Anti-Hypertensive Pharmacology

Question 1

Hypertensive values

Answer 1

>130/80

Question 2

Blood pressure equations

Answer 2

BP is the pressure exerted against the arterial wall

BP=[EDV-ESV] x HR] x SVR

or

BP=CO x SVR

Question 3

Ways to reduce cardiac output?

Answer 3

Reduce blood volume
Reduce heart rate
Reduce stroke volume

Question 4

Ways to reduce SVR?

Answer 4

Dilate systemic vasculature

Question 5

What are the four anatomic sites of BP control?

Answer 5

1. Resistance arterioles
2. Capacitance venules
3. Pump heart output
4. Volume kidneys (Renin-angiotensin-aldosterone)

Question 6

Mechanism of action of Diuretics

Answer 6

1. Deplete body of sodium and H₂O
2. Reduce blood volume (decrease stroke volume)

Question 7

Type of Diuretics?

Answer 7

• *1. Loop diuretics
  2. Thiazide diuretics
  3. Potassium sparing diuretics**
  4. Osmotic diuretics
  5. Carbonic anhydrase inhibitors (renal specialists)
  6. Vasopressin (ADH) antagonists

Question 8

Where do loop diuretics act?

Answer 8

Blocks the Na/K/Cl exchanger in the ascending Loop of Henle, accounts for 25% less Na/K/Cl retention because it inhibits this pump. 25% more Na/K/Cl is excreted in the urine.

Uses:
Treatment/prevention of edamatous conditions (heart failure), hyperkalemia, HTN (2nd line)

Adverse effects (mainly dehydration):
Na/volume depletion leading to hypotension
Hypokalemia (arrhythmias), hypocalcemia (tetany), hypomagnesemia (arrhythmias), metabolic alkalosis
Ototoxicity (tinnitus, vertigo, deafness) in high concentrations
Hyperuricemia (gout) when used chronically

Question 9

Where to thiazide diuretics act?

Answer 9

Act on a Na/Cl pump in the distal convoluted tubule (DCT) where 5% Na/Cl is excreted to the urine. First line of defense against hypertension because it is less potent, can augment the loop effect

Thiazides to remember:
Hydrochlorothiazide
Chlorthalidone
Indapamide
Metalazone (never used alone)

Adverse effects: Hypovolemia, hypokalemia, hyponatremia (common), hypochloremia, hypomagnesemia, hypercalcemia, hyperuricemia (gout), metabolic acidosis

Question 10

Where do potassium sparing diuretics act?

Answer 10

Work in the collecting duct of the nephron by inhibiting aldosterone (antagonist) or blocking a Na/H/K exchanger. Pretty weak diuretics unless used for specific disease states, can cause hyperkalemia

Na Channel Blockers: triamterene and amiloride, inhibitors of renal epithelial Na+ channels

Aldosterone receptor antagonists: Indicated in HF, spironolactone and eplerenone (indirect effect)*
*Do not act on the luminal side of the tubule

Question 11

What is the root cause of hypertension?

Answer 11

Sympathetic overdrive

Question 12

Sympathetic receptor review

Answer 12

Question 13

Drugs that alter sympathetic nervous system function?

Answer 13

Question 14

Mechanism of action of a2 agonists

Answer 14

Stimulate a2 receptors on presynaptic neuron, reduces central sympathetic flow and increased parasympathetic flow

Adverse effects: Dry mouth, drowsiness/sedation, lethargy, constipation, sexual dysfunction, bradycardia, rebound HTN with withdrawal

Question 15

Clonidine’s central mechanism of action?

Answer 15

Activation of a2 receptor initiates more firing of vagus nerve (decreases HR/SV) and decreases firing of sympathetic nerves leading to decrease in BP

Clinical use: Hypertension (not a first line of defense), resistant hypertension
Hypertensive urgency without acute organ damage
ADHD (guanfacine)
Treatment of withdrawal (Narcotics, alcohol)

Question 16

What are the more a2 agonist specific drugs?

Answer 16

Question 17

Alpha 1 adrenergic antagonists mechanism of action?

Answer 17

Inhibit binding of NE to postsynaptic alpha1 receptors by relaxing smooth muscles and decreasing peripheral vascular resistance and venous return

Uses: Mostly used for reducing resistance to urinary flow (relaxes smooth muscle), useful in benign prostatic hypertrophy, n__ot recommended for initial monotherapy

Adverse effects: Drowsiness, fluid retention, diarrhea, postural hypotension, syncope, tachycardia, can increase risk of HF with chronic use
First dose phenomenon: faintness or syncope 30-60min after first dose, use low initial dose (bedtime) and titrate slowly

Question 18

Beta-Blocker effects/adverse effects? Clinical uses?

Answer 18

Adverse effects:

1. Smooth muscle spasm (bronchospasm especially with non-selectives)
2. Exaggeration of cardiac therapeutic actions (too much bradycardia/hypotension)
3. CNS penetration (insomnia, depression, some more lipid soluble than others)
4. Worsened quality of life (weight gain, fatigue, ED)
5. Adverse metabolic side effects (loss of glycemic control, masks hypoglycemia)
6. Withdrawal phenomenon

Clinical uses: Ischemic heart disease, HF with reduced EF (only metoprolol, carvedilol, bisoprolol), tachyarrhythmias, controlling acute panic symptoms, glucoma, variceal bleeding from portal hypertension/cirrhosis

Question 19

Non-selective/cardioselective/vasodilating B-Blockers

Answer 19

Question 20

What are the vasodilating B-Blockers, and what do they do?

Answer 20

BP reduction from decrease in HR and SVR

a1 and B1 antagonist

Question 21

What are the two types of Ca channel blockers?

Answer 21

T (transient) type: opens at more neg. potentials, involved in initial depolarization of SA/AV nodes

L-type: located on vascular smooth muscle, cardiac myocytes, cardiac nodal tissue
Dominant in AV node, required for CICR from SR, Phase 0 and Phase 2 of action potential
Activity increased by catecholamines

Question 22

Difference between DHPs and Non-DHPs

Answer 22

Dihydropyridines (DHP): -pine suffix, act on on arterioles

Non-DHPs: Act directly on the heart decreasing HR and contraction

Question 23

B-blockage effects vs. CCBs

Answer 23

Question 24

Clinical uses of verapamil or diltiazem?

Answer 24

• Hypertension
• Supraventricular tachyarrhythmias
• Coronary spasm
• Chronic stable angina

Question 25

With an ischemic heart, how do non-CCB help? What are some contraindications? Adverse effects?

Answer 25

Decreasing the demand of the heart (decreased HR/contractility) allows more supply Vasodilation increases O2 supply to the heart ``` _Contraindications_: Severe hypotension/cardiogenic shock LV dysfunction (EF \<40%) 2nd or 3rd degree AV block (except with artificial pacemaker) ``` _Adverse effects_: GI distress/constipation (verapamil more so), headache, edema, dizziness, edema, fatigue, bradycardia, HF, AV block

Question 26

Dihydropyridine CCBs

Answer 26

Nifedipine was first DHP CCB. _Long acting capsules are preferred_ _Short acting capsules_ have many routes of administration (nasal, inhalation, rectal), act by rapidly vasodilating to relieve sever HTN and terminate coronary spasm -\> rapid reflex adrenergic activation with tachycardia _Clinical uses_: Hypertension (first line of defense regardless of race), chronic stable angina, coronary spasm, Raynaud's phenomenon (ankle edema is side effect), _no rebound tachycardia_

Question 27

What are the direct vasodilators, and how do they work?

Answer 27

Hydralazine (IV) and Minoxidil _MOA_: specific for arterial resistance vessels (dilates them), lowers afterload (important in HF) _Adverse effects_: headaches, flushing, baroreceptor reflex tachycardia (boxed warning), salt and water retention Minosidil -\> hypertrichosis, pericardial effusion (boxed warning) _Uses_: hypertension, midoxidil is last line of defense if no other therapies work, heart failure (hydralazine combined with isosorbide dinitrate)

Question 28

What combination of drugs are recommended for black HF patients who remain symptomatic despite therapy?

Answer 28

_Isosorbide dinitrate_ -\> venodilation and reduction in preload, increase in NO bioavailability _Hydralazine_ -\> arterial dilation to reduce afterload and increase SV and CO Increase in NO bioavailability secondary to reduction in oxidative stress

Question 29

Sodium nitroprusside

Answer 29

Source of NO, potent and very rapid peripheral vasodilator affecting arteries and venules (decreasing preload/afterload) Keep dose low/short (\<72hours), monitor level and renal function (CI in renal failure), continuous IV required

Question 30

Fenoldopam

Answer 30

**Selective D1-like dopamine receptor, rapid acting arteriolar vasodilator** Induces natriuresis, preventing ARF _Major toxicities_: reflex tachycardia, headache, flushing, hypokalemia, avoid in glaucoma and use with BB -\> substancial hypotension because BB inhibit sympathetic reflex response to fenoldopam

Question 31

Nitrate mechanism of action

Answer 31

Actions of nitrates on circulation _Indications_: Chronic stable/unstable angina and ACS, acute HF and pulmonary edema, CHF (combo with hydralazine), hypertension with pulmonary edema