Antihypertensives - Sue's slides Flashcards
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?
ACE inhibitors
Nonpeptide antagonists
Renin antagonists
BP is influenced by what 2 primary factors?
cardiac output & PVR
Blood pressure is regulated moment to moment at three anatomic sites. What are they?
1) arterioles
2) postcapillary venules
3) heart
(The kidney also contributes to maintenance of blood pressure by regulating the the volume of intravascular fluid)
T/F Local release of vasoactive substances from vascular endothelium may also be involved in the
regulation of vascular resistance.
True
What is meant when we say that hypertensive patients have a different “set point” than normotensive patients?
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.
What are the 4
major classes of anti-hypertensives?
1) Diuretics
2) Sympathoplegic agents
3) Direct vasodilators
4) Agents that block action of angiotensin
General action of diuretics?
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
General effects of sympathoplegic agents?
reducing peripheral vascular
resistance, inhibiting cardiac function, and increasing venous pooling in capacitance vessels;
General action of direct vasodilators?
which reduce pressure by relaxing vascular smooth muscle, thus dilating
resistance in vessels and increasing capitance;
General action of agents that block production or action of angiotensin?
reduce peripheral vascular
resistance and potentially blood volume.
How is sodium expected to alter peripheral vascular resistance?
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…)
Describe ACE inhibitors relationship to bradykinin.
ACE inhibitors inhibit an enzyme that interrupts/impacts the effects of bradykinin (a vasodilator). In this way the ACE inhibitor decreases peripheral vascular resistance.
What effect do ACE inhibitors have on cardiac output and HR?
No significant change as the meds do not activate the sympathetic reflex.
How is BP decreased by diuretic use? Describe how this evolves over time from initial tx.
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.
How much do diuretics decrease BP? Are they typically used alone?
▪ 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.
Name some loop diuretics
g. furosemide, bumetanide and tosemide
MOA of loop diuretics
selectively inhibit NaCl reabsorption
in the thick ascending limb of Henle’s loop (TAL)
T/F Loop diuretics are primarily excreted in the feces
No - by kidneys
** so half life depends on renal fx
Most important indications for loop diuretics
▪ 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.
What normally occurs in the ascending and descending loops of henle?
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
What is the normal action of aldosterone?
stimulates reabsorption of Na from distal nephron & K to be secreted
What kind of diuretic acts on the early DCT of the kidney nephron?
Thiazide diuretics
Which types of antihypertensives act on the late DCT and collective duct?
Spironolactone, triamterene
These are examples of aldosterone antagonists and non-aldosterone antagonists, respectively
Why do loop diuretics typically cause more profound diuresis than thiazide diuretics?
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
What lytes are lost with diuresis in loop diuretics?
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
T/F Lasix increases renal blood flow
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)
What kind of diuretic could potentially lead to hypercalcemia (though rarely occurs)?
Thiazide diuretic (opposite to loop)
MOA of thiazide diuretics - where in the nephron do they act?
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?
What rare adverse effect can occur with LOOP diuretics that doesn’t occur with other types of diuretics?
Ototoxicity
Transient with lasix but can be permanent with other diuretic (ethacrynic acid)
Due to the potential for hypokalemia in diuretics, what additional medication use warrants close observation of K+ levels while on the diuretics?
Digoxin: in presence of low K+, serious risk for digoxin-induced toxicity (ventricular dysrhythmias) - monitor K+ levels closely
Loop diuretics act on COX-2. What other medication does the same and therefore shouldn’t be used concurrently?
NSAIDs
T/F Like loop diuretics, thiazide diuretics can be effective in absence of sufficient renal blood
False - thiazide diuretics are INEFFECTIVE when urine flow is decreased
(text says less than 15 to 20 mL/min)
Is it recommended to use ACE inhibitors and ARBs together?
NO.
Discuss the relationship between ACE inhibitors and kidney function.
Diminsh protenuria
Stabilize renal fx
Increased eGFR
Name 3 thiazide diuretics
Hydrochlorothiazide
Chlorothiazide
Chlorthalidone
Why might ACE inhibitors not be the best option for patients living with a liver disorder?
ACE inhibitors are prodrugs and are converted to active agents by hydrolysis in the liver.
4 major clinical indications for thiazide diuretics
1) hypertension
2) heart failure
3) nephrolithiasis due to idiopathic hypercalciuria 4) nephrogenic diabetes insipidus.
Can you name a few ACE inhibitors that are used clinically?
captopril
enalapril
benazepril
fosinopril
moexipril
perindopril
quinapril
ramipril
trandolapril
ACEs can be problematic if a patient is acutely ill with which symptoms?
Decreased fluid intake
Dehydration
Mineral/electrolyte imbalances
Are ACEs safe to use in pregnancy?
No, they are contraindicated in pregnancy.
What are some possible adverse effects of ACE inhibitors?
Acute renal failure
Hyperkalemia
Dry cough - seems r/t bradykinin and substance P
(Similar to ARBs)
T/F thiazides are useful in treating virtually all patients with essential HTN
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
Diuretics enhance the
efficacy of many agents, particularly ______ (class of drug)
ACEIs
MOA of potassium sparing diuretics?
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
How do ARBs differ from ACEs?
ARBs block angiotensin receptors.
ACEs block conversion of angiotension 1 to angiotensin 2.
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?)
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).
What are some possible adverse effects of ARBs?
Acute renal failure
Hyperkalemia
Dry cough - seems r/t bradykinin and substance P
(Similar to ACEs)
ARBs are contraindicated in pregnancy.
True or false?
True.
When are K+ sparing diuretics most often used clinically?
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
What are some non-pharmacological changes you can recommend to your patient to help manage HTN?
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
Why is diuresis so minimal from spironolactone?
most of Na has already been reabsorbed by the time it reaches the distal nephron
Why is it that sympathoplegic agents are often most effective when used in combination with a diuretic?
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.
WHat type of sympathoplegic agents may be reversible or irreversible & what does this mean?
▪ 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!
MOA of alpha receptor antagonists
What happens when we give them with alpha agonists?
WHat adverse effects to watch for?
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
Name some alpha receptor antagonists
Prazosin, terazosin, doxazosin, indoramin, urapidil, labetalol & carvedilol (last 2 are beta too, right?)
Main adverse effects to look out for in K+ sparing diuretics? (to reiterate…)
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
Clinical use of alpha-recentor antagonists?
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.
MOA of beta antagonist agents?
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).
If you give a beta blocker to a normal healthy person, will it typically cause hypotension
No, These drugs do not usually cause
hypotension in healthy individuals with normal blood pressure.
Which 2 beta blockers are cardioselective?
Metoprolol & atenolol: are cardio-selective beta blockers and the most widely used in this
class for hypertension.
Which beta blockers have both beta blocking and vasodilating effects?
Labetolol, carvedilol & nebivolol
Indications for beta blockers (in the context of antihypertensives)?
▪ 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.
Name some vasodilators
hydralazine, minoxidil, sodium nitroprusside, diazoxide and fenoldopam
MOA of vasodilators.
How do we typically use them in treatment of HTN?
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).
Hydralazine - when do we use it?
▪ 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.
Indications for CCBs?
Calcium channel blockers are useful in the management of
- angina
- dysrhythmias and
- hypertension.
General MOA of CCBs
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.
What are the two kinds of CCBs. Name drugs that fit under each and their key difference in terms of where they act.
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.
Why can’t we use short acting CCBs (nifedipine) for hypertension?
▪ 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.
T/F Many vasodilators are used in hypertensive emergencies
True
Sodium nitroprusside, diazoxide, fenoldopam…
