnant uterus, prostate and iris muscle.
action is contraction of smooth muscle - i.e. like piloerector muscles
which adrenergic receptor activates the G-alpha-s Adenylyl cyclase protein and which inhibits?
beta receptors activate AC causing an increase of IC cAMP
Alpha2 receptors inhibit AC leading to the opposite effect
alpha2 adrenergic receptors
alpha2A/B/C subtypes
found in adrenergic and cholinergic nerve terminals, some vascular smooth muscle, fat cells, pre-synaptic and post-synaptic CNS neurons and platelets/leukocytes.
Acts via Gi GPCR pathway to inhibit adenylyl cyclase activity and neurotransmitter release
in some sites also activates PLC/MAPK pathways - smooth muscle
Beta adernergic receptors
all subtypes - beta1/2/3 - increase activity of adenylyl cyclase
effects - increases HR and heart contractility, stimulates smooth muscle relaxation and enhances secretion of insulin
Beta1 Receptors
found predominately in heart but also juxtaglomerular cells of kidney (activates renin-angiotensin-aldosterone pathway to increase BP)
Beta2 Receptors
found on smooth muscle and pre-/post-synaptic membranes.
Causes smooth muscle relaxation, vasodilation in skeletal muscle, bronchodilation, relaxation of uterine smooth muscle, and decreases motility of the GI tract.
enhances insulin secretions
causes platelet aggregation
found on presynaptic neurons -> release of neurotransmitters (function as auto or heteroreceptors)
Beta3 receptors
On postsynaptic membrane
predominately on adipocytes causing breakdown of TAGs and thermiogenesis
also causes relaxation of detrusor muscle
has a higher affinity for NE than for Epi
resistant to antagonist - propranolol
Dopamine
a central neurotransmitter that regulates rewards, emotion, cognition, memory, and motor activity
circulating DA in periphery mainly binds D1 receptors
two main receptor types - D1 and D5 and D2/3/4
Dopamine Receptors
D1 and D5 Receptors - GsPCR increases adenylyl cyclase, increases cAMP
(causes vasodilation in renal, coronary, mesenteric and cerebrovascular arteries)
D2, D3, and D4 Receptors - GiPCRs decrease activity of adenylyl cyclase causes the activation of hyperpolarizing K+ channels and inhibition of Ca++ channels
(modulates neurotransmission of CNS)
indirect-acting adrenergic agonists
amphetamine and tyramine are releasing agents
cocaine is an uptake inhibitor
selegiline is an MOA inhibitor
entacapone is an COMT inhibitor
what is the mixed-acting adrenergic agonist?
ephedrine - alpha1/2, beta1/2 and releasing agent.
epinephrine - what are it’s pharmacokinetics?
methylated amino-group enhances beta2 activity
exhibits a dose dependent response
Has equal affinity for Beta 1 and 2 receptors, slightly less affinity for alpha 1 and 2
A - given subcutaneous, intramuscular, IV and inhalation. D - does not cross BBB, M- degraded by MAO and COMT. E - excreted in urine. Onset is rapid, slowest being subcutaneous 5-10 minutes
epinephrine - what are it’s pharmacokinetics?
methylated amino-group enhances beta2 activity
exhibits a dose dependent response
Has equal affinity for Beta 1 and 2 receptors, slightly less affinity for alpha 1 and 2. Acts preferentially on Beta2 receptors
A - given subcutaneous, intramuscular, IV and inhalation. D - does not cross BBB, M- degraded by MAO and COMT. E - excreted in urine. Onset is rapid, slowest being subcutaneous 5-10 minutes
How does epinephrine cause an increase in systolic blood pressure?
skeletal muscle is rich in beta2 receptors
epinephrine acts directly on cardiac tissue to increase heart rate and strength of ventricular contraction
causes alpha receptor mediated vasoconstriction in much of the bodies smooth muscle, precapillary vessels of the skin, mucosa, kidney and the mesentery and veins.
How does epinephrine cause a decrease in diastolic BP?
By activation of Beta2 receptors in skeletal muscle vasculature inducing vasodilation which decreases peripheral resistance. The decrease in peripheral resistance decreases diastolic blood pressure
epinephrines cardiac, respiratory, metabolic, CNS effects, effect on peripheral circulation and effect on BP?
Cardiac: increases HR, stroke volume, cardiac output and coronary blood flow. Can cause arrhythmia (Beta1)
Respiratory:
bronchodilation (Beta2)
BP: increases systolic pressure, decreased diastolic pressure, mean pressure is only slightly elevated, mean pulmonary pressure is elevated.
Metabolic: increases oxygen consumption, blood glucose, and lactic acid. Decreases plasma K+
peripheral circulation: decreased or unchanged TPR, slight increase of cerebral blood flow, increase in skeletal muscle flow and decrease in cutaneous and renal blood flow
effect of epinephrine at physiologic concentrations - slow IV infusion
beta2 mediated enhanced blood flow to skeletal muscles which decreases peripheral resistance and diastolic BP
Beta1 mediated increased HR, stroke volume, cardiac output and heart work
typically not much change in MAP
epinephrine at intermediate rates
causes alpha mediated vasoconstriction in skeletal muscles as well
theres a compensatory reflex that can counter the epinephrine caused increase in heart rate
rapid infusion of epinephrine
a high concentration of epinephrine causes the alpha receptor effects to be predominate.
TPR is increased, HR and heart contractility is increased.
systolic and diastolic blood pressure is increased
reflex homeostatic decreases HR
epinephrines cardiac, respiratory, metabolic, CNS effects, effect on peripheral circulation and effect on BP?
Cardiac: increases HR, stroke volume, cardiac output and coronary blood flow. Can cause arrhythmia (Beta1)
Respiratory:
bronchodilation (Beta2)
BP: increases systolic pressure, decreased diastolic pressure, mean pressure is only slightly elevated, mean pulmonary pressure is elevated.
Metabolic: increases oxygen consumption, blood glucose, and lactic acid. Decreases plasma K+
peripheral circulation: decreased or unchanged TPR, slight increase of cerebral blood flow, increase in skeletal muscle flow and decrease in cutaneous and renal blood flow
CNS - increases respiration and subjective sensations: causes anxiety - headache, restlessness, apprehension, tremor and palpitations.
what are the therapeutic uses of epinephrine? What are the adverse affects?
drug of choice for anaphylactic shock
can be used for vasoconstriction with local anesthetics
bronchodilation in acute asthmatic episodes
used to as a cardiopulmonary resuscitation during MI
can be used as a topical hemostat - stop bleeding.
adverse effects - restlessness, apprehension, throbbing headache, tremor, palpitations, premature ventricular contractions, arrhythmias, angina and a very large dose as cause cerebral hemorrhage because of a sharp increase in BP
what are the contraindications of using epinephrine?
cardiac dilatation or coronary insufficiency because of oxygen consumption
cardiogenic shock because of increased myocardial oxygen demand
hypertension - because of pressor effects and cardiac stimulation
organic brain damage because of increased cerebral pressure
hypersensitivity
what are the drug interactions of epinephrine?
interacts with anything that has similar effects (agonists to adrenergic receptors) or anything that would block it’s effect
interacts with alpha (counteracts effect of epi) and beta AR (causes unopposed epi actions on alpha1 ARs) antagonists
drugs that cause hypertension, tachycardia or cardiac arrythmias (increases risk of hypertension and arrythmia)
NO reuptake inhibitors
MAO or COMT inhibitors - causes hypertensive crisis
dihydroergotamine - causes extreme hypertension
Norepinephrine effects and therapeutic uses
Nor-Epi has equal and greatest affinity for alpha receptors and some for beta1 receptors
NorEpi has NO affinity for Beta2 R
NorEpi is a potent vasopressor (a) which increase contractility of the heart and it’s oxygen consumption (B1)
HR is either unchanged or decreased because of homeostatic reflexes
used therapuetically for septic shock and profound hypotension - only after blood volume has been restored (meaning patient has been given fluids)
norepinephrine contraindications, adverse effects and drug interactions
contraindications - in patients with blood loss: needs restoration of BV
Adverse effects - reduced blood flow to organs puts them at danger for organ failure, arrhythmia. digital ischemia and extravasation at injection site -> blood leakage causes ischemia and can lead to gangrene
dopamine pharmacokinetics
DA has the highest affinity for D receptors, then beta1 and then alpha.
given by IV infusion with onset in 5 min
DA is inactivated by MAO and COMT with a half life of 5 mins, meaning it’s duration of action is 10 mins.
dopamine concentration dependent effects - low dose vs. intermediate dose vs high dose
low conc - DA binds D1 receptors in renal, mesenteric and coronary vascular beds causing vasodilation. Net effects include an increase in renal blood flow, GFR and Na+ excretion. Decreased Peripheral vascular resistance
intermediate conc - DA stimulates beta1 R increasing HR and has a inotropic effect (mediated by the releasing of NE from nerve terminal - a side effect of beta1 R stimulation) Increases systolic BP
At high conc DA is a pressor - it activates vascular alpha1 R causing vasoconstriction (this increases peripheral resistance)
what are DA therapeutic uses and adverse effects?
therapeutic uses are for shock with proper fluid administration, decompensated heart failure (short-term) and postop myocardial depression.
adverse effects in high dose are that of any sympathomimetic - headache, tachy, anginal pain, arrhythmias and hypertension. Also, extravasation at injection site which can cause tissue necrosis
isopreterenol
potent, nonselective Beta agonist with no affinity for alpha R
causes cardiac chronotropic and inotropic effects increasing cardiac output and increases Oxy comsumption. Also, relaxes bronchus and GI smooth muscle
decrease peripheral vascular resistance, diastolic BP and MAP.
therapuetic uses and adverse effects of isopreterenol
historically used for bradyarrhythmia, AV block and asthma
adverse effects include headache, tremor, dizziness, palpitations and sinus tachycardia
in patients with underlying coronary or cardiac disease cardiac ischemia and arrythmias can occur
dobutamine
Beta1 selective agonist
Racemic mixture
(+) has high potency for beta ARs
(-) has potency for alpha 1 but the (+) enantiomer is a alpha1 antagoist so the effects are nulled.
Beta 1 effect predominates
Increases contractility of the heart and cardiac output with less reflex tachycardia (like would be seen with isoproterenol)
Used therapeutically short-term. For cardiac decompensation and for cardiac stress testing in patient who cannot perform the exercise stress test.
Adverse effects - tachyphylaxis, prolonged use (24-72hrs) causes receptor desentization and internalization. Causes Beta1 R induced hypertension, angina, arrhyymia, tachycardia
Short acting selective beta2 agonists
Metaproterenol
Albuterol
Levalbuterol
Terbutaline
Onset 10 mins. Last 4-6hrs
Routes - oral systemic, inhalation and IV (IV should only be used in emergencies)
Used from brochodilation
Systemically could prolong labor
Long acting selective beta2 agonists
Formoterol
Indacaterol
Olodaterol
Salmeterol
Last 12hours - these should never be used for an acute bronchial attack because they have a longer onset, 15-19 minutes
Given only by oral inhalation
Metabolized CYP
What are the effects and therapeutic uses of selective beta2 agonsts?
They slow uterine contractions, induce bronchodilation, they can suppress leukotienes and histamine release and they enhance mucocilliary function
Therapeutic uses in asthma and COPD - specifically short-acting. Long-acting is used prophalatically or for symptomatic noctornal asthma.
Also for tocolytic - terbutaline which causes relaction of the myometrium and prolongs labor.
What are the adverse effects of beta2 selective agonists?
Tremor - because of skeletal muscle Beta2 activation
Tachycardia - stimulation of cardiac Beta AR, could be reflex tachycardia as well
Restlessness, apprehension, anxiety - occurs with systemic administration
Metabolic effects include hypokalemia and hyperglycemia
alpha1 selective agents
phenylephrine
oxymetazoline
midodrine
alpha2 selective agents - and the effect?
clonidine
methlydopa
acts on GiPCR and decreases central sympathetic tone both by direct action on alpha2 receptors and inhibiting release of NE.
leads to decrease in BP and HR
therapeutic uses of phenylephrine
phenylephrine is an alpha1 selective agent
it is a vasopressor, temporary nasal decongestant
topical uses are for ocular decongestant, mydriatic, hemostatic agent and hemorrhoids
therapeutic uses of clonidine
decrease BP by decreasing peripheral resistance and renal vascular resistance and HR – Hypertension
pain management - epidural
ADHD and hot flash treatments
assists with withdrawal syndromes - opiod withdrawal or smoking cessation
clonidine adverse effects
dry mouth and sedation are most common
also possible is hypotension, bradycardia, sexual dysfunction
Abrupt withdrawal causes rebound hypertension with reflex tachycardia
interacts with beta blockers, beta blockers must be discontinued first
methyldopa - drug type and overall effects
alpha2 selective agonists
converts into methylnorepinephrine which decrease PVR and BP
methlydopa - therapeutic uses
used for hypertension, even for hypertension in pregnancy
-has no adverse effects in fetus, maintains blood flow to uterus and does not reduce maternal CO or renal perfusion.
methyldopa - adverse effects
dry mouth and sedation
orthostatic hypotension
headache, ejaculation disorder, impotence and reduced libido
endocrine effects that cause tremors similar to whats seen in parkinson’s disease, hyperprolactinemia, gynecomastia and galatorrhea
also - rarely, hepatitis, hemolytic or aplastic anemia, drug fever
ephedrine
mixed action sympathomimetics
increases HR, CO and BP
causes bronchodilation and increases resistance to the outflow of urine - alphaR
therapeutic uses are for spinal anesthesia (induction of hypotension) and nasal congestion
ephedrine - indirect and direct actions
indirect action - enhance’s NE release from sympathetic neurons
Direct action - agonist for both alpha and beta receptors
what are the mech of actions for amphetamine and cocaine?
amphetamine blocks/inhibits VMAT which increases the availability of NE
VMAT re-sequesters NE into storage vesicles
cocaine inhibits monoamine reuptake transporters NET, DAT, and SERT
what are the therapeutic uses of MAO inhibitors?
treatment for depression by inhibiting MAO theres an increase of Epi, NorEpi, Dopamine and serotonin
can cause accumulation of tyramine (from food)
what are the therapeutic uses of COMT inhibitors?
COMT inhibitors are given along Levadopa to treat parkinson’s disease - causes more sustained levodopa serum level
