In general what are the effects of A1 Block?
Non-selective block of both?
A1 Block - Vasodilation and lower BP, Relax Iris Radial Muscle, Relax GU muscle, less viscous salivation
A2 Block - Increase NE - Sympathomimetic AND Incrase Insulin secretion from pancreatic beta cells
Non-selective A1/A2 Block - A1 block effects + Beta agonist effects from increase NE from A2 block
What is Ergot? How does it work?
Ergot is a Partial Agonist at Alpha-1 receptors and serotonin receptors found in Rye that is infected with fungus [Ergot Alkaloids]
Partial Agonist so when increased Epinephrine/Adrenalin then acts like an Antagonist and blocks Alpha-1 to lower BP in presence of increased epi and cause Beta-2 mediated dilation to be predominant effect
What are the 2 Ergot Alkaloid derivatives still used today and what are they used for?
Ergotamine - used for migraines
Ergonovine - used to contract post-partum uterus and prevent hemorrhage
Name the Non-selective Alpha Adrenergic Antagonists (blockers) - how are they used?
Phenoxybenzamine - irreversible antagonist, long acting
Phentolamine - competitive antagonist, short acting
Used for surgical resection of pheochromocytoma
*IMPORTANT - alpha block in place before beta block other wise hypertensive crisis!
What are the Alpha-1 Antagonists?
What are they used for?
Prazosin, Terazosin -
Used for Primary HTN (although see First Dose effets where postural hypotension); Raynaud’s Disease to cause vasodilation, Benign Prostratic Hypertrophy and Kidney stones to relax urinary tract SM
Tamsulosin - A1A selective
used more for relaxants of urinary tract with less vasodilatory effects on BP
What is an Alpha-2 Antagonist?
What happens and how to treat Benign Prostatic Hyperplasia?
BPH causes constriction of upper urethra and so incomplete emptying and incrased urinary frequency
Sympathetic input release of NE onto A1 causes constriction of SM so if use Terazosin or Tamsulosin can act at Alpha1-A receptors at neck of bladder and relax SM and fascilitate voiding
What are adverse effects of Alpha-1 block?
Postural Hypotension - get up and faint
Nasal congestion from mucosal vasodilation
Dry mouth - less VISCOUS salivary secretion
*Intraoperative Floppy Iris syndrome bc relaxed radial and vasc smooth muscle so bad for eye surgery
Retrograde Ejaculation and Delayed ejaculation
Why would Alpha Blockers cause erection????
Normally, sympathetic adrenergic input causes contraction (A1) of vascular arteries to penis and of trabecular smooth muscle so more venous outflow
BLOCK symp and relax BV to increase blood flow and relax trabecular SM to compress veins so get engorgement
Why use A2 block in Dysautonomia? What is the risk with A2 blcok?
Used to increase NE release to prevent orthostatic hypotension but risk increased HR leading to palpitations
In General, what are some systemic effects of Beta-Antagonists?
Decreased HR, CO, O2 Demand, AV Conduction Velocity
Decreased Renin release
Constriction of blood vessels AND bronchioles
Mast cell degranulation incrased
What are the Cardiovascular indications for Beta-Blockers?
1) Angina of Effort - used to decrease oxygen consumption in heart and so less demand
3) Cardiac Arrythmia
4) Systolic Heart Failure - First Exacerbation of symptoms bc short-term CO decreae but long term benefits
5) Primary HTN (less effective than other firstline agents)
What are the non-cardiovascular indications for Beta-Blockers?
1) Hyperthyroidism to decrease HR, Tremor and Anxiety
2) Migraine - prophylaxis
3) Glaucome - decrease aqueous inflow and IOP bc act on beta-rec in ciliary body
4) Tremor and stagefright
What are adverse cardiovascular effects of beta-block / contraindications?
Less exercise capacity, bradycardia, peripheral vasoconstriction
DO nNOT use with AV conduction block - made worse
Can get withdrawal leading to beta-supersensitivity
What are the non-cardiovascular adverse effects of beta-block?
Bronchoconstriction - dont use in ASthma or COPD
Mast Cell destabilization - makes anaphylaxis worse and no response to Epi pen
***BLUNTED subjective signs Hypoglycemia and delayed recovery from it - CAREFUL use in insulin dependent diabetics
Exercise induced hyperkalemia - muscle weakness
What are First generation Beta-blockers? Name them and action
Non-selective onto beta 1 and beta2
Propanolol *(Lipid Soluble)
Pindolol - Partial Agonist
What are the Second Generation Beta-blockers? Name them and action
Beta-1 Selective “Cardioselective”
**Metorpolol ***(Lipid Soluble)
What are the third generation beta-blockers. Name them and action
Beta blockers with additional vasodilator actions including NO production, B2 agonist, A1 block, Ca-entry block, K+ opening and antioxidant activity
Non-selective = Carvedilol *(Lipid Soluble) and Labetalol (a1/beta)
B1 selective = **Betaxolol **
What are the PArtial Agonist Beta blockers and why are they sometimes advantageous?
Pindolol (First generation) and Lavetalol (Third)
Have intrinsic sympathomimetic Actrivity so good for use in patients with **bradycardia or conduction block **
Why is Beta-1 selectivity not gauranteed?
relative advatage of reduced risk of beta-2 adverse effects is diminished with increases doses of beta-1 blocker bc becomes beta-2 blocker at certain levels
What are the 2 beta blockers with Biased Signaling and what is that anyways?
Alprenolol and Carvedilol (third)
stimulate Beta-1 mediated transactivation of EGFR
acitvate PKA to decrease contraction via AC to cAMP But also stimulate Beta-Arrestin to cleave EGF to activate EGFR which is anti-apoptotic and prolongs survival of cardiomyocytes!!!!