Flashcards in Anti-Hypertensive Drugs Deck (102):
What thiazide diuretics are used to treat hypertension?
What are the loop diuretics used to treat hypertension?
Whate are the K-sparing diuretics used to treat hypertension?
What ACEI are used for hypertension?
What ARB is used for hypertension?
What renin inhibitor is used for hypertension?
What are the CCB used to treat hypertension?
What are the direct vasodilators used to treat hypertension?
3. sodium nitroprusside
What 3 sympatholytics are uses to treat hypertension?
1. metoprolol (BB)
2. prazosin (a1 antagonist)
3. clonidine (a2 agonist)
What diuretics work on the thick ascending limb?
Which work in the distal convoluted tubule?
Which work in the cortical collecting tubule?
TAL- loop diuretics (furosemide, torsemide)
DCT- thiazides (hydrochlorothiazide, metolazone
CCT- K-sparing (spironolactone, amiloride, triamterene)
Where is the majority of the Na load reabsorbed in the kidney?
What symporter reabsorbs it?
How much is absorbed in TAL, DCT, CCT?
TAL - 20 to 25% of filter Na gets reabsorbed by NaK2CL symporter
DCT - 5% is reabsorbed by NaCl symporter
CCT- 1-2% is reabsorbed by renal specific Na channels
Movement of water out of the lumen of the nephron into the interstitial space is due to the ________________. Water moves through both ___________ and through __________.
concentration of solutes in the interstitial space.
Water moves through:
1. aqueous pores in luminal and basolateral membranes (transcellular)
2. tight junctions between cells (paracellular)
Which diuretics are the most powerful? Why?
Loop diuretics that act on the NaK2Cl symporter are the most powerful because they work where MOST Na is absorbed.
Anything that increases Na delivery to the distal tubule will increase _______ excretion.
K+ because in the CCT there is a Na channel and a ROMK channel. If there is more Na going into the cell, more K will leave through ROMK
What is the mechanism of action of hydrochlorothiazide? What area of the kidney does it work on? What receptor?
It inhibits the NaCl symporter on the luminal membrane of the DCT to block reabsorption of Na and Cl.
If you have a woman has osteoporosis and hypertension what diuretic would you want to use?
thiazide because it absorbs Ca from the lumen while blocking Na absorption.
This decreases volume while saving Ca.
How do thiazides increase reabsorption of Ca?
The Na/K ATPase on the basolateral membrane makes a negative cell potential. This couples with the Na/Ca transporter on the basolateral membrane.
Thiazides block Na/Cl on the luminal membrane. Less Na goes in from the lumen, so more goes in from the Na/Ca pump. Bc Ca goes from the cell to the interstitium, more Ca gets pulled in from the lumen.
How do thiazides increase excretion of K and H?
They increase delivery of Na to the CCT.
Na goes in an Na specific channel and K leaves through a ROMK resultantly. This increases K excretion and can cause hypokalemia
What are the 3 major pharmacological effects of thiazide diuretics in terms of electrolytes?
1. increased excretion of Na and Cl
2. increased excretion of K and H
3. decreased excretion of Ca WHEN GIVEN CHRONICALLY
How do thiazides enter the lumen of kidney? Why does this matter?
What drug do they interact with?
They enter the proximal tubule by organic acid transporters.
They interact with probenecid (gout drug)
A man has gout (on probenecid) and hypertension. What class of diuretic should you give him? Why?
K-sparing (spironolactone, amiloride, triamterene) because loop and thiazides enter the lumen via organic acid pumps so they interact with the probenecid.
What are the adverse effects of thiazides?
1. volume depletion
6. decrease glucose tolerance and unmask latent DM
What drugs interact with thiazide diuretics?
3. Class III antiarrhythmics (k channel inhibitors)
What are the 2 main uses for thiazide diuretics?
1. treat hypertension- well tolerated, inexpensive, used well alone and in combo
2. edema associated with: CHF, liver disease (hepatic cirrhosis), renal disease (nephrotic syndrome, chronic renal failure, acute glomerulonephritis)
Most thiazides are ineffective with a GFR less than _____________ ml/min. This is because _________.
<30-40ml/min because most of the Na will have been reabsorbed before the DCT.
What is the mechanism of furosemide and torsemide? Where do they enter the kidney? Where in the kidney do they act? What receptor do they work on?
They are the loop diuretics that enter the proximal tubule of the kidney via an organic acid transporter and inhibit the NaK2Cl symporter in the TAL.
They also indirectly inhibit the reabsorption of Ca/Mg (paracellular)
How do loop diuretics decrease reabsorption of Ca and Mg?
They block NaK2Cl symporter. Because of this, there is less K+ going back into the lumen via ROMK and the lumen becomes less positive. This decreases the membrane potential difference from lumen to interstitial space.
Instead of 40/0 difference, it is a 10/0 difference. This will push less Ca and Mg back into the cell.
What are the pharmacological effects of loop diuretics in terms of electrolyte reabsorption and excretion?
1. Na, Cl, K are excreted
2. Ca and Mg are excreted
3. K and H (in the CCT) are excreted
4. Renin release
Why do loop diuretics stimulate renin release?
They decrease Na delivery to the macula densa--> renin release
They also cause reflex sympathetic stimulation due to volume depletion
What are pharmacokinetic considerations for loop diuretics?
1. they enter kidney via organic acid pump so they have drug interactions (specifically probenecid)
2. there is no slow release so they require frequent dosing (problems with compliance.
What are the adverse effects of loop diuretics?
What are the therapeutic uses of loop diuretics?
1. acute pulmonary edema
2. chronic congestive heart failure
3. hypertension (not first choice)
4. mobilize edema due to cardiac, renal, hepatic failure
What is the mechanism of action of triamterene and amiloride? How do they get into the lumen of the kidney? Where in the kidney do they act? What receptor?
They are K-sparing diuretics that enter the kidney through glomerular filtration. They act on principal cells of the cortical collecting duct but inhibiting Na specific channels. Decreased Na absorption reduces transcellular electrical potential (the lumen is less negative) so less K will leave through the ROMK.
This "less negative" lumen potential also reduces Ca and Mg excretion.
Why does increased delivery of Na to the CCD cause K excretion (and Ca and Mg excretion)?
The more Na that is delivered, the more substrate for the Na specific channel on the principal cell.
When Na goes into the cell, Cl is left in the lumen. This generates a - potential.
The negative potential draws K out of the cell through ROMK and Ca and Mg paracellularly.
What are the 3 main pharmacological effects of K-sparing diuretics (amiloride and triamterene)?
1. minimal increase in Na secretion (most has been absorbed before the CCD)
2. decreased K excretion
3. Decreased Ca and Mg excretion
What can increase the toxicity of amiloride and triamterene?
Renal failure because these drugs are absorbed by glomerular filtration. Less filtration = increased drug concentration/decreased drug excretion which can enhance toxic effects.
Liver disease increases triamterene toxicity because the liver metabolizes triamterene.
What are adverse effects associated with amiloride and triamterene?
1. hyperkalemia (contraindicated for renal failure, K+ supplements, ACEI, or other K sparing)
2. drug interactions
What are the therapeutic uses of K-sparing diuretics?
1. used in combo with other diuretics to reduce chance of hypokalemia and increase efficacy
2. Triamterene is used for cystic fibrosis
What is the mechanism of action of spironolactone?
Where in the kidney does it act?
It acts on a mineralcorticoid receptor in the principal cells of the CCD to inhibit the actions of aldosterone (which normally absorb Na and excrete K)
What is the normal action of aldosterone?
It enters the principal cell and binds a mineralcorticoid receptor. This complex translocates to the nucleus and makes aldosterone induced proteins that upregulate Na-specific luminal channels and increase action of the Na/K ATPase.
Increased Na absorption creates a negative membrane potential which drives out K.
The clinical efficacy of spironolactone is a function of the _______________. The higher the ________, the greater the effect.
function of the endogenous aldosterone level.
More aldo= more effect
What are the adverse effects of spironolactone?
2. bind progesterone and androgen receptors (decrease libido)
3. gi disturbances
What are the therapeutic uses of spironolactone?
1. used with thiazides and loops to decrease K excretion when treating edema and hypertension
3. refractory edema
4. used in patients with hepatic cirrhosis
5. slow progression of CHF
Which diuretic is preferentially used for patients with hepatic cirrhosis?
When is the renin-angiotensin-aldosterone system a key regulator of blood pressure?
In response to decreases of effective blood volume:
1. blood loss
2. low Na diet
Describe the RAA system starting with angiotensinogen.
1. Angiotensinogen is continuously secreted from the liver.
2. It is cleaved by renin (released from the juxtaglomerular cells of the kidney in response to low blood volume) to angiotensin I
3. Ang I is cleaved by ACE (on the surface of endothelial cells) to Ang II
What is the rate limiting step of the RAA system formation of Ang II?
Release of renin from the juxtaglomerular cells of the kidney
What three things control renin release from the juxtaglomerular cells of the kidney?
1. rate of Na reabsorption at the macula densa in the TAL. decreased Na delivery =decreased reabsorption = increased renin release
2. BP in the preglomerular vessels. decreased pressure-> baroreceptor-> increased renin release
3. NE activates B1 on juxtaglomerular cells to stimulate renin release
What receptor does most Ang II bond to? Where are these receptors located?
AT1 receptors in vascular smooth muscle, adrenal cortex, kidney, heart and brain.
It is a GPCR that is Gq so it activates PLC->IP3/DAG-> released intracellular Ca to contract smooth muscle
What are the 3 major effects of Ang II?
1. altered PVR
2. altered renal function
3. altered cardiovascular structure
How does Ang II alter PVR?
1. direct vasoconstriction - raise BP
2. enhance noradrenergic transmission
3. increase symp. discharge from adrenal
How does Ang II alter renal function?
1. direct increase of Na reabsorption at proximal tubule
2. release Aldo
3. alter hemodynamics (GFR, RBF)
How does AngII alter cardiovascular structure?
1. Long term effects cause myocyte hypertrophy and fibrosis
2. increase afterload, increase wall tension (remodeling)
What are the major differences in the ACEI drugs?
2. prodrug to active metabolite
3. absorption, half-life, distribution
What are the pharmacological effects of ACEI?
1. Decrease Ang II so inhibits the increase of PVR, the reabsorption of Na in the kidney and cardiac hypertrophy and remodeling
2. ACE usually inactivates bradykinin so if it is inhibited, bradykinin can continue to vasodilate (but also causes cough)
3. MAIN EFFECT: decrease hypertension by lowering PVR. no reflex sympathetic activity.
How are ACEI cleared from the body? Why is this an important consideration?
They are cleared renally so if there is impaired renal function, there will be decreased clearance of ACEI. Adjust dosage!
What are the adverse effects of captopril and enalapril?
1. hypotension-elevated plasma renin renders patients hyper-responsive to ACEI ESPECIALLY following first dose. (elevated renin: low salt diet, blood loss, CHF)
2. Cough - 20% get persistent dry cough due to elevated bradykinin
3. Hyperkalemia- decrease aldosterone will reduce K excretion in the CCD of the nephron
4. acute renal failure in patients with bilateral renal artery sclerosis
What drugs are contraindicated with ACEI due to the chance of hyperkalemia?
3. K sparing diuretics
4. K+ supplements
Patients with bilateral renal artery stenosis can't take what antihypertensive drug?
ACEI because this can induce renal insufficiency.
AII maintains glomerular filtration pressure
Pregnant women shouldn't take what antihypertensive?
ACEI because they are fetopathic in the 2nd and 3rd trimester.
What are the 4 main therapeutic uses of ACEI?
1. Hypertension- first line drug for DM and hypertension
2. CHF- LV systolic dysfunction because they will reduce afterload
3. Past MI, risk for cardio event, risk for chronic renal failure
4. Diabetics ****
What is the main angiotensin receptor antagonist? What is the mechanism of action?
What are the adverse effects?
Losartan is an ARB that is a competitive antagonist for AT1 receptor blocking binding of Ang II in vascular smooth muscle and other sites.
It has the same negative effects as ACEI (hypotension, hyperkalemia) but does not cause cough or angioneurotic edema.
What is the mechanism of action of aliskiren?
What is unique about the pharmacokinetics of the drug?
Why is this drug superior to other drugs of the RAA pathway?
It is an orally active renin inhibitor. It competitively inhibits the active site of renin so angiotensinogen cannot get converted to angiotensin I reducing production of ang II.
It inhibits the rate limiting step so there is less buildup of intermediate products.
What are the 2 major pharmacological effects of aliskiren?
1. like ACEI and ARB, it will lower systolic and diastolic BP
2. do NOT elevate bradykinin, ang I. They do increase circulating renin bc of the loss of Ang II feedback loop but the elevated renin is neutralized by the competitive inhibitor
What are the adverse effects of aliskiren?
3. increased uric acid (bad for gout)
4. GI disturbance/diarrhea
What are the 2 classes of CCB? What are the drugs we need to know for each class?
1. dihydropyridine- nifedipine
2. non-dihydropyridine- verapamil and diltiazem
What is the mechanism of action of CCB?
It blocks Ca channels so decrease Ca entry into cells and decrease contractility and tone of vascular smooth muscle decreasing PVR.
In addition verapamil and diltiazem effect Ca entry in myocytes (specifically at AV and SA nodes) to decrease HR and contractility
What is the effect of CCB on vascular smooth muscle? What drugs act on this site?
Which part of the circulatory system do they have the largest effect on? Why is this important?
All of the CCB (dihydropyridine and non) decrease Ca influx through voltage-gated Ca channels resulting in relaxation of the vascular smooth muscle and decreased PVR.
They act mainly on arteries and have little effect on veins so they will cause a mild sympathetic reflex.
What is the effect of CCB on cardiac muscle? Which drugs act at this site?
Verapamil and diltiazem block Ca channels in cardiac cells causing a negative ionotropic effect. (this is offset by reflex due to vasodilation of arterial smooth muscle though so there is no change in contractility.
They act preferentially at AV and SA nodes so will depress the sinus node pacemaker slowing AV conduction.
What are the pharmacological effects of nifedipine?
Nifedipine blocks CC in the vascular smooth muscle dilating arterioles. This lowers BP and increases peripheral blood flow.
There is increased CO due to the decreased afterload and HR increases modestly due to reflex sympathetic response.
What are the pharmacological effects of Verapamil?
1. Arterial dilation (less potent that dihydropyridines)
2. Reflex tachycardia is abolished bc it has negative chronotropic effects on the myocytes (AV and SA nodes)
3. Negative ionotropic effect is offset by decreased afterload and increased sympathetic tone)
Verapamil usually does not change ventricular contractility except in what patients?
A patient with CHF because IV verapamil will decrease contractility.
What are the pharmacological effects of diltiazem?
1. Arterial dilation (least potent)
2. negative chronotropic effects
3. weak negative ionotropic effects offset by reflex sympathetic stimulation
What is the major pharmacokinetic consideration that needs to be taken into account with CCB?
They are all metabolized in the liver so clearance is reduced in patients with hepatic function compromise (cirrhosis)
What are the adverse effects of CCB?
1. excessive vasodilation - dizziness, hypotension, headache, flushing, nausea
2. Aggravate MI with nifedipine
3. bradycardia, transient asystole, exacerbated heart failure caused by IV verapamil in patients with SA/AV disturbances, or when given with Bblocker
What are the therapeutic uses of CCB?
1. hypertension- lower BP by relaxing arteries and decreasing PVR without causing fluid retention or a reflex response.
2. angina and cardiac arrhythmias
What patients would you NOT want to use a CCB for?
2. SA or AV node abnormalities
What are the pharmacological effects of metoprolol?
Metoprolol is a b-blocker with no intrinsic sympathomimetic activity. So:
Initially decreases CO with an increase in PVR and no change in BP.
Hours later, PVR returns to normal but the CO is still decreased so BP decreases.
How do BB with intrinsic sympathomimetic activity take effect?
Decrease HR and CO to achieve the long term effect of reduced BP.
Decreased BP linked to decreased PVR due to B2 stimulation
What are the adverse effects of BB?
3. AV block
4. decreased pulmonary function
6. masks hypoglycemia so avoid in diabetes
What are the therapeutic uses of BB?
1. hypertension- decrease BP with no retention of salt or water
2. SVT, angina, prevent MI recurrence
What is the mechanism of action of clonidine?
What does it treat?
It is an a2 agonist in cardio centers of CNS to reduce sympathetic outflow.
It is used as a supplement with other antihypertensive drugs.
What is the mechanism of action of prazosin? What does it treat?
It is an a1 antagonist so it will decrease PVR and venous return.
It is used in hypertensive patients with benign prostatic hyperplasia.
What is the pharmacological effect of hydralazine?
What is a pharmacokinetic factor to be aware of with this drug?
It acts on smooth muscles of arterioles to cause relaxation and vasodilation.
It can be oral (or IV or IM) and is absorbed in the GI but bioavailability varies with acetylation (major form of inactivation) and this varies from person to person
What are the adverse effects of hydralazine?
1. hypotension, headaches, flushing, nausea, palpitations, tachycardia
2. If sole agent, Na retention in CHF
3. Lupus-like immune reactions resembling serum sickness, glomerulonephritis, hemolytic anemia
What are the therapeutic uses of hydralazine?
1. used in chronic treatment of hypertension ONLY when combinations of other drugs failed (use with BB and diuretic)
What is the mechanism of action of minoxidil?
What specific vasculature does it work on?
What are pharmacokinetic properties?
It activates ATP sensitive K channels in vascular smooth muscle causing hyperpolarization which makes it harder for Ca channels to reach threshold to contract smooth muscle.
It is a powerful vasodilator WITH NO EFFECT ON VEINS so there is a strong sympathetic reflex response
It also stimulates renin.
Taken orally, absorbed for peak plasma in 1 hour, slow conversion to active drug, eliminated in liver.
What are the adverse effects of minoxidil?
1. fluid and salt retention because it upregulates renin and decreased renal flow increases proximal reabsorption
2. tachycardia due to sympathetic reflex
3. hair growth (used as rogaine)
What 2 drugs must be given with minoxidil to decrease side effects?
1. BB to decrease sympathetic reflex
2. diuretic to reduce Na and water retention
What is the mechanism of action of sodium nitroprusside?
What vessels does it work on?
It gets converted to NO in the endothelial cell which activates guanylyl cyclase -> increase cGMP-> PK-> Ca pulled into SR relaxing cell.
It works on arterioles AND venules so there is a decreased preload (venous pooling) and decreased afterload (decreased artery resistance)
Unlike arteriolar vasodilators, sodium nitroprusside causes only a modest _________ and overall reduction in _____________.
modest increase in HR and overall reduction in oxygen demand
What are the unique pharmacokinetic properties of Na nitroprusside?
It can only be given IV and the compound decomposes in light.
Onset of action - 30 sec
Peak - 2 minutes
Drug stops in 3 minutes. Give for emergency hypertension in the ER
What is the main toxicity of nitroprusside? What drug can be administered to reduce this?
It reacts with sulfhydryls to NO and cyanide.
It can cause accumulation of cyanide at infusion rates over 5mg/kg/min.
Give with sodium thiosulfate to reduce this.
What drug should be given in a hypertensive emergency?
IV nitroprusside (to rapidly reduce preload and afterload)
What drugs should be given with acute aortic dissection?
1. IV nitroprusside
What are the 5 therapeutic uses for sodium nitroprusside?
1. hypertensive emergency
2. acute aortic dissection
3. increase CO in ACUTE heart failure
4. decrease O2 demand after MI
5. reduce bleeding in surgery
What is the first treatment for people with stage 1 hypertension (above 140/90)?
1. lifestyle modification- change diet, increase exercise, DASH diet to reduce sodium
If the person has no compelling indications and present with stage 1 hypertension, what drugs should be given?
1. DIURETIC- thiazide type
2. can consider ACEI, ARB, BB, CCB or combo
3. if combo of 2 doesn't reduce it enough look for a secondary cause (renovascular disease, aldosteronism, pheo, etc)
What drugs should be given for patients with stage 2 hypertension (over 160, 100)?
combo of 2 drugs
Diuretic (thiazide) + ACEI, ARB, BB, or CCB
What should drug should be given for a hypertensive patient with diabetes?
(and a diuretic)
What drug should be given as first choice for a hypertensive patient with CAD/angina?