moa of alpha receptors
Gq couple receptor located on vascular smooth muscle
hormone binds to alpha 1 receptor which activates Gq protein (which has a intracellular domain composed of alpha, beta, and gamma subunits), when binded, g protein is activated and alpha subunit dissassociates from beta and gamma and starts the downstream signaling. Upon activation, the receptor causes a confirmational change and exchanges GDP for GTP on the alpha subunit which allows the diassociation. Gq alpha activates an enzyme called PLC which then cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into
Inositol 1,4,5-trisphosphate (IP3)
Diacylglycerol (DAG)
which increases intracellular calcium and binding of calcium to calmodulin which activates MLCK.
MLCK phosphorylates myosin and allows interaction of actin and myosin and ultimately –> smooth muscle contraction and an increase in SVR!!!
what about beta adrenergic receptors
π¬ Mechanism:
NE binds to Ξ²1 receptor β activates Gs protein
Gs activates adenylyl cyclase
Adenylyl cyclase converts ATP β cAMP
β cAMP activates protein kinase A (PKA)
PKA phosphorylates:
L-type CaΒ²βΊ channels β β CaΒ²βΊ influx
Phospholamban β β CaΒ²βΊ reuptake into SR β more CaΒ²βΊ available for next beat
Troponin I β enhances actin-myosin interaction
in all,
β Inotropy (contractile force)
β Chronotropy (heart rate)
β Dromotropy (AV node conduction)
BETA 2
Norepinephrine or epinephrine binds to the beta-2 adrenergic receptor
The receptor is coupled to a Gs protein (stimulatory G protein)
The Gs alpha subunit activates adenylate cyclase
Adenylate cyclase converts ATP to cyclic AMP (cAMP)
cAMP activates protein kinase A (PKA)
PKA phosphorylates key proteins, leading to:
Decreased intracellular calcium in smooth muscle
Inhibition of myosin light chain kinase (MLCK)
alpha 2
Norepinephrine binds to the alpha-2 adrenergic receptor
This receptor is coupled to a Gi protein (inhibitory G protein)
The Gi alpha subunit inhibits adenylate cyclase
β cAMP levels β β protein kinase A (PKA) activity
alpha 1 alpha 2 beta 1 beta 2 simple word
Alpha-1 (Ξ±1) β vasoconstriction
Alpha-2 (Ξ±2) β inhibition of NE release, CNS sedation
Beta-1 (Ξ²1) β β heart rate & contractility
Beta-2 (Ξ²2) β bronchodilation, vasodilation, insulin release
norepi
A1, B1 and SLIGHT A2
increases HR contractility and arterial and venous vasoconstriction
FIRST LINE for hypotension in sepsis!
Talk about epinephrine
strong A1, B1 moderate A2, and B2
1mg-4mg/250 mL (dose 1-10 mcg/min)
Nonselective!! works on all!
also stimulates increased secretion of renin
side effects: tachy, htn, arrythmias, stroke
neo or phenylephrine
ALPHA 1111 may cause reflex brady
What are inotropes?
a class of medications that increase contractility and thereby, with the end goal with increasing the CO/CI
What are catecholamines?
Effect on adrenergic receptors
So Beta and alpha receptors and mostly beta 1 which increase heart rate and contractility
Talk about dopamine
Treatment for brady and shock!
At low low doses, 1-3, stimulates dopaminergic receptors which causes vasodilation (works very similar to Beta 2 in that activates Gs –>adenylyl cyclase –> increase in atp to camp –> PKA –> inhibits MLCK –> renal VASODILATION!
D2- inhibits adenylyl cyclase ie the whole process for negative feedback. so works primarily on d1!
at low doses - beta, MORE CHRONOTROPY
at higher doses - alpha >10 mcg/kg/min
400mg/250ml bag
dose 5-20 mcg/kg/min
for inotropy? 5-10 mcg/kg/min
peripherally or centrally, but central preferred!
side effects - tachy, palpilations, chills, anxiety, tachyarrythmias, tissue necrosis, and anaphylaxis
Talk about dobutamine
FOR CARDIOGENIC SHOCK!!
works primarily on B1, but limited effect on HR, also works on B2 so might cause vasodilation (but usually negated bc of the increase in CO) and very small effect on alpha
500mg/250 ml **Very similar to dopamine!
dose: 2.5-20 mcg/kg/min but usually provider dependent titrations!
beta blockers will work against this!
can take up to 10 to take effect!
SE: tachy, htn, n/v, palpitations, ectopy can even cause rvr in afib pts
What is isoproterenol?
primary effects on B1, and B2
greater impact on HR so for mainly used for brady but also has a strong ionotropic effect too but NO alpha
might cause hypotension bc B2
Milrinone/Primacor
Phosphodiesterase III inhibitor! (usually BREAKS DOWN cAMP to AMP)
remember, does NOT work on receptors!!!)
allows more cAMP –> β protein kinase A (PKA) activation. PKA phosphorylates calcium channels β β calcium influx –> INCREASED CONTRACTILITY!
In vascular smooth muscle:
β cAMP β activates PKA –> inhibits myosin light chain kinase (MLCK)
β Vasodilation (β SVR)
(Even though PKA is responsible for inotropy, its because its acting on cardiac myocytes, its diff when its on vascular smooth muscle by inhibiting MLCK and decreasing calcium)
20mg/100ml or 40mg/200ml
Dose 0.125-1mcg/kg/min
USED for:
acute decompensated HF
can cause arrythmias, and cause headache and monitor electrolytes and tele
Labetolol vs Metoprolol vs Hydralazine
Metoprolol = cardioselective, best for rate control or post-MI/a fib (works on B1 only)
BLOCKS THESE!!!!
Labetalol = great for rapid BP lowering without reflex tachycardia (works on B1, B2, and a1) so its mixed!
Hydralazine = potent arterial dilator, but use carefully due to reflex sympathetic activation (works on arterial vasodilation)
Remember! Works antagonistically
Tell me everything you know about Vasopressin!
also known as ADH
produced in hypothalamus and stored in posterior pituitary
works on V1 - vascular smooth muscle –> vasoconstriction (works the same way as alpha1)
v2 - -> renal tubules which increases fluid retention and increase preload (very similar to beta 2, but Gs stimulates
adenylyl cyclase
β cAMP
cAMP activates protein kinase A (PKA)
PKA stimulates:
Insertion of aquaporin-2 channels into the luminal (apical) membrane
Water moves from tubule β cell β blood β β water reabsorption
Result = β plasma volume, β blood pressure
FIXED!!! 0.03 -0.04 (units/minute)
Nicardipine
same class as amlodipine, nifedipine, its a DHP CCB
Calcium channel blocker . for angina or hypertension
more selective for smooth muscle vs cardiac. work directly on ion channels
found to be 40mg/200ml
2.5 to 15 mg/hr
work on L- type calcium channels in smooth muscle and cardiac tissue
so decrease in Ca –> decreases in ca - calmodulin and –> dereases in MLCK –> vasoilation
may cause reflex tachy bc drop in bp
compare and contrast DHPs vs non DHP
- Dihydropyridines (DHPs)
Amlodipine, Nifedipine, Nicardipine, Clevidipine
More selective for vascular smooth muscle
Effect Potent vasodilation, minimal cardiac suppression
Clinical uses Hypertension, angina, vasospasm, hypertensive emergencies (nicardipine/clevidipine)
- Non-Dihydropyridines (Non-DHPs) also known as Class IV agents
Verapamil, Diltiazem
Selectivity
Act on both heart and vessels
Effect: β HR (chronotropy), β AV conduction (dromotropy), β contractility (inotropy)
Clinical uses Atrial fibrillation, SVT, rate control, angina
Talk about Procainamide
It’s a class 1a antiarrythmic!
Essentially, it works by blocking the voltage gated Na+ channel and prolongs the action potential.
It binds to the open Na channels and slows the phase 0 depolarization phase of the cardiac myocyte action potential
It also blocks K channels which prolongs phase 3 and prolongs AP duration and increases the refractoy period (which prevents re-entry arrythmias)
BUT WATCH FOR EKG!! esp qt interval so risk of torsades
typical infusion dose 1-4 mg/min
What about lidocaine?
CLASS 1B
shortens the action potential duration and refractory period and does NOT increase QT interval
Lidocaine binds to NaβΊ channels that are in open or inactivated states, which are more common in ischemic ventricular cells. This prevents those channels from reopening, thereby reducing depolarization in damaged tissue and suppressing ventricular arrhythmias.β
helps for ventricular arrthymias, such as vtach, vfib or frequent pvc’s
also use for local anesthetic purposes
Talk about esmolol
its a class II ANTIARRTHYMIC.
its a beta blocker, cardio selective b1 adrenergic receptor antagonist
blocks Gs PCR which decreases camp, decreases pka, and decreases phosphorylation of calcium channels –> β intracellular CaΒ²βΊ so net effect is:
β Heart rate (negative chronotropy)
β Contractility (negative inotropy)
β AV node conduction (negative dromotropy)
used for SVT, rate control for afib or aflutter, hypertensive emergencies associated with tachycardia
2500mg/250ml bag
dose; 50-300mcg/kg/min
titrate 3-5 min
Talk about Amio
Amiodarone is a Class III antiarrhythmic that primarily works by blocking potassium efflux during repolarization, thereby prolonging the action potential and refractory period, which helps prevent reentrant arrhythmias. Works on Phase 3 K efflux!
but also then has common QT Interval prolongtion
for Vt, Vf, Afib, Aflutter
esp in new A fib!!!
kinda mimics all classes
so can sometimes lead to brady, hypotension and torsades
900/500ml with inline filter!!
150 mg over 10 min first
1mg/min for 6 hours –> 0.5 mg/min for 18 hours
acls - 300 mg to 150 mg IVP
Talk about verapamil and cardizem
CCBs so class IV agents
serves as a decrease in contractlity and heart rate
blocks Ltype calcium chells
β Calcium entry during phase 2
β Calcium-induced calcium release from the sarcoplasmic reticulum
β Contractility (negative inotropic effect)
Slows AV node conduction (negative dromotropic effect)
Decreases heart rate (negative chronotropic effect) β mostly at AV node
for SVT, a flutter, a fib
can cause brady and dereased contractility
cardizem -> found in 100-125mg in a 100ml
5-20 mg/hr
Adenosine
depresses SA node automaticity and transient AV node conduction stopping
for SVT , stops heart for a second, and rhythm will come back
so essentially increases decreases calcium so it can’t contract, increase k+ so all cells are repolarized and then transiently blocks the av node
Receptor: Binds to A1 adenosine receptors (which are Gi protein-coupled receptors) primarily in the heart, especially the AV node.
Effects:
Inhibits adenylate cyclase β decreases cAMP β reduces activity of L-type calcium channels β decreased calcium influx.
β Leads to slower depolarization in AV node cells.
Activates potassium channels (GIRK channels) β increases KβΊ efflux β hyperpolarizes the cell membrane.
β Makes it harder for the cell to reach threshold and fire an action potential.
Result:
β Transient AV nodal block (lasting seconds)
