Antihypertensives - Sue's slides

Question 1

Medications that inhibit angiotensin are 1st line for patients that are producing too much renin as they have renal productive properties. What are the 3 classes?

Answer 1

ACE inhibitors
Nonpeptide antagonists
Renin antagonists

Question 2

BP is influenced by what 2 primary factors?

Answer 2

cardiac output & PVR

Question 3

Blood pressure is regulated moment to moment at three anatomic sites. What are they?

Answer 3

1) arterioles
2) postcapillary venules
3) heart
(The kidney also contributes to maintenance of blood pressure by regulating the the volume of intravascular fluid)

Question 4

T/F Local release of vasoactive substances from vascular endothelium may also be involved in the
regulation of vascular resistance.

Answer 4

True

Question 5

What is meant when we say that hypertensive patients have a different “set point” than normotensive patients?

Answer 5

Blood pressure in a hypertensive patient is controlled by the same mechanisms that are operative in
normotensive individuals. Hypertensive patients however, seem to be ‘set’ at a higher level of blood
pressure for the baroreceptor and renal blood volume-pressure control regulation.

Question 6

What are the 4
major classes of anti-hypertensives?

Answer 6

1) Diuretics
2) Sympathoplegic agents
3) Direct vasodilators
4) Agents that block action of angiotensin

Question 7

General action of diuretics?

Answer 7

lower blood pressure by depleting the body of sodium and reducing blood
volume

blockade of sodium and chloride reabsorption –> create osmotic pressure within the nephron, which prevents the passive reabsorption of water –> water and solutes retained in nephron –> excretion of both

Question 8

General effects of sympathoplegic agents?

Answer 8

reducing peripheral vascular
resistance, inhibiting cardiac function, and increasing venous pooling in capacitance vessels;

Question 9

General action of direct vasodilators?

Answer 9

which reduce pressure by relaxing vascular smooth muscle, thus dilating
resistance in vessels and increasing capitance;

Question 10

General action of agents that block production or action of angiotensin?

Answer 10

reduce peripheral vascular
resistance and potentially blood volume.

Question 11

How is sodium expected to alter peripheral vascular resistance?

Answer 11

Sodium is believed to contribute to vascular resistance by increasing vessel stiffness and
neural reactivity, possibly related to altered sodium-calcium exchange with a resultant
increase in intracellular calcium. These effects are reversed by diuretics or dietary sodium
restriction

(I’ve never really thought of diuretics as influencing more than blood volume so this is interesting…)

Question 12

Describe ACE inhibitors relationship to bradykinin.

Answer 12

ACE inhibitors inhibit an enzyme that interrupts/impacts the effects of bradykinin (a vasodilator). In this way the ACE inhibitor decreases peripheral vascular resistance.

Question 13

What effect do ACE inhibitors have on cardiac output and HR?

Answer 13

No significant change as the meds do not activate the sympathetic reflex.

Question 14

How is BP decreased by diuretic use? Describe how this evolves over time from initial tx.

Answer 14

Initially, diuretics reduce blood pressure by reducing blood volume and cardiac output and
peripheral vascular resistance may increase.

▪ After 6-8 weeks, cardiac output returns toward normal while peripheral vascular resistance
declines.

Question 15

How much do diuretics decrease BP? Are they typically used alone?

Answer 15

▪ Diuretics are effective in lowering BP by 10-15mmHg in most patients and effective for mild or
moderate essential hypertension. In more severe hypertension, diuretics are used in
combination with sympathoplegic and vasodilator drugs to control BP.

Question 16

Name some loop diuretics

Answer 16

g. furosemide, bumetanide and tosemide

Question 17

MOA of loop diuretics

Answer 17

selectively inhibit NaCl reabsorption
in the thick ascending limb of Henle’s loop (TAL)

Question 18

T/F Loop diuretics are primarily excreted in the feces

Answer 18

No - by kidneys
** so half life depends on renal fx

Question 19

Most important indications for loop diuretics

Answer 19

▪ The most important indications for the use of loop diuretics include acute pulmonary edema and other edematous conditions as the treatment of fluid overload will also serve as an effective
anti-hypertensive effect.

▪ Loop diuretics are also useful in the treatment of mild hyperkalemia, acute renal failure and
anion overdose.

Question 20

What normally occurs in the ascending and descending loops of henle?

Answer 20

Descending limp = freely permeable to WATER – as passes through hypertonic renal medulla, water pulled into interstitial space –> urine becomes concentrated

Thick segment of ascending limb: ~20% of filtered Na and Cl reabsorbed. Water NOT able to follow –> tonicity of filtrate returns to same as original filtrate

Question 21

What is the normal action of aldosterone?

Answer 21

stimulates reabsorption of Na from distal nephron & K to be secreted

Question 22

What kind of diuretic acts on the early DCT of the kidney nephron?

Answer 22

Thiazide diuretics

Question 23

Which types of antihypertensives act on the late DCT and collective duct?

Answer 23

Spironolactone, triamterene
These are examples of aldosterone antagonists and non-aldosterone antagonists, respectively

Question 24

Why do loop diuretics typically cause more profound diuresis than thiazide diuretics?

Answer 24

Drugs that act early in the nephron have the opportunity to block the greatest amount of solute reabsorption (because the greates amount of filtrate still remains in the tubule) = greatest diuresis

Question 25

What lytes are lost with diuresis in loop diuretics?

Answer 25

Basically everything I think: Na, Cl, mg, Ca, K….

She emphasizes Mg2+ and Ca2+ in her slides (Prolonged use can cause significant
hypomagnesemia)
*Ninja nerd emphasizes can also lead to hypocalcemia

Question 26

T/F Lasix increases renal blood flow

Answer 26

True!
Depending upon the specific agent, loop agents may have direct effects on blood flow through
several vascular beds (e.g. furosemide increases renal blood flow via prostaglandin actions on
kidney vasculature.

**Textbook states that for this reason, they may be used in kidney failure (as can promote diuresis even when low GFR/renal blood flow)

Question 27

What kind of diuretic could potentially lead to hypercalcemia (though rarely occurs)?

Answer 27

Thiazide diuretic (opposite to loop)

Question 28

MOA of thiazide diuretics - where in the nephron do they act?

Answer 28

inhibit NaCl reabsorption from early
DCT by blocking the Na+/Cl- transporter

▪ Thiazides enhance Ca2+ reabsorption in both the proximal tubule and the DCT (rarely cause hypercalcemia)

**Also potentially cause mild vasodilation?

Question 29

What rare adverse effect can occur with LOOP diuretics that doesn’t occur with other types of diuretics?

Answer 29

Ototoxicity

Transient with lasix but can be permanent with other diuretic (ethacrynic acid)

Question 30

Due to the potential for hypokalemia in diuretics, what additional medication use warrants close observation of K+ levels while on the diuretics?

Answer 30

Digoxin: in presence of low K+, serious risk for digoxin-induced toxicity (ventricular dysrhythmias) - monitor K+ levels closely

Question 31

Loop diuretics act on COX-2. What other medication does the same and therefore shouldn’t be used concurrently?

Answer 31

NSAIDs

Question 32

T/F Like loop diuretics, thiazide diuretics can be effective in absence of sufficient renal blood

Answer 32

False - thiazide diuretics are INEFFECTIVE when urine flow is decreased
(text says less than 15 to 20 mL/min)

Question 33

Is it recommended to use ACE inhibitors and ARBs together?

Answer 33

NO.

Question 34

Discuss the relationship between ACE inhibitors and kidney function.

Answer 34

Diminsh protenuria
Stabilize renal fx
Increased eGFR

Question 35

Name 3 thiazide diuretics

Answer 35

Hydrochlorothiazide
Chlorothiazide
Chlorthalidone

Question 36

Why might ACE inhibitors not be the best option for patients living with a liver disorder?

Answer 36

ACE inhibitors are prodrugs and are converted to active agents by hydrolysis in the liver.

Question 37

4 major clinical indications for thiazide diuretics

Answer 37

1) hypertension
2) heart failure
3) nephrolithiasis due to idiopathic hypercalciuria 4) nephrogenic diabetes insipidus.

Question 38

Can you name a few ACE inhibitors that are used clinically?

Answer 38

captopril
enalapril
benazepril
fosinopril
moexipril
perindopril
quinapril
ramipril
trandolapril

Question 39

ACEs can be problematic if a patient is acutely ill with which symptoms?

Answer 39

Decreased fluid intake

Dehydration

Mineral/electrolyte imbalances

Question 40

Are ACEs safe to use in pregnancy?

Answer 40

No, they are contraindicated in pregnancy.

Question 41

What are some possible adverse effects of ACE inhibitors?

Answer 41

Acute renal failure

Hyperkalemia

Dry cough - seems r/t bradykinin and substance P

(Similar to ARBs)

Question 42

T/F thiazides are useful in treating virtually all patients with essential HTN

Answer 42

True - often used a first line tx

The thiazide’s modest efficacy sometimes limits their use as monotherapy however, the
literature is still supportive of their use as first line and more affordable treatment for
hypertension.
▪ Thiazides are also useful as co-agents in the control of blood pressure

Question 43

Diuretics enhance the
efficacy of many agents, particularly ______ (class of drug)

Answer 43

ACEIs

Question 44

MOA of potassium sparing diuretics?

Answer 44

Potassium-sparing diuretics increase Na+ excretion in the collecting tubules and ducts.
Potassium absorption (and K+ secretion) at this site is regulated by aldosterone. Aldosterone
antagonists interfere with this process.

▪ Spironolactone and eplerenone bind to mineralocorticoid receptors and blunt aldosterone
activity.
Amiloride and triamterene do not block aldosterone but instead directly interfere with
Na+ entry through the epithelial Na+ channels in the apical membrane of the collecting tubule.
Since K+ secretion is coupled with Na+ entry in this segment, these agents are also effective
K+ sparing diuretics.
▪ The actions of aldosterone antagonists depend on renal prostaglandin production

Question 45

How do ARBs differ from ACEs?

Answer 45

ARBs block angiotensin receptors.

ACEs block conversion of angiotension 1 to angiotensin 2.

Question 46

Tell me some things about spironolactone. (May not need to know this specific drug for exam but I feel like we should have the gist!
(important side effects to consider?)

Answer 46

K+ sparing diuretic

Blocks the action of aldosterone in distal nephron –> causing retention of potassium and increased excretion of sodium

Onset and duration of action are determined substantially by the active metabolites which are
produced in the liver and have long half-lives (12-20hrs).

*** Spironolactone binds with high affinity, and potently inhibits the androgen receptor, which is an important source of side effects in males (decreased libido and gynecomastia).

Question 47

What are some possible adverse effects of ARBs?

Answer 47

Acute renal failure

Hyperkalemia

Dry cough - seems r/t bradykinin and substance P

(Similar to ACEs)

Question 48

ARBs are contraindicated in pregnancy.

True or false?

Answer 48

True.

Question 49

When are K+ sparing diuretics most often used clinically?

Answer 49

states of mineralocorticoid excess or
hyperaldosteronism due to either primary hypersecretion (Conn’s syndrome etc) or, secondary
hyperaldosteronism (evoked by heart failure, hepatic cirrhosis etc).

From textbook: Diuretic effects limited, so rarely used alone – often used to counteract K loss from thiazide and loop diuretics

Question 50

What are some non-pharmacological changes you can recommend to your patient to help manage HTN?

Answer 50

Sodium restriction - DASH diet (Dietary Approaches to Stop Hypertension)

Weight loss - weight reduction has been shown to normalize BP in 75% of overweight patients

Regular exercise

Smoking/ETOH cessation

Decreased stress

Sleep hygiene

Question 51

Why is diuresis so minimal from spironolactone?

Answer 51

most of Na has already been reabsorbed by the time it reaches the distal nephron

Question 52

Why is it that sympathoplegic agents are often most effective when used in combination with a diuretic?

Answer 52

All of the agents that lower blood pressure by altering sympathetic function can elicit compensatory effects through
mechanisms that are not dependent on adrenergic nerves hence, these agents are most effective when used
concomitantly with a diuretic.

Question 53

WHat type of sympathoplegic agents may be reversible or irreversible & what does this mean?

Answer 53

▪ Alpha-receptor antagonists may be reversible or irreversible in their interaction with receptors.
It is important to understand the meaning to clinical effect of reversible versus irreversible
antagonism.

▪ The duration of action of a reversible antagonist is largely dependent on the half-life of the drug
in the body and the rate at which it dissociates from its receptor

▪ The effect of an irreversible antagonist may persist long after the drug has been cleared from the plasma – sometimes requiring synthesis of new receptors!

Question 54

MOA of alpha receptor antagonists
What happens when we give them with alpha agonists?
WHat adverse effects to watch for?

Answer 54

Alpha-receptor antagonists cause a lowering of peripheral vascular resistance and blood
pressure. These drugs can prevent the ‘pressor’ effects of usual doses of alpha agonists (in fact
selective alpha receptor antagonism may convert a pressor to a depressor response!

▪ These agents often cause orthostatic hypotension and reflex tachycardia due to antagonism of
sympathetic nervous system stimulation of alpha1 receptors in vascular smooth muscle

Question 55

Name some alpha receptor antagonists

Answer 55

Prazosin, terazosin, doxazosin, indoramin, urapidil, labetalol & carvedilol (last 2 are beta too, right?)

Question 56

Main adverse effects to look out for in K+ sparing diuretics? (to reiterate…)

Answer 56

1)Hyperkalemia (even when used with K+-wasting agents)

2) Endocrine effects: drug is a steroid derivative & has similar structure to steroid hormones – can cause gynecomastia, menstrual irregularities, impotence, hirsutism (dark thick hair growing in male-like pattern) & deepening of voice

Question 57

Clinical use of alpha-recentor antagonists?

Answer 57

1) Hypertensive emergencies (labetalol)
2) Chronic HTN

prazosins are efficacious drugs in the treatment of mild to moderate
systemic hypertension. They are generally well tolerated but are not usually recommended
as monotherapy.

Question 58

MOA of beta antagonist agents?

Answer 58

Beta blocking agents occupy beta receptors and competitively reduce receptor occupancy by
catacholamines and other beta agonists.

Beta blocking agent mechanism of action are not fully understood but probably include
suppression of renin release and effects in the CNS.

▪ Most beta blocking drug in clinical use are pure antagonists = the occupancy of a beta
receptor by such a drug causes no activation of the receptor.

▪ The beta blocking agents differ in their relative affinities for beta 1 and beta 2 receptors =
some have a higher affinity for beta 1 than beta 2 and this selectivity has important clinical
implications.

In the vascular system, beta receptor blockade opposes beta2 mediated vasodilation. This may
acutely lead to a rise in peripheral resistance but over time, continued drug administration leads
to a fall in peripheral resistance in patients with hypertension.

▪ Beta receptor antagonists also have a role in carbohydrate metabolism, and endocrine
hormones including glucagon (as such should be used cautiously for insulin-dependent diabetic
patients).

Question 59

If you give a beta blocker to a normal healthy person, will it typically cause hypotension

Answer 59

No, These drugs do not usually cause
hypotension in healthy individuals with normal blood pressure.

Question 60

Which 2 beta blockers are cardioselective?

Answer 60

Metoprolol & atenolol: are cardio-selective beta blockers and the most widely used in this
class for hypertension.

Question 61

Which beta blockers have both beta blocking and vasodilating effects?

Answer 61

Labetolol, carvedilol & nebivolol

Question 62

Indications for beta blockers (in the context of antihypertensives)?

Answer 62

▪ All beta blocking agents are useful in lowering blood pressure in mild to moderate
hypertension. In severe hypertension, beta blockers are especially useful in preventing the
reflex tachycardia that often results from treatment with direct vasodilators.

Question 63

Name some vasodilators

Answer 63

hydralazine, minoxidil, sodium nitroprusside, diazoxide and fenoldopam

Question 64

MOA of vasodilators.
How do we typically use them in treatment of HTN?

Answer 64

All vasodilators that are useful in hypertension relax smooth muscle of arterioles, thereby
decreasing systemic vascular resistance.

▪ Vasodilators work best in combination with other antihypertensive drugs that oppose the compensatory cardiovascular responses (mediated by baroreceptors and the sympathetic nervous system as well as renin, angiotensin and aldosterone).

Question 65

Hydralazine - when do we use it?

Answer 65

▪ Hydralazine, especially when used in combination with nitrates is effective in both hypertension
and heart failure especially for Black patients and those individuals with severe hypertension.

Question 66

Indications for CCBs?

Answer 66

Calcium channel blockers are useful in the management of
- angina
- dysrhythmias and
- hypertension.

Question 67

General MOA of CCBs

Answer 67

They work as antihypertensives as they reduce peripheral vascular
resistance and blood pressure through inhibition of calcium influx into arterial smooth muscle cells.

Exert their effects on the heart and blood vessels b preventing Ca ions from entering cells

More detail from the text:
Vascular Smooth Muscle
- In VSM, Ca channels regulate contraction
- Ca channel blockage –> contraction prevented –> vasodilation
- At therapeutic doses, CCBs act selectively on peripheral arterioles and arteries and arterioles of the heart. CCBs have no significant effect on veins.

Heart:
- Ca channels help regulate myocardium, SA, and AV nodes –> with blockage of Ca channels in these places will see decrease in contractility, HR, and slowed conductino of impulse to AV node
- Coupled with β1 -adrenergic receptors – when cardiac β1 receptors are activated, calcium influx is enhanced (and vice versa) –> Because of this relationship, CCBs and β blockers have identical effects on the heart.

Question 68

What are the two kinds of CCBs. Name drugs that fit under each and their key difference in terms of where they act.

Answer 68

dihydropyridines (nifedipine), and nondihydropyridines (verapamil & diltiazem)

**At therapeutic doses: dihydropyridines act primarily on arterioles
in contrast, verapamil and diltiazem act on arterioles and the heart

Verapamil has the greatest depressant effect on the heart and may decrease heart rate and cardiac output.

Question 69

Why can’t we use short acting CCBs (nifedipine) for hypertension?

Answer 69

▪ There is epidemiologic evidence that short-acting dihydropyridines (including nifedipine) are associated with increased risk of MI therefore, short acting oral dihydropyridines are not to be used for hypertension.

▪ Sustained release CCBs or calcium blockers with long half-lives provide smoother blood pressure control and are more appropriate for tx of chronic hypertension.

Question 70

T/F Many vasodilators are used in hypertensive emergencies

Answer 70

True
Sodium nitroprusside, diazoxide, fenoldopam…