Exam 6 Flashcards
How can you define hypertension and how do you distinguish primary from secondary HTN? How do you calculate blood pressure?
HTN: Needs to me measured 2 separate times, need to eliminate white coat HTN
- systolic over 130mmHg
- diastolic over 80mmHg
- resting pulse pressure (SBP-DBP) over 65mmHg
Primary - No identifiable cause
Secondary - Can determine the cause (ABCDE)
- Aldosteronsim, Bad kidneys, Cushing’s/Coarctation, Drugs, Endocrine disorders
BP = Cardiac Output x Peripheral Vascular Resistance
What are the risk factors for HTN and what diseases are linked with HTN?
Risk factors - Lifestyle factors like being overweight, smoking, drinking, excess sodium/too little potassium, lack of exercise. Also hyperlipidemia, depression, age, sex, genetic factors, and race.
Isolated systolic HTN - Risk factor is agin due to vasculature being less flexible
Diseases - Diabetic nephropathy
What is the baroreceptor reflex? How does the baroreceptor reflex alter CO, vascular resistance, and BP when someone stands up really fast?
The baroreceptor reflex is a system for the body to measure and maintain blood pressure.
Pressure = CO x VR (vascular resistance)
- vascular resistance is primarily controlled by the SANS
Cardiac Output = SV x HR
- stroke volume and heart rate is controlled by the PANS and SANS
For example, if someone stands up ready fast, SANS will increase the heart rate, stroke volume, and vasoconstrict vessels, so more blood will then get to the brain.
If BP is high, the baroreceptor reflex will stimulate PANS, which will slow down SA node to decrease heart rate. It will also decrease the force of contraction of the heart and dilate arteriolar smooth muscle. These all result in decreased peripheral resistance and decreased cardiac output, leading to a decrease in BP.
What organs are the sites of action for antihypertensive agents and which organs are at risk for damage due to hypertension?
Targets - Heart (reduce cardiac output), resistance of arterioles, resistance of veins, kidney (reduce fluids and blood volume).
HTN damages the heart (HF, CAD, angina, MI), kidney (kidney disease/failure), brain (stroke), and eyes (vision loss)
Where do these sympathetic nervous system receptors work and what is their MOA for controlling BP? NE, EPI, a1, a2, b1, b2 receptors
NE stimulated beta and alpha receptors in the heart and vessels by directly getting released into tissues.
In the adrenal glands, NE and EPI are released into the blood stream to stimulate alpha and beta receptors in the heart and vessels.
a1 - very present in vascular smooth muscle (constriction)
b1 - very present in cardiac muscle; stimulation increases HR (SA node) and force/stroke volume (AV node), thus increasing BP. Also, renal b1 receptors (juxtaglomerular cells) secrete renin into vasculature, which increases BP.
b2 - minimal in cardiac muscle, present in vascular smooth muscle (dilation); stimulation increases cAMP, which inhibits MLCK, which inhibits contraction and promote relaxation.
a1 is stronger than b2, so that’s why it’s more the focus for HTN therapy.
What does stimulation of the M3 receptor do in the vasculature? What does stimulation of M2 do?
M3 - Stimulation of M3 in endothelium results in increased production of NO. NO activates guanylyl cyclase, which converts GTP to cGMP, which leads to relaxation.
M2 - Stimulation of M2 decreases HR and force/stroke volume, resulting in a decrease in BP. M2 is inhibitory, so it decreases cAMP in the heart, resulting in decreased HR.
How does dopamine impact BP?
When renal sympathetic nerves are stimulated, they release dopamine from proximal tubules. At low dopamine concentrations, vasodilation occurs, but at high dopamine concentrations, dopamine causes vasoconstriction.
Dopamine purges NA+, which causes diuresis (lowers BP).
What drugs are in these classes: a1 antagonists, a2 agonists, nonselective a-blockers, b-blockers, a1/b blockers, catecholamine depleters
a1 antagonists - (-osins) prazosin, terazosin, doxazosin
a2 agonists - Methyldopa (Aldomet), clonidine
nonselective a-blockers - phentolamine (reversible), phenoxybenzamine (irreversible)
b-blockers -
- 1st gen (non-selective): carvedilol, propranolol, pindolol
- 2nd gen: metoprolol tartrate, metoprolol succinate, atenolol
- 3rd gen: nebivolol, betaxolol
a1/b blockers - carvedilol, labetalol
catecholamine depleters - reserpine
What are the mechanistic differences between non-selective a-blockers, a1-blockers, central acting a2 agonists, and catecholamine depleters?
a1 antagonists - in vascular smooth muscle and CNS. Activation by NE causes vasoconstriction, so antagonism dilates arteries and veins, causing a decrease in vascular resistance.
central acting a2 agonists - mainly in CNS. Activation decreases the firing of sympathetic nerves by inhibiting a1 and b receptors, thus decreasing heart rate, stroke volume, and increasing vasodilation in arteries, all resulting in a decrease in blood pressure.
non-selective a-blockers - these block a1 to dilate arteries and veins, which decreases vascular resistance. By also blocking a2 receptors, they prevent the negative feedback of NE release, which causes reflex tachycardia.
a1/b blockers - these decrease SVR through inhibiting a1 and also block the increase in HR, SV and CO from inhibiting b receptors.
catecholamine depleters - These irreversibly inhibit VMAT, which packages monoamines into vesicles. Without VMAT, monoamine storage is depleted, which decreases synaptic transmission. Decreasing NE causes vasodilation
What are the mechanistic differences between 1st, 2nd, and 3rd generation b-blockers and a1/b blockers?
b1 is primarily in cardiac muscle. b2 is widespread throughout cardiac muscle, skeletal muscle, vascular smooth muscle, bronchial smooth muscle, liver, and CNS.
1st gen - non-selective; Blocks b1 and b2. Inhibiting b1 reduces HR and SV to reduce blood pressure, which leads to reduction in renin release. These can cause rebound tachycardia
2nd gen - these are b1 selective, so there’s less bronchoconstriction
3rd gen - these are b1 selective, but they also have a 2nd mechanism of action. Nebivolol also has b3 stimulation to increase NO, which causes vasodilation. Betaxolol also has CCB effect.
How does antagonism of a1 and a2, agonism of a2, and antagonism of b1 and b2 impact VR, CO, and BP?
a1 antagonism - decrease vascular resistance by dilating arteries and veins
a2 agonists - decrease cardiac output and vascular resistance by increasing inhibitory effect of SNS (inhibits a1 and b receptors)
a2 antagonism - decreases the NE blockade, which does the opposite of what we want. It increases sympathetic effect, increases HR and VR
b1 antagonist - Reduces heart rate and stroke volume. Due to reduction of renin release, it can also cause vasodilation.
b2 antagonist - causes vasoconstriction when blocked, but causes adverse effects due to widespread location of b2 receptors.
What are the indications and contraindications of these: a1 antagonists, a2 agonists, nonselective a-blockers, b-blockers, catecholamine depleters
a1 antagonists - rarely used for HTN, except good for pheochromocytoma, otherwise 3rd or 4th choice.
- Contraindicated in…
a2 agonists - methyldopa first choice for pregnancy
- Contraindicated in…
nonselective a-blockers - hypertensive emergency (rarely used)
b-blockers - not 1st line for HTN
- Contraindicated in asthma, COPD, and CHF
a1/b blockers - labetalol can be used in pregnancy (pre-eclampsia), also useful in aortic dissection
catecholamine depleters - 2nd line for HTN
What is the biosynthesis pathway of angiotensin II and what is its role in HTN?
- Renin is released to the blood
- Angiotensinogen is released from liver into the blood
- Renin + angiotensinogen converts to angiotensin I
Angiotensin-converting enzyme (ACE) in pulmonary blood converts angiotensin I -> angiotensin II
Angiotensin II in BP -
1. Stimulates adrenal cortex to release aldosterone, which causes NaCL + H2O retention, increasing BP
2. Causes constriction of smooth muscle cells, increasing BP
3. Activates thirst center in pituitary gland to release ADH, causing person to drink more, increasing BP
4. Modulate baroreceptor reflex, increasing BP without reflex bradycardia
5. Causes cardiovascular hypertrophy by increasing contraction, increasing BP
By what mechanisms is renin released? What role does renin play in HTN?
Renin is released by juxtaglomerular cells in the kidney.
This happens due to:
- drop in BP in the pre-glomerular arteries (<90 systolic)
- low NaCl in the distal tubule of the kidney (via sensors in Macula Densa)
- increased sympathetic nervous activity (b1), or other signaling mechanisms
Renin increases blood pressure by producing angiotensin II downstream
What are the RAAS modulators and what class are they in?
RAAS: Renin-angiotensin-aldosterone system
Renin inhibitor:
- Aliskirin (Tekturna) directly inhibits renin.
- b1-blockers indirectly inhibit renin by blocking b1-AR mediated release of renin
ACE inhibitor: (-pril) lisinopril, enalapril (prodrug), captopril
AT 1 Receptor blocker: (-sartans) losartan, valsartan
What are similarities and differences between ACE-Is and AT1 receptor blockers in terms of clinical use, adverse effects, and contraindications?
ACE-I:
- use: HTN, HFrEF, MI, diabetic nephropathy, captopril good for orthostatic HTN
- adverse effects: first dose hypotension, hyperkalemia, acute renal failure, dry cough, angioedemia
- contraindications: pregnancy, SCr > 2.5, african-americans
AT1 receptor blockers: reduce BP and vasoconstriction
- use: HTN, CHF, diabetic nephropathy, stroke prophylaxis, losartan is good for gout
- adverse effects: first dose(s) hypotension, hyperkalemia (less than ACE-Is), teratogenic
- contraindications: pregnancy, hyperkalemia
What is the role of bradykinin in HTN and the therapeutic efficacy of ACE-Is?
Inhibition of ACE would stimulate bradykinin production. Bradykinin causes natriuresis and vasodilation, which is good for BP. Bradykinin also causes bronchoconstriction, which is why ACE inhibitors are known to cause a dry cough.
Thiazides - MOA?
MOA - Inhibits Na+-Cl- symport, so Na+ stays in the lumen. This happens primary in the distal convoluted tubule. This also impacts K+ reuptake
Ex. HCTZ, Chlorthalidone, Metolazone
Loop diuretics - MOA?
MOA - Inhibit Na+-K+-2Cl1 symport, thus preventing Na+ from leaving the lumen. Because water follows sodium, more water is excreted. This action is in the thick ascending limb
Ex. Furosemide, Bumetanide, Ethacrynic acid, Torsemide
K-sparing diruetics- MOA?
MOA -
- 1st class: Inhibit renal epithelial Na+ channels, thus preventing Na+ from leaving the lumen. This also keeps K+ out of the lumen. This happens primarily in the last distal tubule and collecting duct. Ex. Amiloride, Triamterene
- 2nd class: MRAs block the production of ATP-ase, which prevents Na+ from leaving the lumen and K+ getting into the lumen. Ex. Spironolactone, Canrenone, Eplerenone
What are the intracellular/extracellular distributions of Na+, K+, and Ca2+ in excitable cells?
Na+: high outside of the cell (145mM), low inside of the cell (12mM)
K+: low outside of the cell (4mM), high inside of the cell (155mM)
Cl-: high outside of the cell (1.5mM), very low inside the cell (100nM)
What is the role of voltage-gated calcium channels in cardiac, vascular, and skeletal muscle?
Cardiac muscle - Blocking the channels has an antiarrhythmic effect. When Cav1.2 is phosphorylated (activated), the Ca2+ influx would increase contractility and force of contractions, and increase AV nodal action potential conduction rate.
Vascular smooth muscle - Blocking the channels causes vasodilation, resulting in a decrease in BP and relief of angina. This is because it inhibits the influx of calcium (from RYR2 stores)that triggers contraction.
Skeletal - Unlike cardiac/vascular muscle, skeletal muscle does not require extracellular calcium for contraction. Skeletal muscle contraction is between Cav1.1 and RYR1, which is not what CCBs interfere with.
What are the three chemical classes of calcium channel blockers? What are the names of the members in each class and what are the recognizable structures?
- Dihydropyridines: stucture has dihydropyridine ring. Ex. nifedipine, isradipine, felodipine, amlodipine
- Phenylalkylamines: Long alkyl chain with phenyl rings. Ex. verapamil
- Benzothiazepines: Ex. Diltiazem
What are the MOAs and tissue selectivities of the 3 types of CCBs?
Dihydropyridines - Interferes with gating. The (+) enantiomer interferes with opening of channel, (-) interferes with closing. Binds allosterically to the outside of the pore when the channel is closed, in order to prevent its opening. (tonic block)
- Most potent in smooth muscle (ex. coronary artery), doesn’t compromise cardiac function. These are voltage-dependent, which explains their action in vascular muscle instead of the heart
Phenylalkylamines - Slows conduction through SA node (HR) and AV node (force). Blocks inside the pore to prevent Ca2+ influx. Also causes some vasodilation.
- These are more cardioselective due to frequency-dependent block.
Benzothiazepines - These have a frequency-dependent block of Ca2+ channels and also some tonic block. They cause vasodilation (less than DHPs) and slow conduction through SA/AV nodes. The binding side overlaps the inside and outside of the pore.
- Directly inhibit the heart (less than verapamil, but more than DHPs).
What is the basis for frequency-dependent block and what is its role in calcium channel blocker tissue selectivity?
Frequency-dependent drugs, like verapamil, bind to the inside of the pore to block Ca2+ influx. This means the drug only works if the channel is open, resulting in a frequency-dependent block. The more time the channel is open, the better the drug works.
