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Cardio Week 3 > Lecture 33: Antihypertensive and Vasodilator Drugs > Flashcards

Lecture 33: Antihypertensive and Vasodilator Drugs Flashcards

1
Q

What is BP?

A

CO x SVR
Pressure = Flow * Resistance
V = IR
R = V/I

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2
Q

What is SVR?

A

peripheral vascular resistance * renal vascular resistance

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3
Q

What is CO?

A

SV * HR

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4
Q

What are the 5 types of HTN drugs?

A
  1. Diuretics
  2. Calcium Channel Antagonists (Calcium channel blockers)
    i. non-Dihydropyridines
    ii. Dihydropyridines
  3. RAAS inhibitors
  4. Vasodilators
  5. Sympatholytics
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5
Q

What is the pathophysiology of hypertension?

A
  1. increased CO
  2. increased PVR (peripheral vascular resistance)
  3. increased fluid volume
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6
Q

What is the rate limiting step in the RAAS pathway?

A

Renin

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7
Q

What happens when you have reduction in blood pressure?

A
  1. SNS activity = increase in HR and contractility = increased CO
  2. SNS activity = increase in peripheral vascular resistance (through adrenergic receptor) = increased PVR
  3. Increased renin activity = increased angiotensin II = increased PVR
  4. Increased renin = increased aldosterone/Na retention = increased fluid volume retention
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8
Q

Where does thiazide act?

A

At the DISTAL tubule of the nephron
Distal convoluted Na-Cl symporter
Example: Hydrochorthiazide (HCTZ)

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9
Q

What are loop diuretics?

A

Acts on the loop of henle
MoA: Inhibits the Na-K-2Cl Symporter on the Loop of Henle
-therefore, inhibits reabsorption of Na, K and Cl and promotes natriuresis and kaliuresis
Example: Furosemide

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10
Q

What is furosemide?

A

A loop diuretic

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11
Q

What is Hydrochorthiazide (HCTZ)?

A

A thiazide diuretic

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12
Q

What is the mechanism of diuretics?

A

Acute effect = sodium loss that leads to decreased in volume and BP
Chronic effect = decrease in vascular resistance that then decreases BP

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13
Q

What are the compensatory mechanisms counteract the acute effects long term?

A

Decreased plasma volume, increased renin + aldosterone

Plasma volume is restored but somehow the BP is still depressed (that’s the mystery)

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14
Q

What is the difference between a responder and nonresponder?

A

Responder is someone who responded well to the therapy (blood pressure dropped)

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15
Q

What is the MoA of Thiazide diuretics?

A

NaCl cotransporter in apical cell membrane of the Distal Convoluted Tubule (DCT)
Blocks Na-Cl symporter
Therefore blocks reabsorption of Na and Cl in DCT
(also thought to increase calcium reabsorption)

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16
Q

What are the key characteristics of thiazide diuretics?

A
  1. diuretic, natriuretic and kaliuretic
  2. Long duration of action
  3. African-Americans are generally more responsive
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17
Q

What is CRI?

A

Cardiac Risk Index

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18
Q

What is kaliuresis?

A

Process of excreting potassium in the urine

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19
Q

What are the toxicities of thiazide diuretics?

A
  1. Sulfa Allergy
  2. hypokalemia
  3. promote insulin resistance (increase plasma glucose)
  4. increase TG and LDL cholesterol
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20
Q

What is a diuretic that promotes insulin resistance, increases TG and increases LDL?

A

Thiazide diuretics

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21
Q

What diuretic should someone with sulfa allergy NEVER be put on?

A

Thiazide

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22
Q

What is the clinical use of thiazide diuretics?

A

First line treatment for uncomplicated hypertension, elderly patients with ISH and African-American patients

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23
Q

What is ISH?

A

Isolated systolic HTN

When systolic pressure is the only one that is high

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24
Q

How do thiazides reduce BP?

A
  1. reduces SV

2. reduces Peripheral Vascular Resistance

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25
Q

How do CCAs reduce BP?

A
  1. Reduce heart rate
  2. Reduce PVR
    Specifically blocks “L”-type calcium channels
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26
Q

What is the role of calcium in vascular smooth muscle cells?

A
  1. Ca influx via voltage channels and binds to calmodulin
  2. Calmodulin-Ca complex activates MLC kinase
  3. myosin is phosphorylated and activated
  4. Activated myosin combines with actin resulting in a contraction
    Maintains smooth muscular tone that allows you to stand, etc
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27
Q

What is the role of Ca in cardiac MYOCYTES?

A
  1. Ca influx via voltage sensitive channels after initial depolarization
  2. Ca influx causes release of Ca stores from SR
  3. Ca binds troponin and allows contraction to occur
  4. In SA and AV nodes, Ca influx is also important in spontaneous depolarization
    • necessary for pacemaking because Ca is important in slow myocyte tissue
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28
Q

What is the role of Ca in muscle function?

A

A. Voltage-sensitive channels are an important pathway for Ca entry
B. Vascular SMCs depend mostly on Ca influx
C. Cardiac myocytes depend upon both Ca influx and intracellular stores
D. Skeletal muscle depends almost exclusively on intracellular Ca STORES

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29
Q

What are the specific calcium specific channels?

A

L, T, N, R and Q types
L is found on membrane of ALL muscle cells
Majority of CCAs affect only L type channels

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30
Q

Why are cardiac and smooth cells most affected by extracellular Ca?

A

Because they are the tissues most affected by agents

Skeletal muscles are not in tetany because they get their calcium from intracellular stores

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31
Q

What are the Calcium channel antagonists?

A
  1. Non Dihydropyridine

2. Dihydropyridine

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32
Q

What are the types of NON-dihydropyridine calcium channel antagonists?

A
  1. verapamil (Isoptin)

2. Diltiazem (Cardizem

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33
Q

What is verapamil?

A

A calcium channel antagonist
A non-dihydropyridine
Aka Isoptin
Binds to L-type calcium channels in the OPEN state

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34
Q

What is Diltiazem?

A

A calcium channel antagonist
A non dihydropyridine
Aka isoptin
Binds to L-type calcium channels in the OPEN state

35
Q

What are the types of dihydropyridines?

A
  1. Nifedipine (Procardia)

2. Amlodipine (Norvasc)

36
Q

What is Nifedipine?

A

A calcium channel antagonist
A dihydropyridine
Aka Procardia
Binds to L-type calcium channels during the RESTING state

37
Q

What is the MoA of CCAs?

A 
All CCAs interfere with Ca entry into cells via voltage sensitive “L” channels”
Each class preferentially binds during a specific functional state of the channel
38
Q

What is the difference between non-dihydropyridines and dihydropyridines?

A

Non diyhydropyridines bind while the L channel is OPEN

Dihydropyridines bind during the RESTING STATE of the L channel

39
Q

When do you want to administer non-dihydropyridines?

A

When your target cell (with the L-type channel) has rapid frequency of stimulation
Eg. Tachycardic tissue
This is because faster conduction tissue leads to more of the L-type Ca being in the open state
So faster conducting tissue = more effective blockade by non-dihydropyridines (verapamil and diltiazem)

40
Q

When do you administer dihydropyridines?

A

When you have cells that are slow-normal conducting so that it can bind to L-type during resting state
Example: Nifedipine, amlodipine

41
Q

How can you tell if something is a dihydropyridine?

A

If it ends with “-ipine” it is a DHP

42
Q

What is significant of MoA of CAAs in cardiac myocytes?

A

When targeting myocardium to reduce HR use Verapamil first
Verapamil > diltiazem > nifedipine
If you want to decrease cardiac contractility and reduce O2 demand
Use Verapamil as well

43
Q

What is the MoA of CCAs in SMCs?

A

Channels are infrequently activated in SMCs
Use nifedipine for first line (by a long shot)
Nifedipine (amlodipine)&raquo_space; verapamil&raquo_space; diltiazem
Leads to vasodilation in all arteries including coronary arteries

44
Q

What are the key characteristics of verapamil?

A

MoA: binds to L-type Ca channels during the OPEN state
Treats:
i. paroxysmal SVT
ii. Angina (to decrease myocardial O2 demand and increase coronary blood flow by slowing down heart rate and increasing diastolic filling)

45
Q

What is the most notable side effect of verapamil?

A

Constipation

Can also be contraindicated in CHF and post-MI

46
Q

What are the key characteristics of Diltiazem?

A

MoA: binds to L-type calcium channels during the OPEN state
Treats: SVT
Not a great antihypertensive drug
But has the lowest incidence of side effects

47
Q

What are the key characteristics of Nifedipine?

A

MoA: binds to L-type calcium channels in the RESTING state (acts predominately on SMC)
Treats:
i. HTN by reducing PVR (through vasodilation)
ii. May be used in conjunction with Bblocker to prevent reflex tachycardia

48
Q

What is Nifedipine contraindicated for?

A 
Post MI (because it causes further hypovolemia)
Congestive heart failure (because it causes further hypovolemia)
49
Q

What are the side effects of Nifedipine?

A 
Post MI (because it causes further hypovolemia)
Congestive heart failure (because it causes further hypovolemia)
50
Q

What are the side effects of Nifedipine?

A

Most side effects out of the CCA’s

  1. Facial flushing
  2. Headaches
  3. dizziness
  4. ankle swelling
51
Q

What are important considerations when prescribing dihydropyridines like nifedipine?

A

Dihydropyridines cause profound peripheral vasodilation and limited DIRECT myocardial effects
May produce reflex tachycardia and increase contractility
This increases myocardial work load and can increase the risk of having a MI in patients who are susceptible

52
Q

What drug produces reflex tachycardia and increased contractility?

A

Dihydropyridines

Nifedipine…contraindicated in patients with angina that can’t get enough supply to coronaries

53
Q

What are the key characteristics of peripheral vasodilators?

A

Drugs that produce a direct relaxation of vascular smooth muscle cells
Direct = not dependent upon innervation and their effect is not mediated by known receptors

54
Q

What are the types of peripheral vasodilators

A
  1. venous = nitrates
  2. arterial = hydralazine, minoxidil
  3. both venous and arterial
    i. nitroprusside
55
Q

What are the venodilators?

A

Organic nitrates

AKA Nitrates

56
Q

What are the key characteristics of hydralazine?

A

MoA = unknown
Direct arteriolar dilation with no effect on veins
Preferentially affects the renal, peripheral, splanchnic and coronary arteries
Decrease in PVR leads to lower blood pressure

57
Q

What is the toxicity of hydralazine?

A

Excessive vasodilation (flushing, sweating, palpitations, hypotension and angina)
SLE like syndrome (for boards)
-arthralgia, myalgia, fever and rash
-seen in females who are slow acetylators within 6 months

58
Q

What vasodilator leads to SLE symptoms?

A

Hydralazine if given for over 6 months

59
Q

What are the limitations of the hydralazine?

A

Limited utility…only used for HTN during pregnancy or preeclampsia
Frequently used for HTN during pregnancy including preeclampsia
Used in combination with beta adrenergic antagonist to blunt SNS reflex

60
Q

What are the key characteristics of minoxidil?

A

MoA = activates ATP modulated K channel in arteries to allow K+ to leave cell, causing hyperpolarization and relaxation
Increase K channel permeability = decreased excitability = decreased SMC contractility
Direct arteriolar vasodilation with no effect on veins
Decrease in PVR and thus lowers BP
Compensatory mechanism:
Reflex SNS activation, Na retention and increased renin production to return BP to baseline

61
Q

What are important side effects/consequences of minoxidil use?

A

Can increase hair growth: HYPERTRICHOSIS
Can be blunted with concomitant use of beta blockers and diuretics
Minoxidil = rogaine because it increases hair growth lol

62
Q

What are the characteristics of sodium nitroprusside?

A

MoA = metabolized by SMCs into NO which activates guanylate cyclase
Vasodilates both arterioles and veins; decreases PVR and venous return (afterload and preload respectively)

63
Q

What are the consequences associated with taking nitroprusside?

A

Formed by a complex of Fe, cyanide and nitrosamine
Can be metabolized to cyanide so you need to add SODIUM THIOSULFATE to prevent cyanide toxicity
Unstable in direct sunlight

64
Q

What are the therapeutic applications of sodium nitroprusside?

A
  1. Drug of choice for HTN emergencies
  2. Rapid onset (2 mins) and consistent (because everyone responds)
  3. Easily titrated
  4. Initiated therapy with beta blocker prior to discontinuing infusion
65
Q

What should we remember about diuretics, CCAs, and vasodilators?

A
  1. Potent vasodilators of vasculature (direct vasodilator)
  2. All of them induce reflex tachycardia/compensatory mechanisms
  3. Use beta blocker and ACE inhibitors to account for the compensatory mechanisms
  4. Hydralazine can lead to SLE
66
Q

Where are the adrenergic receptors located?

A

Alpha1 = vascular smooth muscle (vasoconstriction) and genitourinary smooth muscle (constriction)
Alpha 2 = vascular smooth muscle (vasoconstriction
Beta 1 = heart and kidney
Beta 2 = vasodilation and bronchodilation

67
Q

What are the type of sympatholytic antihypertensive drugs?

A
  1. beta-blocker (beta adrenergic antagonists)
  2. peripheral alpha 1, alpha 2 adrenergic antagonists
  3. centrally acting alpha2 adrenergic agonists
  4. adrenergic neurotransmitter release blockers
68
Q

What are the beta-blockers used for HTN?

A
  1. propranolol (B1 and B2 blockers)
  2. metoprolol (B1 blocker)
  3. atenolol (B1 blocker)
69
Q

What are the MoA of beta-blockers as only antihypertensives?

A
  1. reduction in HR

2. reduction in renin release

70
Q

Which of the beta-blockers are selective to beta 1 receptor?

A

Metoprolol

Atenolol

71
Q

Which of the beta-blockers are non-selective?

A

Propanolol

72
Q

What are the key characteristics of peripheral alpha adrenergic antagonists?

A

Prototypical:
i. Prazosin (Alpha 1 and 2 antagonist)
ii. Doxazosin (alpha 1)
iii. Terazosin (alpha 1)
MoA = vasodilates and reduces in PVR by antagonizing alpha adrenergic receptors
Used to treat benign prostate hypertrophy
3rd line HTN

73
Q

What are the key characteristics of alpha and beta receptor antagonist combination drugs?

A 
Alpha 1 receptor antagonist effect
Non selective beta receptor antagonist effect
Include:
	i. Labetolol
	ii. Carvedilol
74
Q

What are the effects of carvedilol and labetolol?

A

Combined alpha/beta receptor antagonist

  1. antagonize peripheral vasoconstriction actions of NE
  2. Reduces heart rate
  3. reduces renin release
75
Q

What are the key characteristics of centrally-acting alpha 2 adrenergic AGONISTS?

A

MoA = stimulate preganglionic A2 receptors on adrenergic neurons in medulla
Reduces sympathetic outflow creating unopposed vagal tone because A2 receptor agonist is done on the PREganglionic receptor

76
Q

What is significance of methyldopa?

A

Not used because of CNS depressant effect

Can cause suicide

77
Q

What is the significance of clonidine?

A

MoA: binds the Presynaptic ganglionic Alpha2 receptors in the vasomotor system of medlla
-this decreases presynaptic calcium levels, thereby DECREASING NE release
-decreasing NE release leads to lower PVR and CO
Prevents autonomic variability that we see in blood pressure
Ideal patient = autonomic neuropathy because clonidine will act as a compensatory system in place of the autonomic neuropathy that occurred

78
Q

Which beta-blocker has a sympathomimetic effect?

A

Oxprenolol, pindolol, penbutolol, acebutolol
These guys can exert a low level of agonist activity at B-receptor site despite being antagonists as well
Useful for patients with bradycardia but don’t give post-MI

79
Q

What is TLC?

A

Therapeutic Lifestyle Change

80
Q

What are the complications of hypertension?

A
  1. hemorrhage/stroke
  2. retinopathy
  3. peripheral vascular disease
  4. LVH, CHD and CHF
  5. nephropathy
81
Q

What is uncomplicated HTN?

A

HTN without compelling causation

Diastolic BP <11 mmHg without symptoms of end HTN and does not require acute treatment

82
Q

What is the best antihypertensive drug combination?

A 
Beta blockers + CCAs
Diuretics + Beta blockers
ACEIs, ARBs + CCAs
ACEIs, ARBs + Diuretics
Nothing horrible
83
Q

What antihypertensives do you want to avoid?

A

Alpha1 receptor blockers like Prazosin

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