What are the sympatholytics and generally how do they work?
Reserpine - depletes NE from storage veisicles (blocks VMAT)
Methyl-DA and Clonidine = inhibit Symp outflow from CNS; central A2 agonists
Met-tyrosine = inhibition of NE synthesis
How does Reserpine work and what is it used for? adverse effects?
Reserpine selectively and irreversibly binds VMAT2 and blocks it so no Da into vesicles to become NE . Therefore, inactivates NE-releasers bc depletes NE from vesicles
Causes upregulation in adrenoreceptor!!!
High doses is tranquilizer/sedative. Lower doses anti-HTN
Adverse Effects = increased depression and lower seizure threshold; exacerbation of Parkinsons
Bc lipid soluble, NOT safe for pregnancy bc crosses Placenta
What are the central A2 agonists and how do they work?
Clonidne and Methyl-Dopa act on brainstem nuclei to decrease the sympathetic activity coming out
Baroreceptors remain intact! therefore no postural hypotension!
Clonidine acts on Locus Ceruleus of Pons to inhibit spontaneous firing
What are other uses for Clonidine?
opiate withdrawal, Anesthetic adjunct, Stimulates GH release
Analogue (Bromolidine) used in the eye to lower IOP
How is Methyl-Dopa used?
Ingest and needs to be converted to Methyl-NE in the brain to act as a false neurotransmitter and block sympathetic outflow. Taken up and stored and released like neurotransmiter
FIRST LINE Anti-Hypertensive in pregnancy! does not reduce maternal CO or flow to placenta
What are the adverse effects of central A2 agonists?
Withdrawal and exacerbation of HTN and MI: up-regulation of sympathetic outflow onto system that up-regulated receptors in response to decreased input leads to greatly raised BP and can lead to ischemia (do NOT stop suddenly taking, need to wean off)
What is Moxonidine and how does it work?
[not used in US]
Acts on Imidazoline receptors in Lateral Retiucate Nucleus and stimualtes A2 causing reduced BP without the adverse effects of withdrawal or dry mouth
What is Met-tyrosine and how is it used?
Competitive inhibitor of tyrosine Hydorxylase and stops NE synthesis at the rate limiting step!
Used for management of Catecholamine secreting tumors
What are the 2 main classes of calcium channel blockers? What drugs are in these classes?
Dihydropiridines (DHPs) = Nefidipine or Amlodipine -"ipines"
Non-DHPS = Verapamil and Diltiazem
What are the targets of the Calcium Channel Blockers?
Target the pore-forming A1 sub-units of the L-type Calcium channels 1.2 and 1.3
1.2 in Cardiac cells, SM, and neurons
1.3 in SA node, cochlear hair cells, neurons
How do the CCB act on vascular SM?
RELAX vascular SM
Nifedipine > Verapamil > Diltiazem
Describe the binding affiniy for the non-DHP CCB
Bind better at Cardiac cells!
Cardiac cells are phasic and so intermittently switching between C and O conformation. Non-DHP bind more effectively to O so increased O when higher rate and can bind more frequently
Describe the binding affinity for the DHP CCB
Bind more to vascular SM
Vascular SM in tonic depolarization so alternating between O and I conformations, DPH bind more tightly to I (inactivated) form and so tends to be in more tonically depolarized cells in SM.
Which CCB classes act more as cardiodepressors and which more as vasodilators?
Cardiodepression seen more in Non-DHP bc "Frequency Dependent"
Vasodilation seen more in DHP bc "Voltage Dependent"
What are the adverse effects of DHP CCBs?
Hypotension, Flushing Headache
Reflex Sympathetic Activation! acts to increase CO in response and therefore increase O2 demand on heart which could be bad in cardiac ischemia - therefore combined with Beta-blocker to reduce angina that would result from ischemic effects.
Swollen Ankles - changes capillary dynamic
What are the adverse effects of Non-DHP CCBs?
LV Dysfunction, AV block
DO NOT give in combination with Beta-blockers bc will severely cardiodepress the heart
(unlike DHP CCB which give with Beta-Blockers to prevent Reflex Sympathetic activation)
Verapamil causes constipation
How are the CCB metabolized?
In liver by Cyp450 Cyp3a4!!!
Drug interactions with Statins, Erythromycin, antifungals, Protease inhibitors, grapefuit juice to all increase CCB levels bc comepetetive substrates for Cyp3a4
Interactions can reslut in severe Hypotension or Bradycardia
What is Amlodipine?
Long acting Calcium channel blocker - DPH used in primary HTN
used for AA and elderly
Long half life and protects against Sympathetic reflex!!! better than short-acting
What drugs Prolong QT?
Some Risky Meds Can PRlong QT
Some Risky Meds Can Prolong QT
Protease Inhibitors (-navir)
Quinidine (Class 1a…Also Class 3)