Lecture 3: Direct Acting Vasodilators Flashcards
1
Q
What is preload?
A
- The passive stretching of muscle fibers in the ventricles.
2
Q
What causes the stretching in Preload?
A
- The stretching results from blood volume in the ventricles at the end of diastole
- The more the heart muscles stretch during diastole, the more forcefully they contract during systole
3
Q
What is contractility
A
- Refers to the inherent ability of the myocardium to contract normally
4
Q
What influences contractility?
A
Preload, the greater the stretch the more forceful the contraction
5
Q
What is afterload?
A
(Resistance) Refers to the pressure that the ventricular muscles must generate to overcome the higher pressure in the aorta to get the blood out of the heart
6
Q
What is the narrow range that Arterial blood pressure is regulated?
A
120/80
7
Q
Why is arterial BP regulated within a narrow range?
A
to provide adequate perfusion of the tissues without causing damage to the vascular system, particularly the arterial intima
8
Q
Arterial BP is directly proportional to _ _ and _ _ _
A
cardiac output and peripheral vascular resistance
9
Q
What two overlapping mechanisms control cardiac output and peripheral resistance? ⭐️
A
- Baroreflexes (symp nervous system)
- Renin-angiotensin-aldosterone system (RAAS)
10
Q
What are the effect of most antihypertensive drugs?
Antihypertensive: decreasing BP
A
Reducing cardiac output and/or decreasing peripheral resistance
11
Q
What is the speed of the BP response mediated by baroreflexes (SNS)?
A
FAST= rapid, moment to moment
12
Q
What is the speed of BP response mediated by the renin-angiotensin-aldosterone system (RAAS)?
A
SLOW= Long-term
13
Q
What are the locations and nerves used for baroreceptors?
A
- Aortic arch receptors via the vagus nerve (CN X)
- Carotid sinus receptors via carotid sinus nerve to nerve IX (glossopharyngeal)
14
Q
Fill in the blanks for the factors that affect cardiac output
A
- Heart rate
- Contractility
- Filling pressure (blood volume & venous tone)
15
Q
Explain the pathway of the baroreflexes (mediated by SNS) response to a decrease in BP (SHORT TERM)
A
Decrease in BP→ ↑ Sympathetic activity via baroreceptors → Activates ⍺1 on the heart (↑ venous return and ↑ resistance) & β1 on smooth muscle (↑ CO, contractility, releases renin)→Increases BP
16
Q
Explain the pathway of the Renin-angiotension-aldosterone systen (RAAS) response to a decrease in BP (LONG-TERM)
A
Decrease in BP→↓ in renal blood flow→Release renin (&↓ glomerular filtration)→↑ Angiotensin 2→↑ Aldosterone→ ↑ water/Na+ retention→ ↑ blood volume→ ↑CO→Increases BP
17
Q
What are the two ways in which renin is released?
A
- Activation of β1 receptors (short-term)
- Low renal blood flow (long-term)
18
Q
Explain the renin-angiotensin-aldosterone system
A
Angiotensinogen w/ release of RENIN→Angiotensin I w/ ACE →Angiotensin II →( increases SNS activity, tubular reabsorption (Na+,Cl-,H2O), aldosterone, vasconstriction and ADH)→ALL leads to increase in BP
ACE= Angiotensin Converting Enzyme
ADH=Antidiuretic hormone
19
Q
What is the negative feedback in the renin-angiotensin-aldosterone sytem
A
Kidney decreases the release of RENIN
20
Q
From the RAAS pathway, what organ secretes Angiotensinogen?
A
Liver
21
Q
From the RAAS pathway, what organ secretes renin?
A
Kidney
22
Q
From the RAAS pathway, what organs secretes Angiotensin Converting Enzyme (ACE)?
A
Lungs and kidneys (surface of pulmonary and renal endothelium)
23
Q
From the RAAS pathway, what organ secretes Aldosterone?
A
Adrenal gland cortex
24
Q
From the RAAS pathway, what organ secretes ADH?
A
Pituitary gland (posterior lobe)
25
Explain the pathway for cardiac myocyte contraction & relaxation
Symph. activation→releases NE→binds to β1 receptors→Gs increases cAMP→Increase Pk-a→Increases extracellular Ca2+ release→Intracellular Ca2+ release from SR→Binds to Troponin→Actin binds to Myosin→Contraction
26
What type of contractions does vascular smooth muscle undergo?
Slow, sustained, tonic contractions
27
List the 3 ways contractions in VSM (vascular smooth muscle) are initiated?
1. Mechanical stimuli
2. Electrical stimuli
3. Chemical stimuli
28
Explain the mechanical stimuli that cause contraction in vascular smooth muscle (VSM).
* **Passive stretching of VSM** can cause contraction.
* Termed a **Myogenic response**
29
Explain the electricial stimuli that causes contractions in the (VSM).
**Electrical depolarization** of the VSM by opening voltage dependent Ca2+ channels, causing an increase in the intracellular concentraction of calcium
30
Explain the chemical stimuli that causes contractions in vascular smooth muslce (VSM).
A number of chemical stimuli such as **norepinephrine, angiotensin II, vasopressin, endothelin-1, and thromboxane A2** can cause contraction.
31
Explain vascular smooth muscle (VSM) contraction
Contraction: An increase in free intracellular Ca2+ (through Ca2+ channels or by release from internal stores (SR))
* The free Ca2+ binds to **calmodulin (CM)**
* Calcium-calmodulin activates **myosin light chain kinase (MLCK)** an enzyme that **phosphorylates myosin light chains (MLC)** in the presence of ATP
* MLC phosphorylation leads to cross-bridge formation b/w the myosin head and actin filaments→VSM contraction
32
Explain vascular smooth muscle (VSM) relaxation
Relaxation: Reduced phosphorylation of MLC. This can result from:
1. Reduced relase of Ca2+ by the SR or reduced Ca2+ entry into the cell
2. Inhibition of MLCK by **increased intracellular conc. of cAMP (Gs-R pathway)**
3. MLC dephosphorylation **(nitric oxide (NO)→cGMP pathway)**
## Footnote
Gs-R: Gs-linked vascular receptor
33
What type of drugs target MLC dephosphorylation?
Nitrate drugs
34
What is the pharmacodynamics of direct acting vasodilators?
Affects venous side with preload (capacitance) and affects resistance with afterload
35
List the different drug classes of direct-acting vasodilators.
* Nitrates
* Hydralazine
* Phosphodiesterase V inhibitors
* Calcium Channel Blockers (non-dihydropyridine)
* Calcium Channel Blockers (dihydropyridine)
36
What drugs are Nitrates (nitric oxide donors)? (3)
* Isosorbide dinitrate
* Nitroglycerine
* Nitroprusside
37
What drugs are Hydralazine? (1)
Hydralazine
38
What drugs are Phosphodiesterase V inhibitors? (1)
Sildenafil
39
What drugs are non-DHP calcium channel blockers (CCBs)? (2)
* Diltiazem
* Verapamil
40
What drugs are DHP calcium channel blockers (CCBs)? (2)
* Amlodipine
* Nifedipine
41
What is the mechanism of action of nitrates (nitric oxide donors)?
##Footnote##
Drugs: Isosorbide dinitrate, Nitroglycerine, Nitroprusside
* Release NO when metabolized
* Relax smooth muscle: Vascular, corpora cavernosa, short-lived in others (e.g. bronchial, GI)
* Inhibit platelet aggregation
42
Explain the natural pathway of Nitric Oxide Donors in the smooth muscle cells
* Nitric Oxide (NO) is **synthesized in the endothelial cell by eNOS (endothelial nitric oxide sythase) which turns L-arginine into NO**
* NO enters the smooth muscle cell (SMC) and **activates guanylyl cyclase which produces cGMP**
* **cGMP activates MLCP (myosin light chain phosphatase) which dephosphorylates myosin→Relaxtion**
43
Explain the drug pathway of Nitric Oxide Donors (Nitrates)
## Footnote
Drugs: Isosorbide dinitrate, Nitroglycerine, Nitroprusside
* **Direct administration of NO into the SMC** (skips the synthesis step in the endothelial cell)
* **Increase cGMP (via guanylyl cyclase) activating MLCP**
* **MLCP dephosphorylates myosin→relaxation**
## Footnote
Targeting MLCP (wouldn't want drugs that target the same thing, e.g. Vigara)
44
* What are the organic Nitrites & Nitrates (+ how many NO do they have)?
* Where are they metabolized?
* How long is their half-life?
* What does it target?
* Amyl Nitrate (1 NO)
* **Isosorbide dinitrate (2 NO)**
* **Nitroglycerin (3 NO)**
* Metabolized ONLY in the vein (↓preload)
* Short half-life
* ONLY IN VEINs
45
What is the inorganic NO donor?
Where is it metabolized?
What does it target?
What is a Side Effect?
* **Nitroprusside (1 NO)**
* Metabolized in blood cells
* Targets BOTH veins and arteries
* Cyanide toxicity (d/t cyanide in formula)
| Cannot use a lot, only in emergency
46
Explain the effects (on the heart) caused by Organic NO donors. (Pharmacodynamics)
## Footnote
Amyl NItrate (1 NO), **Isosorbide dinitrate (2 NO), Nitroglycerin (3 NO)**
Target is the vein
* Increase capacitance venules to decrease preload
* ↓ preload→the heart doesn't have to work as hard
* Increase oxygen demand, improved collateral flow
* Increase blood flow to coronary arteries to supply the heart
* **Less blood in the heart to pump, more blood supplying the heart**
47
Explain the effects (on the heart) caused by Inorganic NO donors (pharmacodynamics)
## Footnote
**Nitroprussside (1 NO)**
Works on both arteries and veins
* Increase capactiance of the vein to reduce preload
* Decrease resistance of the arteries to reduce afterload
48
What are the factors of
* Oxygen supply?
* Oxygen demand?
Oxygen Supply
* AV Oxygen Difference (O2 in arteries vs O2 in vein)
* Regional Myocardial Distribution
* Coronary Blood Flow (How much blood supplies O2 to the heart)
Oxygen Demand
* Contractility
* Heart Rate
* Preload
* Afterload
49
What is the ideal difference between oxygen supply and oxygen demand? And how is this equilibrium reached?
* Ideal: O2 supply equal to or greater than O2 demand
* Occurs by increasing O2 supply and decreasing O2 demand
50
What happens when there is ischemia?
* Heart isn't getting enough blood which can cause angina (no O2 to the heart so pain)
* O2 supply < O2 demand (more demand than supply)
* If left too long will lead to MI
51
What can we give to help ischemia?
Give organic NO donor (**Isosorbide dinitrate (2 NO), Nitroglycerin (3 NO)**)
* Can increase coronary blood flood and give the heart more O2
* Reduce Preload=Less O2 demand
* Increase O2 supply, decrease oxygen demand
52
What are the classes of ANGINA? (3)
1. **Stable angina-Exertion**
* When you work hard and have heart pain
2. **Unstable angina - Plaque**
* severe atherosclerosis-> coronary is blocked by platelet
3. **Variant angina-Spasm**
* Contracts and blocks blood flow
53
What angina can organic NO donors treat?
## Footnote
**Isosorbide dinitrate (2 NO), Nitroglycerin (3 NO)**
Stable angina
54
What angina(s) can Organic NO donors NOT treat? and why?
## Footnote
**Isosorbide dinitrate (2 NO), Nitroglycerin (3 NO)**
* Unstable angina
* Variant angia
* Reducing preload in these cases does not help
55
What is the clinical use of Isosorbide dinitrate (mononitrate)?
## Footnote
Nitrites ( Organic NO donor)
* STABLE angina
* Heart failure
56
What are the clinic use(s) of Nitroglycerin?
## Footnote
Nitrates (Organic NO donor)
* Acute decompensated heart failure
* acute myocardial infarction
* **Stable angina**
* **hypertensive emergency**
* **hypotension induction**
* **perioperative hypertension**
* acute pulmonary hypertension
57
What is important about nitrates (nitroglycerin) and HTN?
* It is only used for emergency: hypertensice emergency, hyptension induction, perioperative hypertension
* NOT CHRONIC TXT OF HTN
58
What is the clinical use of Nitroprusside?
## Footnote
Nitrite (Inorganic NO donor)
Hypertensive emergency
59
What are the short acting NO donors and what are the long acting NO donors?
* Short: **nitroglycerin, nitroprusside**
* Long: nitroglycerin and **isosorbide dinitrate**
60
What is the fate and excretion of nitroprusside
LOW yield
Metabolized by intraerythrocytic reaction with hemoglobin, further metabolism in liver, metabolites excreted in urine
61
Explain the Organic nitrate/nitrite tolerance
* **Continous 24-hour** plasma levels of organic nitrates result in **insurmountable tolerance (tachyphylaxis)**
* Nitrate-free period of more than 10 hours is needed to prevent or attenuate tolerance
* **TOLERANCE IS NOT DEVELOPED TO NITROPRUSSIDE**
62
Which Nitrate has NO tolerance?
Nitroprusside
63
What are the Adverse effects, contraindications, and interactions with Isosorbide dinitrate (mononitrate) and nitroglycerin?
Adverse Effect
* Hypotension
* Dizziness
* Headache
* Flushing
* Syncope
Contraindications:
* Tolerance
* Increased intracranial pressure,
* Pregnancy
interactions:
* Sildenafil (e.g. Viagra will kill you)
64
What are the Adverse Effects, and Contraindications of Nitroprusside?
Adverse Effects:
* Hypotension
* Dizziness
* Headache
* Flushing
* Syncope
* **Cyanide toxicity**
Contraindications:
* Prolonged infusion
* Pregnancy
65
List the drugs that are phosphodiesterase V inhibitors
* **Slidenafil**
* Tadalafil
* Vardenafil
66
Explain the pharmacodynamics of phosphodiesterase V inhibitors (PDE5 Inhib.)
##Footnote##
Sidenafil
* PDGE5 inhibitors inhibit PDE5 which breaks down cGMP
* cGMP is not broken down (↑ cGMP)
67
What is the route of adminstration, onset of action and absorption, fate, excretion of sildenafil, tadalafil and vardenadil
68
What are the clinical use(s) and side effects of Sildenafil?
## Footnote
PDE5 Inhibitor
* Clinical use: Erectile Dysfunction, Pulmonary arterial hypertension
* Side effects: Severe hypotension and death if combined with nitrates (priapism)
69
The image below shows the mechanism of Sildenafil and other nitrates affect on SMCs. Explain how the major side effects occur
sildenafil and nitrates both increase cGMP so this would lead to severe dilation and hypotension so severe is can cause death
70
What is the mechanism of action and pharmacology of Hydralazine?
* MOA is unknown
* Required NO from the endothelium so if endothelial is not working the drug will not work
* Targets arteries and decrease resistance to decrease afterload
71
What are the clinical use(s) and side effects/adverse reactions of Hydralazine?
Clinical use:
* **Hypertension**
* **Hypertensive emergency in pregnancy**
* Heart failure
Side Effects:
* Dizziness
* Headache
* **Angina**
* Tachycardia
* Peripheral edema
* Lupus-like syndrome
72
What do we NOT use for angina?
Hydralazine
73
What is the effects of hydralzine on organic nitrate tolerance?
What is the drug name?
* Can cause tolerance to disappear
* NOT used for angina BUT can be adminstered w/ mitrate to ↓ tolerance
* Drug Name: **BiDil**
74
Explain why Hydralazine is not used for angina.
| ⭐️
Coronary steal phenomenon
* Will vasodilate healthy vessels and less O2 will go through constricted vessels leading to angina
75
What is the ROA, onset and absorption, fate and excretion of hydralazine
| LY
76
What are the effects on distinct vascular beds with Nitrates, Nitroprusside and Hydralazine?
* Nitrates=Affect VEINS only (↓ Preload)
* Nitroprusside=Affect BOTH veins and arteries (↓ Preload and Aferload)
* Hydralazine= Affects ARTERIES onl (↓Afterload)
77
What is the MOA and pharmacology of Calcium channel blockers (CCBs)?
## Footnote
non-DHP: Diltiazem, Verapamil
DHP: Amlodipine, Nifedipine
* Block calcium channels
* **Decrease calcium influx into the cell- decrease ER/SR calcium loading** (can NOT activate MLCK)
* Effects depend on selectivity
78
What are the cardiac and vascular effects of CCBs?
## Footnote
non-DHP: Diltiazem, Verapamil
DHP: Amlodipine, Nifedipine
Cardiac Effects (↓ Afterload)
* Decrease contractility (negative inotropy)
* Decrease HR (negative chronotropy)
* Decrease conduction velocity (negative dromptropy)
Vascular Effects
* Smooth muscle relaxation (vasodilation)
79
Explain what happens when a CCB is bound to the calcium channels on the SMCs.
No extracellular Ca2+=No intracellular Ca2+= NO constriction
80
How do CCBs effect distinct vascular beds?
Affects mainly the ARTERIES
81
What is the difference between DHPs and NON-DHP CCBs?
## Footnote
non-DHP: Diltiazem, Verapamil
DHP: Amlodipine, Nifedipine
* DHPs: Just target Vasculature (arteries)
* NON-DHPs: Target the Heart (HR and contractility) and Vasculature (arteries)
82
What are the relative vascular and cardiac effects of CCBs (NON-DHPs & DHPs)?
* Non-DHP (D.V.): causes Vasodilation and decrease HR/Contractility
* DHP(-dipine): just affect vasculature
## Footnote
non-DHP: Diltiazem, Verapamil
DHP: Amlodipine, Nifedipine
83
Explain the pharmacokinetics of DHP CCBs (amlodipine and nifediphine) with onset of action and plasma half life
* Amlopine takes longer to work but last longer
* Nifedipine has a quick onset but doesn't last long
84
What is the first line of treatment of adults with systolic/diastolic hypertension without other compelling indications?
## Footnote
Target: <130/80 mmHg
1. Thiazide/thiazide-like
2. ACEI
3. ARB
4. CCB
85
What do we do if 20 mmHg above target?
duel therapy, triple or quadruple therapy
86
What are CCBs particularly useful for treating? And in what population?
Treating hypertension in low renin producers such as African-Americans and elderly patients
87
What has less effect on exercise performance than β-blocker and will not affect electrolytes like diuretics?
Dihydropyridine CCBs (DHP CCBs)
* Amlodipine
* Nifedipine
88
Long duration of action (CCBs) provides what?
superior long term outcomes
89
Explain the ACCOMPLISH Trial
* Patients were given two different drug combinations
* Combination 1: ACEI/HCTZ (hydrocholorothiazide)=Red line
* Combination 2: ACEI/CCB (amlodipine)=Blue line
* Over 42 months, combination 2 decreased risk by 20%, this is due to the long duration of action of the CCB
90
List out all the preferred antihypertensive combinations? (3)
* ACEI or ARB + Thiazide
* **ACEI or ARB + CCB**
* **CCB + Thiazide (black population)**
91
List out the Acceptable antihypertensice combinations? (4)
* **CCB + Thiazide (non-black population)**
* **β-blocker + DHP CCB or thiazide**
* Thiazide + K sparing diuretic
* **Aliskiren + Thiazide or CCB**
92
List out the NOT Preferred antihypertensice combinations? (4)
* ACEI + ARB (Contraindications)
* β-blocker + ACEI or ARB (perferred only post-MI of HF)
* **β-blocker + Non-DHP CCB** (will decrease HR too much)
* β-blocker + central acting (i.e. clonidine, etc, changing nerve impulses in the brain)
93
What is the first line of treatment for isolated systolic hypertension?
NO ACE if just systolic HTN
1. Thaizide/thiazide like
2. ARBs
3. CCB
94
How does DHPs and Non-DHP work on oxygen supply and oxygen demand factors?
* DHPs: Coronary Blood flow & Afterload
* Non-DHPs: Contractility, Heart rate, Afterload and Coronary blood flow
95
What CCBs are used for stable angina, unstable angina and variant angina?
* Stable Angina : ALL CCBs + (organic nitrates)
* Unstable Angina: Non-DHP CCBs ( blocked vessel. Non-DNP dec HR/contaction so will decrease O2 demand)
Variant Angina: All CCBs
96
What are the Adverse effects, contraindications and interactions with Non-DHP CCBs?
## Footnote
Non-DHP (Diltiazem, Verapamil)
Adverse Effects
* Headache
* Dizziness
* Constipation
* Edema
* **AV block**
* **Bradycardia**
* Hypotension
Contraindications
* Sick sinus syndrome
* Heart failure
* 2nd/3rd heart block
* Hypotension
Interactions
* Beta-blockers
* Grapefruit (Inhibits metabolism, can increase concentration)
97
What are the Adverse effects, contraindications and interactions with DHP CCBs?
## Footnote
DHP (Amlodipine, Nifedipine)
Adverse Effects
* Headaches (7.5%)
* Edema
* Hypotension
* Palpitations
* Nocturia/polyurea
Contraindications
* Hypotension (Amlodipine & Nifedipine)
* Heart failure (Nifedipine)
Interactions
* Beta-blocker withdrawal
Grapefruit
98
What are the clinical uses of Non-DHP CCBs?
## Footnote
Non-DHP (Diltiazem, Verapamil)
* Effort, variant and unstable angina
* Hypertension
* Atrial fibrillation and atrial flutter (injection)
* Paroxysmal supraventricular tachycardia (PSVT)
99
What are the clinical uses of DHP CCBs?
## Footnote
DHP (Amlodipine, Nifedipine)
* Hypertension
* Effort and variant angina
* Subarachnoid hemorrhage (Nimodipine)
100
7. A patient goes to the ER after experiencing chest pain. He states that he just finished an intense workout prior to the pain. Which of the following medications could be prescribed to the patient to treat his angina?
a. Nitroprusside
b. Isosorbide dinitrate
c. Sildenafil
d. Hydralazine
b. Isosorbide dinitrate
101
8. Which of the following is a NOT PREFERRED antihypertensive medication?
a. Metoprolol and Diltiazem
b. Thiazide and Verapamil
c. Diltiazem and Aliskiren
d. Atenolol and Amlodipine
a. Metoprolol and Diltiazem
102
9. Nitroglycerin can be given during a hypertensive crisis due to its drastic effects on blood pressure. What is the mechanism of action to allow this?
a. Blocks Ca channels
b. Decreases cGMP.
c. Produces NO within smooth cells.
d. Increases cGMP
d. Increases cGMP
103
10. Which of the following drugs does not have an affect with an injured endothelium?
a. Nitroprusside
b. Nitroglycerin
c. Hydralazine
d. Amlodipine
c. Hydralazine
