Treatment of HTN Flashcards
1
Q
What is essential HTN?
A
HTN due to an unknown cause
2
Q
What is unique about the approval process of drugs for the Rx of HTN?
A
They require evidence that they are superior to the drugs that proceeded them for use.
3
Q
What are some distal diuretics?
A
- Hydrochlorothiazide (HCTZ)
- Metolazone
- Indapamide
4
Q
What are some loop diuretics?
A
- Furosemide 2. Torsemide 3. Bumetanide
5
Q
What are some K+sparing diuretics?
A
- Triamterene 2. Amiloride
3. Spironolactone 4. Eplenerone
6
Q
What is a sympatholytic antihypertensive?
A
Reserpine (peripheral action)
7
Q
What are some α-blockers?
A
a. Nonselective: Phenoxybenzamine
b. Selective: Prazosin, Doxazosin, Terazosin
8
Q
What are some BB’s?
A
A. Non-selective: Propanolol, Carvedilol, Pindolol, Timolol, Acebutolol, Labetalol
B. Selective: Metoprolol, Atenolol, Betaxolol, Esmolol
C. 3rd Generation: Bisoprolol, Nebivolol
9
Q
What are the drug classes that have antihypertensive effects?
A
- Diuretics
- Agents affecting SNS
- Agents interfering w/ RAS
- L-type CCBs
- Direct Vasodilators
- Centrally-acting α2-agonists
- Endothelin Receptor Blockers
10
Q
What are the types of diuretics useful in the Rx of HTN?
A
- Distal
- Loop
- K-sparing
11
Q
What types of agents affecting the SNS are useful in the Rx of HTN?
A
- Sympatholytic
- α-blockers
- BB’s
12
Q
What types of agents that interfere with the renin-angiotensin activity are useful in the Rx of HTN?
A
- ACEi’s
- ARB’s
- Renin inhibitors
13
Q
What are the ACEi’s?
A
the PRILs
- Captopril
- Lisinopril
- Enalapril
- Ramipril
14
Q
What are the ARB’s?
A
the SARTANs
- Losartan 2. Valsartan 3. Irbesartan
- Candesartan 5. Telmisartan
15
Q
What is the drug that acts as a renin inhibitor?
A
Aliskerin
16
Q
What are the two groups of L-type CCB’s?
A
- Verapamil and Diltiazem
2. The PINEs: Amlodipine, Nifedipine, Nicardipine Nimodipine
17
Q
What are the direct vasodilators?
A
- Minoxidil
- Sodium Nitroprusside
- Diazoxide
- Fenoldopam
18
Q
What are the centrally acting α2-agonists?
A
Clonidine, Guanabenz, Guanfacine, Methyldopa
19
Q
What is the drug that acts as an endothelin receptor blocker?
A
Bosentan
20
Q
What is normal BP? Pre-HTN? Stage 1 HTN? Stage 2 HTN?
A
Normal:160/>100
21
Q
Do you start Rx for HTN during the pre-HTN stage?
A
No, during pre-HTN, you monitor the patient and tell them to modify their diet, particularly to reduce their salt intake. Treatment does not begin until Stage 1 HTN.
22
Q
Even though we do not know the specific cause of essential HTN, we treat it anyway. Why?
A
B/c HTN has a straight-forward route to the development of CHF, stroke, and organ failure, and by treating it, you can help prevent these things.
23
Q
What are the organs involved in the regulation of BP?
A
heart, kidneys, and blood vessels
24
Q
The tone of resistance (arterioles) and capacitance (veins) blood vessels is regulated by what three things? What is their effect?
A
- SNS exerts its control via a barometric reflex: vasoconstriction or increase HR/contractility
- RAAS: vasoconstriction and hypervolemia (Na and water retention)
- Local release of hormones (Endothelin, NO, kinins, etc)
25
How does the SNS affect/regulate BP? On what organs does it act on?
1. It acts on the heart to increase the HR and the force of myocardial contraction.
2. It acts on the kidney to increase the production/release of Renin (RAAS).
3. It acts on the resistance vessels, which are precapillary arterioles to produce rapid vasoconstriction. It also acts on the veins, thereby preventing the pooling of blood and returning it to the heart faster.
26
How does the RAAS regulate/affect BP? How quickly?
In general, this is a slower acting system, but it has both fast actions and slower actions.
1. Fast Action: Production of ANGII, the most powerful vasopressor/constrictor in the body. ANGII is also acts on the PCT to increase reabsorption of NaCl and water, leading to hypervolemia and an increase in BP.
2. Slower Action: ANGII acts on adrenal cortex to increase production of aldosterone, which stimulates reabsorption of Na+ and excretion of K+.
27
How does the release of local hormones factor into the regulation of BP? Examples?
The locally released hormones, such as bradykinin and other kinins and NO cause vasodilation and a decreased in BP. While others such as endothelin, cause vasoconstriction and an increase in BP.
28
What is the nt of the SNS? What receptors does it act on?
Norepinephrine (NE); it acts on α and β receptors.
29
What type of receptor are α1-R's and ANGII-R's? What is net result of activating this type of receptor?
They are coupled to Gq proteins. The net result is increased intracellular Ca2+ causing contraction of smooth muscle cells, and vasoconstriction of vessels.
30
How does activation of a Gq-coupled receptor lead to increased intracellular Ca2+ concentration? What does the increased Ca2+ then cause? (aka what is the result of SNS stimulation of vessels)
Gq activation→Phospholipase C activation→cleavage of PIP2 into DAG and IP3→ IP3 acts on IP3-R's of SR→release of Ca2+ from SR into the cell→smooth muscle cell contraction→vasoconstriction
31
What is the currency smooth muscle cell tone?
Ca2+: As [Ca2+] increases, there is more vasoconstriction
32
What type of adrenergic receptors are located in the heart?
β-R's, primarily β1's
33
What type of receptor are the β-R's?
They are coupled to Gs proteins
34
What happens in the cardiac cells when activation of the β-R's results in Gs activation? (aka what is the result of SNS stimulation of the heart?)
Gs activation→activation of adenylate cyclase (AC)→increased production of cAMP from ATP→cAMP activates PKA→phosphorylation of L-type Ca2+ Channels (L-tCCs)→increased entry of extracellular Ca2+ into heart cells→increased force of myocardial contraction and increased HR
35
What type of effects does SNS have? What receptors does it signal thru? What is the mechanism of these receptors?
The SNS has both excitatory and inhibitory effects.
It signals thru two major GPCRS (metabotropic):
α and β adrenergic receptors
36
How are α and β-mediated responses accomplished? Where?
1. α1 responses occur in blood vessels are due to Ca2+
2. Centrally located α2 responses inhibit the vasomotor center (RVLM)
3. β responses are due to cAMP, the heart is the major site
37
What are the two main nt's of the SNS? Where are they released from? What type of transmission are they involved in?
NE is the nt released from postganglionic sympathetic nerve terminals. While E is made in the adrenal medulla and enters the blood stream, where it acts as the circulating arm of the catecholamines/SNS.
This is adrenergic transmission.
38
On what receptors does NE act and where? Result?
1. β1's in the heart (not on β2's in lungs or vessels), where it increases force of myocardial contraction, HR, and the rate of relaxation of heart muscle. Net result: pumps more volume at higher rate.
2. It acts primarily on α1's of blood vessels, causing vasoconstriction of arterioles and venules.
3. α2's on presynaptic terminal membrane, inhibiting the further release of NE.
39
How are catecholamines (Dopamine, NE, E) made?
Tyrosine is transported into presynaptic terminal→tyrosine hydroxylase converts it to DOPA→Dopamine (transported into vesicle by VMAT aka Uptake2)→NE→E
40
What antihypertensive is an adrenergic neuron blocker (ANB) aka peripheral sympatholytic?
Reserpine
41
What is the mechanism of action of Reserpine?
It inhibits Uptake2 (VMAT), which transports NE/dopamine into presynaptic vesicles, so it prevents the packaging of NE into vesicles→depletion of NE and 5-HT from neurons and depletion of E from adrenal gland
42
What is the net effect of Rx with reserpine?
Depletion of NE/E→decreased NE/E release→decreased sympathetic tone→reduced TPR, CO, Renin release, and BP
43
What is the clinical use of Reserpine?
Reserpine is used orally for mild to moderate HTN
44
What are the side effects and contraindications of Reserpine?
1. Mostly CNS Effects: sedation, mental depression, bad dreams. Do NOT give to someone w/ history mental depression (INCREASES SUICIDAL TENDENCIES)
2. Increased incidence of duodenal and gastric ulcers, and is contraindicated in pt's w/ PUD or ulcerative colitis
45
What are the three prototypical α1-blocker agents?
the OSINs or AZOSINs
1. Prazosin
2. Doxazosin
3. Terazosin
46
How does NE generate vasoconstriction thru α1-R's? Where are α1's located?
NE binds α1-R→Gq activation→PLC→PIP2 to DAG and IP3→IP3 releases Ca2+ from SR→sm m contraction→vasoconstriction
α1's are located in arterioles and a little bit in veins
47
What is the mechanism of action of α1-blockers?
They block peripheral α1-R's in arterioles and venules, causing vasodilation, which reduces TPR and BP.
48
What is the pharmacologic effects of α1-blockers?
1. Decrease TPR and BP
2. Relieve symptoms of BPH by relaxing bladder and prostate muscles
3. Increase HDL-C and lower LDL-C, and also have a beneficial effect on insulin resistance
49
What is the clinical use of Prazosin?
Mainly used as an antihypertensive
50
What is the clinical use of Terazosin and Doxazosin?
They are the preferred drug of older for older men w/ BPH and HTN who are otherwise healthy
51
What are the side effects of α1-blockers?
1. First dose hypotension (faint when try to stand up; goes away w/ time), esp w/ PRAZOSIN, so give them at bed time
2. Dizziness and vertrigo, drowsiness, palpitations
52
What are the nonspecific α-blockers? Mech of action? Clinical Use?
Phentolamine, Phenoxybenzamine. They block both α1 and α2-R's.
Used to control HTN in pt's w/ Pheochromocytoma (prevention of hypertensive crisis due to NE excess)
53
What are four important parameters to pay attention to w/ BB's?
1. Intrinsic sympathomimetic activity (ISA)
2. Membrane Stabilizing Activity (MSA)
3. Cardioselectivity (β1-selectivity)
4. Lipid Solubility
54
What does it mean if a BB has ISA?
The drug binds to the β1-receptor and blocks it, but somehow it activates it a little bit. This ISA is referred to as partial antagonist or an antagonist partial agonist activity.
55
What is a BB with ISA? What is BB that is pure antagonist with no ISA?
ISA: Pindolol
| No ISA: Propanolol
56
What is a BB with high MSA? What is MSA associated with?
Propanolol (most of the others have low MSA).
MSA is related to the anti-arrhythmic activity of the drug. If it stabilizes the neuronal membrane, then it prevents the spread of currents involved in arrhythmias.
57
What is cardioselectivity? Why is it important to consider cardioselectivity when giving a patient a BB?
Cardioselectivity refers to BB's that have specificity for β1's in the heart over β2's in the lungs. BB's can be β1-selective or nonselective (act on β1 and β2). A nonselective BB can block β2's in the lungs and cause difficulty breathing, so they should be avoided w/ asthma/COPD.
58
Why is lipid solubility of BB's important?
The more lipid-soluble they are, the easier they can cross the BBB and enter the CNS.
59
What are some nonselective BBs? What are some β1-selective BBs?
Nonselective: Propanolol, Timolol, Pindolol
Selective: Metropolol, Atenolol
60
What is the mechanism of action of BB's with no ISA? (4)
a. They block myocardial β1-R's→decrease HR, contractility, and CO
b. All but Pindolol lock β1-R's in JGA of kidney→inhibit renin release
c. Reduced central sympathetic outflow (unless low lipid solubility)
d. Decreased release of peripheral NE by blocking presynaptic β-R's
61
Due to their actions in the kidney, BB's are especially useful in lowering BP in what type of patients?
Patients w/ high renin HTN (but they do work in patients with normal to low renin)
(low renin HTN is volume-dep HTN)
62
What is the result of chronic use of BB?
1. Decrease CO
2. Decrease peripheral resistance
3. Decrease arterial pressure
63
Other than the extended actions of 3rd-generation BBs, how do 1st and 2nd generation BBs differ from those of the 3rd generation?
1st and 2nd generation BBs have more side effects in general and they have more metabolic side effects than the 3rd generation.
64
What are BB's effective in treating?
All grades of HTN.
65
Are BBs more effective in high-renin or low-renin HTN?
They are more effective in high renin HTN (easier to tx; in young and caucasians) b/c they lower renin levels. They still work in low-renin HTN (hard to tx; in elderly and african americans) but are less effective.
66
The antihypertensive effect of BBs is additive when given in combination w/ what drug? Why? Does it have to be given w/ this drug?
BBs do not cause retention salt and water and can be administered w/out a diuretic. However, their anti-hypertensive effect is additive w/ a diuretic.
67
What are the compelling indications for the use of a BB (aka BB is the preferred choice of tx)?
1. Highly preferred in hypertensive pt's w/ conditions such as MI, ischemic heart disease (IHD), or CHF.
2. Preferred in hypertensive pt's w/ hyperthyroidism and migraines. (b/c BB's protect the heart from the effect of thyroid hormone).
68
What are some additional uses of BB's in general? (4) What are two of their off-labeled uses? (2)
1. CHF: decreased mortality in patients w/ HF, so esp useful in those patients who also have HTN.
2. MI: useful in preventing 2nd MI in pt's w/ IHD by causing bradycardia.
3. Sinus and AV arrhythmias
4. Open angle glaucoma: given as eyedrop to reduce production of aqueous humor.
Off-labeled uses:
1. Stage fright
2. To erase memories of horror
69
Which BB's are associated w/ reduced mortality in CHF?
1. CARVEDILOL
2. Metropolol-XL
3. Bisoprolol
70
What is the effect of propanolol? What is useful as? Why?
It's a nonspecific BB that produces bradycardia and decreases HR during exercise→Hypotension.
B/c of its MSA, it's useful as an antiarrhythmic.
71
In what type of pt is the use of Propanolol contraindicated in? Why?
Asthmatics. B/c it's not cardioselective, it causes bronchospasm.
72
How should propanolol be discontinued when it's no longer needed for a patient? Why?
Withdraw it slowly to prevent reflex tachycardia, as chronic blockage of the β-R's led to increased density (upregulation) that can now be activated by NE.
73
What are the two most cardioselective BBs?
Metropolol and Atenolol
74
What is important about Bisoprolol?
a. Long acting β1-specific (only have to take it once a day)
b. Commonly used bc decreases ALL cases of mortality
c. As eye drops for glaucoma
75
What is the selectivity/activity of Pindolol and Acebutolol? What does this result in?
They are non-selective BB's w/ partial agonist activity (ISA). Thus, they reduce CO and HR less than other BBs
76
What is important about the PK's of Esmolol? How is it used and for what?
It is β1-selective w/ a very short half-life (8 min); given IV for management of tachycardia, arrhythmias during surgery and postoperative tachycardia caused by HALOTHANE ANESTHETIC.
77
Timolol (and 5 other BB's) has what type of selectivity? What is it used for?
Non-selective BB used as eye drops for Rx of chronic open angle glaucoma.
78
What are the side effects of 1st and 2nd generation BB's? (7)
1. Cold Extremities
2. Bradycardia (sometimes this is the desired effect but can be in excess)
3. Bronchospasm
4. CNS side effects
5. Metabolic effects
6. Drug withdrawal syndrome
7. Others (fatigue, decreased exercise tolerance, impotence)
79
Why do BB's cause cold extremities? What happens in this respect w/ prolonged BB use?
Unopposed α-mediated action constricts blood vessels in the skin and limits blood flow, causing cold extremities.
Prolong use worsens peripheral arterial insufficiency and can cause Raynaud's Phenomenon
80
What effect of BB's leads to bradycardia? What type of drugs are contraindicated w/ BB's?
Decreased AV nodal conduction.
| Contraindicated w/ Verapamil and Diltiazem, which also slow AV nodal conduction
81
What are the contraindications of BB's given that they cause vasospasm?
Avoid ALL BB's in pt's w/ ASTHMA.
| BB's are permitted w/ COPD, but generally aren't used.
82
What are some of the CNS side effects caused by BBs?
Bad dreams, and even hallucinations and depression
83
What are the two metabolic side effects of BB's?
1. They block glycogenolysis and delay recovery from hypoglycemia in Type 1 Diabetics (more commonly w/ non-selective, but also w/ selective).
2. They block hormone-sensitive lipase (HSL) in adipocytes and increase LDL and triglycerides, while decreasing HDL.
84
Why are BBs associated w/ drug withdrawal syndrome? What is the effect? How is it prevented?
Prolonged drug use upregulates β-R's in the heart. So, abrupt w/drawal causes TACHYCARDIA. To prevent this, w/draw the BB SLOWLY.
85
What are two 3rd generation BB's w/ combined α and β-blocking activity? What does this mean?
1. Labetalol 2. Carvedilol
| These are nonslective β and α1 antagonists (blockers)
86
What is the clinical use of Labetalol?
Given IV for hypertensive (HT) emergencies
87
Why does Carvedilol give a little more of a reducing effect on BP?
By blocking α1-R, CO is maintained while peripheral resistance falls.
88
What is another additional role of Carvedilol? What are the 3 effects of this?
It's an ANTIOXIDANT (scavenges ROS). It protects membranes from lipid peroxidation, prevents LDL oxidation, and reduced LDL uptake into coronary blood vessels.
89
Carvedilol is the #1 drug used to treat what? Why?
Pt's w/ CHF and HTN b/c it reduces mortality and morbidity in patients w/ mild to moderate CHF.
90
What are two important things about Carvedilol's PKs?
Extensively protein-bound
| Hepatic CYP2D6 metabolism
91
What is the additional action of the BB Celiprolol? What about Nebivolol? Are they cardio-selective?
1. Celiprolol: Cardioselective and β2-R agonism.
| 2. Nebivolol: Cardioslective and NO-mediated vasodilation
92
What is the result of Celiprolol's β2-agonism? What is it used for clinically?
It directly vasodilates blood vessels due to partial β2-agonist activity.
Used for tx of pt's w/ HTN and ANGINA
93
What are 4 important characteristics of Nebivolol activity?
Highly β1-selective; no ISA, no MSA, and no α1-blocking activity
94
What is the additional action of nebivolol?
It promotes endothelial NO-mediated vasodilation (it increases NO).
95
Nebivolol is the drug of choice in the Rx of what? Why?
Drug of choice for HTN w/ Metabolic Syndrome (obese pt's w/ T2DM and HTN). This is b/c it has ANTIOXIDANT activity w/ neutral to favorable effects on both carbohydrate and lipid metabolism. It a) decreases BP, HR, and PVR, b) increases SV, c) maintains CO and systemic blood flow.
It does all this w/out hurting metabolism.
96
What are the 3 antihypertensive drug classes that affect the RAAS?
1. ACEi's
2. ARB's
3. Renin Inhibitors (RI's)
97
What is the affect of ANGII on blood vessels? How does it do this?
It is a powerful vasconstrictor/vasopressor.
| This action it mediated by ANGII binding to ANG Type 1 Receptors.
98
What are four examples of ACEi's?
The PRILs
1. Captopril
2. Lisinopril
3. Enalapril
4. Ramipril
99
What are the two functions of ACE?
1. It converts ANGI to ANGII
| 2. It breaks down Bradykinin (potent vasodilator), Substance P, and Ekephalins
100
Is ACE the only the enzyme in the body that can convert ANGI to ANGII?
No, there are others, but it is the major enzyme that does this.
101
What is the mechanism of action of ACEi's?
They inhibit the conversion of AngI to AngII and the degradation of the potent vasodilator bradykinin.
102
The hypotensive effects of ACEi's result from what?
a) inhibiting the action of ANGII
| b) stimulating the action of the kallikrein-kinin system (vasodilator)
103
How are aldosterone, renin, and ANGI levels affected by ACEi's?
1. Aldosterone secretion is reduced (bc ANGII stimulates its release), but not seriously impaired.
2. Production of Renin and ANGI are increased.
104
What is the result of the increased ANGI levels caused by ACEi's?
Accumulating ANGI is directed down alternative metabolic routes, increasing the production of vasodilator peptides ANG1-7.
105
What is the importance of increased ANG1-7?
They are believed to be cardioprotective
106
How do ACEi's influence renal blood flow (RBF) and filtration fraction (FF)?
Some (but not all) ACEi's increase RBF via vasodilation of afferent and efferent arterioles.
Increased RBF occurs without an increase in GFR, thus FF decreases. (FF=GFR/RBF)
107
What are the pharmacological effects of ACEi's? (5)
1. Inhibit all known effect of ANGII.
2. Decrease TPR and BP in hypertensive states.
3. Dilate BOTH arteries and veins
4. Reduced BP is rarely followed by minor increase in HR.
5. Reduce ANGII-mediated thickening and neo-intima formation (narrowing) in blood vessels.
108
What is the basis for the use of ACEi's in CHF?
They dilate both arteries and veins, which reduces both the afterload and preload, which are normally both increased in CHF.
109
The decrease in BP caused by ACEi's is greatest in what type of patients?
patients with Na+ retention (high levels of Na+ and H2O in their body) or high renin
110
Is postural hypotension seen with ACEi's? Why?
Postural hypotension is not seen because the baroreceptor mechanisms remain intact.
111
What kind of effect do ACEi's have on people with CHF and HTN?
Their use is associated with positive impact on longevity of pt's with CHF and HTN.
112
What are the 5 actions of ANGII in the CV system that are blocked by ACEi's?
1. ANGII acting on ANG Type I Rec causing vasoconstriction
2. ANGII acting on PCT to increase Na and H2O retention, causing hypervolemia.
3. ANGII acts on adrenal cortex to increase secretion of Aldosterone to increase Na retention and increase K excretion.
4. ANGII increases perception of thirst
5. Thru the transcr. factor PKC, ANGII increases the genes in the blood vessels that cause neointimal thickening and remodeling of blood vessels and the heart (cardiac and vascular hypertrophy).
113
What is the mechanism of action of Captopril? What does this result in?
Captopril increases the synthesis of vasodilatory PG's in vascular and RENAL endothelium. This is RENOPROTECTIVE (increase RBF)→ it delays (or even prevents) the progression of the renal disease in type 1 diabetics as RBF increases.
114
What is the compelling indication for the use of Captopril?
It's the preferred antihypertensive drug in pt's who have or are risk of renal failure (b/c it increases renal PG synthesis).
115
What is important about the PK's of Enalapril? What is its clinical use?
It's a PRODRUG.
| It's a potent ACEi that's available IV for HTensive emergencies.
116
What is Lisinopril derived from? How is it useful?
It's a lysine derivative of active from of enalapril. It's renoprotective.
117
What are the two renoprotective ACEi's?
Captopril and Lisinopril
118
What is important about the PKs of Ramipril?
It's a prodrug, that has a long half-life, so it only has to be given once a day.
119
What are the side effects of ACEi's? (5: especially know 3, 4, and 5)
1. Hypotension in hypovolemic and/or Na-DEPLETED pt's, esp w/ 1st dose.
2. Hyperkalemia (esp in pt's w/ renal insuff, taking K-sparing diuretics, or K supplements)
3. DRY COUGH (most common)
4. ANGIOEDEMA (or angioneurotic edema) is infrequent but potentially fatal.
5. FETOTOXICITY/TERATOGEN, so contraindicated in pregnancy
120
What causes the dry cough associated with ACEi's? What do you do if a pt has a dry cough from and ACEi?
Increased levels of Bradykinin, which interact with stretch receptors in the throat/trachea causing the cough in 10-15% of pt's on ACEi's.
Switch them to an ARB.
121
In what patients are ACEi's contraindicated in?
1. Pregnancy
| 2. Patients on K-sparing diuretics or K+ supplements→HYPERKALEMIA (also patients with renal failure).
122
What are the five Angiotensin Receptor Blockers (ARBs)?
The SARTANS
1. Losartan
2. Valsartan
3. Irbesartan
4. Telmisartan
5. Candesartan
123
What is the mechanism of action of ARBs?
They selectively block ANGII Type 1 Receptors, which are responsible for all of the vascular, renal, and central effects of ANGII.
124
What is the effect of Rx w/ and ARB?
They cause vasodilation and increase Na+ and water secretion.
Thus, they decrease TPR, plasma volume, CO, and BP.
125
Why are patients on ACEi's who develop a dry cough switched to an ARB?
ARBs have no effect on bradykinin, and therefore, don't cause the cough.
126
What is an important off-label use of Losartan?
It is a competitive antagonist of TXA2 Receptors so it attenuates platelet aggregation.
127
Losartan is the only ARB that has what two effects?
1. It increases Uric Acid urinary excretion (Uricosuric).
| 2. It inhibits CYP3A4 activity
128
Losartan is the preferred drug in the Rx of what?
HTN in patients with gout (b/c it increases uric acid urinary excretion)
129
Which two ARBs are prodrugs?
Losartan and Valsartan
130
Which ARB has the shortest half-life? Which has the longest?
a. Shortest→Losartan, take it 2x a day
| b. Longest→ Telmisartan, 1x a day
131
Which ARB is the ARB of choice in pt's with HTN and renal failure? Why?
Telmisartan, b/c it is the only ARB that is not cleared renally (by the kidney)
132
Why do you need to worry about possible drug-drug interactions with Losartan?
It inhibits CYP3A4, which may interfere with the metabolism of drugs that are degraded by CYP3A4
133
What are the side effects of ARBs? (4)
1. Hypotension (in hypovolemic and/or Na-depleted pt's)
2. Hyperkalemia (esp in renal insufficiency, or in pt's using K-sparing diuretics or K+ supplements)
3. Hepatic Dysfunction (losartan and valsartan)
4. Fetotoxicity (avoid ARBs and ACEi's in pregnant women)
134
What two ARBs are known to Hepatic dysfunction as a side effect?
Losartan and Valsartan
135
What drug is a renin inhibitor (RI)?
Aliskiren
136
What is the mechanism of action of the renin inhibitor aliskiren?
It's a non-peptide inhibitor of renin. Therefore, it decreases ANGII levels.
137
What are the clinical effects of the RI Aliskiren?
An effective antihypertensive that induces a significant dose-dependent decrease in BP.
138
What are is the therapeutic use of the RI aliskiren?
It is NOT used as a monotherapy.
| It is used in combination with other antihypertensives such as ACEi's or ARB's or with a diuretic such as HCTZ.
139
What are the two major classes of L-type Ca2+ Channel Blockers (LtCCB's)?
1. Non-DHPs→Verapamil ( a phenylalkylamine) and Diltiazem (a benzothiazepine)
2. The Dihydropyridines (DHPs; the diPINEs)
140
What is the effect of blocking LtCC's?
LtCCs are conduits for Ca2+ to enter smooth muscle cells. If blocked:
a) Less Ca2+ can enter the VSM, resulting in vasodilation.
b) In the heart, reduced Ca2+ reduced CO (not a good thing)
141
What is the main general difference between the DHPs and non-DHPs?
The non-DHPs block LtCC's in the blood vessels and in the heart. They have CARDIAC EFFECTS and can cause CHF.
The DHPs only block LtCC's in blood vessels, and thus, they do NOT have cardiac effects.
142
What is the relative selectivity of Verapamil for cardiac vs. vascular LtCC's?
Relatively selective for myocardium; less effective as systemic vasodilator
143
What is the relative selectivity of Diltiazem for cardiac vs. vascular LtCC's?
Intermediate b/t verapamil and DHPs in its selectivity
144
What is the relative selectivity of DHPs for cardiac vs. vascular LtCC's?
DHPs selectively block LtCCs in blood vessels.
145
Which CCBs are used to treat HTN? Why?
DHPS, b/c they reduce SVR and arterial pressure
146
What is the pharmacologic effect of DHPs?
They reduce BP by relaxing arteriolar and venous VSM (vasodilation) which reduces peripheral vascular RESISTANCE.
They do NOT cause a large baroreceptor-mediated symp discharge and changes in HR are mild to non-existent.
147
Why should short-acting DHPs not be used for HTN? What is an example?
Nifedipine; they should not be used for HTN b/c they they produce a very rapid decrease in BP, which results in an increase in HR by reflexively activating the SNS.
148
Compared to other antihypertensives, DHP CCBs are more effective in lowering BP in what type of patients?
DHPs are more effective in lowering BP in patients with LOW RENIN HTN, which is common in the ELDERLY and AFRICAN-AMERICANS.
149
DHPs are the preferred drug for what patients?
Older or african-american patients with SYSTOLIC HTN.
150
What are the general side effects associated with DHPs?
1. Peripheral (ankle) edema
2. Reflex Sympathetic response→ Reflex Tachycardia (increase HR)
3. Hypotension
4. Constipation (pt may need a laxative)
151
What DHP is associated with the side effect of reflex tachycardia (sympathetic reflex that increases HR)?
Regular Nifedipine (less often with sustained release form)
152
What are the five Direct Vasodilators used as antihypertensives?
1. Hydralazine
2. Minoxidil
3. Diazoxide
4. Fenoldopam
5. Nitroprusside
153
In what setting are Direct Vasodilators used? For the management of what?
The majority of direct vasodilators are used in the hospital setting for the management of HTensive emergencies, such as Pre-eclampsia during pregnancy.
154
What does hydralazine do? What does this cause?
It is a selective arteriolar smooth muscle relaxer. This arteriolar dilation alone (no venous dilation) triggers REFLEX SYMP stimulation→increases catecholamine and renin secretion→ refliexively increases HR and contractility, while causing venoconstriction and Na/H2O retention.
155
What is the net effect of Rx with hydralazine?
Decrease in BP that causes fluid retention
156
What is the clinical use of hydralazine?
IV use in HTensive emergency from eclampsia.
LImited use elsewhere b/c it causes SNS activation and Na+ retention (if you give them for more than a week, have to add a diuretic)
157
What are the side effects of Hydralazine?
1. Palpitations; pronounced tachycardia (may trigger angina)
| 2. Autoimmune Rxns: hemolytic anemia, glomerulonephritis, Lupus-like syndrome (most common)
158
Why can you not use direct vasodilators alone for a long period? What do you need to combine them with?
They cause an increase in contractility and HR due to reflex stimulation of SNS and Na/H2O retention.
So, you give them with a BB (to decrease HR and contractility) and DIURETIC (to prevent water retention).
159
What is the mechanism of action and effect or Minoxidil?
It relaxes arteriolar smooth muscle (vasodilates) by OPENING POTASSIUM CHANNELS in arteriolar smooth muscle.
160
Does Minoxidil dilate arterioles, veins, or both? What does this result in?
It dilates Arterioles but NOT veins. This leads to reflex tachycardia and activation of renin secretion. (so take with BB and diuretic if for long period)
161
What are the side effects of Minoxidil?
1. Powerful activator of renin release
| 2. Causes Hirsutism (increased hair)→ topical minoxidil is rogaine used to treat baldness.
162
What are the mechanism of action and effects of Diazoxide?
It prevents VSM contraction by opening K+ channels, which stabilizes the resting membrane potential.
It acts mostly on arterioles, causing sympatho-excitation and reflex tachycardia→retention of Na/H20, increases renin, increased CO.
163
Hypotensive effects of Diazoxide are greater if it's given with what drug? Why?
The hypotensive effects are greater if given with a BB to prevent reflex tach and increase in CO.
164
What are the side effects of diazoxide?
1. Na and water retention
2. Pronounced tachycardia, palpitations
3. Hyperglycemia
165
Why does diazoxide cause hyperglycemia? What clinical use does this give diazoxides?
It inhibits insulin release. Therefore, it is used to treat Insulinomas.
166
What is Fenoldopam? What is its clinical use?
Fenoldopam is an agonist of Dopamine D1 receptors that has a very short half-life given by continuous IV drop to Rx HTensive emergencies (and renal HTN b/c D1 receptors are in renal arterioles)
167
What are the side effects of Fenoldopam? Contraindication?
1. Reflex Tach
| 2. Increased intraocular pressure→DONT give to pt's with glaucoma
168
What is the mech of action of Nitroprusside?
Mainly works a prodrug→forms NO→stimulates smooth muscle GC→increases levels of cGMP in VSM→VSM relaxation/vasodilation
169
What are the pharmacologic effects of Nitroprusside?
It dilates BOTH arteries and veins→decreases both afterload and preload (b/c it does both, its useful in Rx of HF), as it reduces TPR and induces venous pooling
170
How does Nitroprusside affect CO? Why is this important?
a. It decreases CO in normal patients
| b. It increases CO in pt's with LV Failure (LVF) b/c TPR (afterload) is reduced.
171
What are the qualities of drugs that make them useful in the Rx of HF?
they reduce both preload and afterload
172
What is the durability of Nitroprusside? What is it used for?
It has a very short half-life.
| It's given IV for HTensive emergencies in patients with LVF.
173
What are the side effects of nitroprusside?
1. Excessive hypotension
2. Pronounced tachycardia, palpitations
3. It's metabolized to CYANIDE and can cause CYANATE or thiocyanate toxicity
174
Why do you give the smallest dose of nitrprusside for the shortest periode possible?
to avoid cyanate poisoning
175
What are the centrally-acting α2A-R agonists? (4)
1. Clonidine
2. Guanfacine
3. Guanabenz
4. α-methyl-Dopa
Clonidine and α-methyldopa are the principal agents in this class
176
What is the mechanism of action and effect on the CV system of Clonidine, Guanfacine, and Guanabenz?
The agonists bind and activate postsynaptic α2-R's (inhibitory when activated) in the rostral ventrolateral medulla (RVLM) →reduced sympathetic impulses from RVLM to heart and blood vessels→a)reduced peripheral vascular resistance and b)SIGNIFICANTLY REDUCED HR.
177
In addition to being an antihypertensive, what are two additional uses of Clonidine?
1. It releases endogenous opiates so, its used as an ANALGESIC in neuropathic pain.
2. Rx of ADHD
178
What is an additional effect of Guanabenz?
It lowers cholesterol in the plasma by 5-10%
179
What are the side effects of α2-agonists?
1. ***SEDATION (KNOW THIS ONE)***(less so with guanfacine), drowsiness, fatigue
2. Contact dermatitis with patch formulation
3. Clonidine withdrawal→severe hypertension, so you have to withdraw it slowly
180
What is the mech of action of α-methyl-Dopa?
Prodrug converted to α-methyl-NE, which a) is a FALSE TRANSMITTER→the addition of the methyl group inhibits the activity of NE, and b) it's also an α2-agonist in RVLM→reduces SNS tone/activity.
181
What is the pharmacologic effect of α-methyl-Dopa/NE?
Stimulation of central α2-R decreases sympathetic tone and leads to reduction in BP, mainly due to decrease in TPR.
182
What is the clinical use of α-methly-dopa?
Pretty much obsolute; sometimes for HTN in pre-eclampsia
183
What are the side effects of α-methyl-dopa?
1. SEDATION, sleep disturbances, erectile dysfunction
2. Na and water retention
3. Lactation due to increased prolactin secretion
4. Immunolocial (+) Cooms in less than 25% of pt's
184
What is Bosentan? What is its clinical indication for use?
An endothelin-1 and endothelin-2 receptor antagonist (endothelin is a powerful vasocontrictor).
Bosentan tablets are indicated for Rx of Pulmonary Artery HTN (caused by RHF).
185
What side effects of Bosentan has severely restricted its use?
1. Severe Liver Toxicity
| 2. Potential Fetotoxicity
186
How are diuretics used in the Rx of HTN?
As a monotherapy or adjunctive w/ other antihypertensives, as they augment the actions of ALL antihypertensives.
187
What are the best monotherapies for Rx of HTN?
Low dose Diuretics and ACEi's
188
Diuretics alone, or in combination w/ BBs, have what major general effect on pt's with HTN?
they reduce mortality in pt's with HTN
189
a) What type of pt's require a diuretic for optimal control of BP?
b) What type of pt's show better responses to diuretics?
a) pt's with edematous conditions, such as heart failure or renal insufficiency
b) pt's with volume-dependent (low renin) HTN show better responses (poor response indicated very high Na+ levels)
190
What is the special advantage of α1-blockers?
They improve both lipid profile and insulin resistance
191
How does α1-blocker use compare to a diuretic in the Rx of HTN?
α1-blockers are associated with a higher incidence of HF than diuretics
192
What types of patients are α1-blockers particularly useful in?
1. Young pt's with HTN who wish to remain physically active
| 2. Elderly pt's with HTN who also have BPH and otherwise normal CV function (b/c they relieve symptoms of BPH)
193
What is the main side effect of α1-blockers?
orthostatic hypotension, especially in the elderly
194
What is a major advantage of using BB's in the Rx of HTN compared to other antihypertensives?
In addition to antihypertensive effects, they provide secondary protection in CAD (coronary artery disease).
195
In what type of hypertensive patients are BB's particularly useful in?
1. HTensive pt's with tachycardia, high CO, and/or high renin (not elderly or african-americans)
2. HTensive patients with hyperthroidism, stage fright, migraines, or glaucoma
196
Why are 3rd generation BBs preferred over older BBs?
They have a smoother clinical effect and substantially fewer side effects
197
Which 3rd generation BB is considered the standard treatment option and used with ACEi's and diuretics?
Bisoprolol (b/c it has 34% mortalility benefit)
198
Why should BBs not be discontiuned abruptly?
If you dont taper off them slowly, the pt can get compensatory tachycardia due to upregulation of beta-receptors with long-term use of BB
199
What are the clinical uses of ACEi's?
1. Management of all degrees of HTN, but superior in hypertensives with high renin levels (young and middle-aged caucasians)
2. They increase efficacy of diuretics
3. They should be the initial anti-HTensive in *DIABETICS* with HTN (can then add a CCB)
4. Initial anti-HTensive in pt's prone to *CHF*
200
What are the contraindications of ACEi's?
1. Any condition that may cause hyperkalemia
2. Pregnancy
Also, if dry cough develops, switch to ARB
201
DHP CCBs are particularly useful in what type of pt's with HTN?
African-american and elderly who have low-renin HTN and also patients who want to remain active
202
Why do some patients wait to give CCBs until the pt has shown to be unresponsive or intolerant to diuretics, ACEi's, or BBs?
the risk of CAD and HF may be higher with CCBs than the others
