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Diuretics: CA Inhibitors
- Ethacrynic Acid
Diuretics: Collecting Duct
Diuretic Braking: Steady State
activation of RAAS and SNS to counterbalance diuretic (to avoid losing too much volume/pressure)
CA Inhibitors: MOA
- reduce NA reabsorption by preventing reabsorption of BICARB
- INCREASE excretion of BICARB, NA, K, urine pH
- DECREASE plasma pH
- *metabolic acidosis risk
CA Inhibitors: Uses
- Glaucoma (high aqueous humor = HIGH [CA]
- ICU Tx metabolic alkalosis (excessive loops) **monitor pH for CHF
- Acute Mt. Sickness- pulmonary edema
Osmotic Diuretics: MOA
- Freely filtered at glomerulus and NOT reabsorbed!
- Exerts osmotic force WITHIN tubule, reducing movement of water out of tubule (and Na)***does not effect permeability of anything else.
Osmotic Diuretics: SOA
Osmotic Diuretics: Uses
- Head Trauma (change in osm gradient of blood...water leaves neurons and goes into blood to decrease pressure)
- Reduce IOP
- Targets Na/K/Cl symporter, resulting in higher osm in lumen. **REVERSIBLE
- Transports Na out of the filtrate, thereby diluting it before it is delivered to the DCT.
- HIGH K excretion due to Na load presented to the collecting duct activates RAAS in the DCT
- TAL is impermeable to water!
- "High Ceiling Diuretics"
apical side more positive. blocking K/Na/Cl symporter increases excretion. this abolition of transepithelial potential difference prevents abs of Mg and Ca
Loops: Drug interactions
Anything affecting renal blood flow (NSAIDS) can decrease loop effectiveness.
Loops: Adverse Effects
- Hyponatremia/volume depletion
- Hypokalemia (causing cardiac arrhythmia)
- Hypomagnesia (card. arr)
- Ototoxicity (at high dose/long term)*reversible
- Edema (associated with heart failure)
- ARF (increased flow=flush deposits in kidney)
- inhibits Na/Cl symporter in DCT
- EXCRETION Na and Cl
- REABSORPTION Ca (osteoblasts stimulated)
Thiazides: Adverse Effects
- DECREASED tolerance of glucose (unmask DM...decreased K=decrease insulin need= increased blood glucose)
- Arrythmias ( hypokalemia)
- Increased LDL and TGs
INEFFECTIVE at GFR<30-40 ml/min
Thiazides: Drug Interactions
- Potentially lethal interaction: QUINIDINE (due to hypokalemia and reduced elim of this drug)
- ***prolongs QT interval
- Additive effects with A/H agents
HCTZ is a SULFONAMIDE!!!
- HT: only class that causes VD, alters pressure-natriuresis curve: as Pressure increases, Sodium excretion increases
- CHF: (decrease volume)
- Nephrogenic diabetes insipidus: (loss of response to ADH...increase urine output with no regulation....lowers amt of fluid reaching DCT ***MECHANISM UNCLEAR
Potassium Sparing Diuretics: SOA
K Sparing: MOA
- Inhibits the ENaC (competitive); by inhibiting the reabsorption of Na in the Cd, K excretion is reduced (Na reabs is 'balanced' by K excretion)
- Small INCREASE Na Cl excretion
- Small DECREASE K H Ca Mg excretion
K Sparing: Adverse Effects
Hyperkalemia (no cardiac pts. or K supps)
K Sparing: Uses
HT (not stand alone therapy)
What metabolic disturbance is acetazolamide often used to treat in the ICU setting and why?
Metabolic alkalosis caused by excessive loop diuretic use. Bicarb can't be reabsorbed which decreases the plasma pH
what is a potentially lethal drug interaction that may occur with thiazide use and why?
Quinidine (hypokalemia and the reduced elimination of this drug)
Major Steps of RAAS Cascade
- Angiotensinogen (secreted by liver)-RENIN-Ang I-ACE-Ang II:
- 1. adrenal (zonal glomerulosa)...ALDOSTERONE (inc. Na abs) acting @ TAL/LOH, DCT, CD
- 2. PCT (inc Na abs)
- 3. Efferent (VC/mant. GFR)
- 4. Hypothalamus (thirst, inc. ADH secretion)
4 factors affecting JG cell activation of renin
- 1. hypotension
- 2. hypovolemia
- 3. hyponatremia
- 4. high sympathetic outflow
aldosterone activation chain
ang II, adrenal (zona glomerulosa), aldosterone (increased NaCl absorption) at TAL/LOH, DCT, CD
Major FXN of RAAS
regulation of TPR and blood volume via reabsorption mechanisms
activation goal: to increase blood volume and TPR = increase blood pressure
Renin is released by the JG cells in the walls of the afferent arteriole. The 3 places it works are:
- 1. Intrarenal macula densa pathway: chemoreceptors sense low NaCl via transporter and increase renin release
- 2. Intrarenal baroreceptor pathway: pressure receptors sense high pressure and decrease renin release
- 3. Beta adrenergic pathway: an increase in SNS increases NE, which activates B1 receptors on JC cells, which increases renin ***this is why beta blockers decrease renin
The short loop and long loop negative feedback of renin
short: ang II binds to AT1 receptors causing inhibition of renin
long: increased BP= increase RPP= decrease renin release.....increased baroreflex=decreased SNS= decreased NE= decreased renin release ***increase PNS!
Ang II acts on 6 key areas:
- 1. Vascular smooth muscle- VC arterial & venous
- 2. Adrenal cortex- aldosterone release (high H2O/Na reabs & low K secretion)
- 3. Kidney- efferent arteriole VC (high GFR, Pgc)
- 4. CNS- Increase thirst and ADH (to inc. vol)
- 5. SNS- pressure sensing**reset pressure threshold!
- 6. CV structure- wall thickening/remodelling
Therapeutic targets in RAAS
(ultimate goal is prevent effects of Ang II= decrease VC, aldosterone secretion, ADH release)
- ACE (Ang I to Ang II)
- Renin (Angiotensinogen to Ang I)
- AT1 receptor (Ang II to AT1 receptor)
Normal end results of activated RAAS
- *Na/H2O retention
- *K/Mg loss
- *CV remodelling
- *decrease arterial compliance
- *increase sensitive to catecholamines
Secondary factors that regulate aldosterone secretion
ACTH, K, Mg, vasopressin, serotonin, catecholamines, endothelin
ACE inhibitors: MOA
- 1) ACE cleaves the His-Leu off Ang I to create Ang II. ACEi prevent this cleavage.
- 2) Prevent the degradation of Bradykinin
*discovered via SA pit viper. 1st drug=Captopril
Adverse effects of ACEi
- 1. dry cough
- 2. hyperkalemia (due to blocking of RAAS)
- a. k supp
- b. cv conditions
- c. renal insufficiency
- d. other RAAS blocking drugs!
- 3. angioedema***must switch to CCB
- 4. ARF (extra caution with NSAIDS)
CI with ACEi
- 1. renal artery stenosis
- 2. angioedema
- 3. black box- pregnancy ***blocking AT1 & AT2(cell growth and development)
PK of ACEi
**all cleared by kidney EXCEPT fosinopril (urinary and biliary route)
Only ACEi with a sulfhydryl group
Only ACEi that is crushable
Only ACEi that is cleared both by urine and biliary routes
ARB vs. ACEi
ARB binds to AT1 receptor with high affinity/selectivity vs. AT2. This is important because ACE is not the only enzyme that can convert Ang I to Ang II. Binding AT1 ensures selective inhibition of Ang II, meaning ARBs do not affect bradykinin.
by binding competitively to AT1, this forces Ang II to bind to AT2 receptors, which contributes to vasodilation.
- HT- all
- Diabetic Neph- Irbesartan & Losartan
- Stroke prophylaxis- Losartan
- Heart Failure- Valsartan
- *no dry cough
- hyperkalemia (k supp, cv pts, renal insuff)
- ARF (NSAID caution!)
- **low risk angioedema, but put on CCB if prob
- renal artery stenosis
- angioedema (place on CCB)
- black box- pregnancy cat d
- minor P450
- all eliminated by LIVER and KIDNEY
Renin Inhibitors: what's so great about it?
The ONLY FDA approved direct renin inhibitor= Aliskiren (Tekturna).
Monotherapy or combo with diuretics and ARBs for Tx of HT.
Renin inhibitor: MOA
inhibits renin upstream of RAAS. **potential benefit and favorable AE profile.
Inhibiting renin prevents cleavage of Angiotensinogen to Ang I, reducing both Ang I and Ang II levels.
Renin Inhibitors: AE
- *dose related GI
- *Low incidence cough and angioedema
Renin Inhibitors: CI
- black box- preg D
- angioedema (low risk, but there)
Renin Inhibitors: PK
- poor oral absorption
- METABOLIZED by 3A4!!!!! (Drug-Drug: macrolides, a/depressants, a/fungal)
Aldosterone Antags (K sparing): MOA
ENaC on apical membrane of CD is affected by two ways. End result is inhibition of Na reabs and K excretion.
2 ways ENaC is inhibited by Aldosterone antagonists
- 1. ENaC inhibitors (direct): TRIAM/AMILORIDE
- directly block reabsorption of NA on the apical side in the CD, which inactivates Na/K ATPase on basolateral side, so there is no K to be excreted on apical side
- 2. Aldosterone antagonists (indirect): SPIRONOLACTONE/EPLERENONE prevents aldosterone from binding to eh mineralocorticoid receptor in the nucleus, which decreases expression of ENaC and Na/K ATPase
Advantage of Eplerenone vs. Spironolactone
Newer, more selective, less adverse effects
**both of these drugs might cause Metabolic Acidosis (by blocking secretion of H along with K)
Contraindications/AE with Spironolactone
- Peptic Ulcers (use Eplerenone)
Uses of Spirinolactone vs. Eplerenone
Spironolactone: HT, hyperaldost, edeme (heart failure), hypokalemia
Eplerenone: HT, heart failure, post-MI, edema, hypokalemia, hyperaldosterone
CCB's (general info)
- *Critically involved in initiation of cardiac and smooth muscle contraction. (Sm musc.=IMPERMEABLE to Ca...increases with depolarization due to activation of VGCC)
- *Involved in depol or nodal in heart (SA/AV)
- *Required for fusion of synaptic vesicles w/in nerve terminal (NT release)
- *subunits vary depending on location=targeting!
Normal Calcium Channel activation
Ca enters via VGCC, then binds to calmodulin. This complex activates MLCK, which phosporylates MLC. MLC-P binds to Actin and causes contraction. ***cGMP dephosphorylated MLC-P, leading to relaxation!
CCB's and Vascular Smooth Muscle
- EXTREMELY sensitive to voltage changes
- Unlike cardiac and neuronal, VSM has RMP b/t -40 and -20. Therefore some VGCC are always open= Basal "tone".
This can be regulated by altering K efflux as well as by cell surface receptors.
What drug can regulate membrane voltage, causing a similar response/indirect effect as VGCC CCB's? How?
Minoxidil (Vasodilator) promotes opening of ATP-modulated K channels. This hyperpolarizes the cell (more negative), decreasing VGCC activity, thus decreasing contractility
2 Classes of CCB's
- 1. DHP (Nifedipine)
- 2. non-DHP (Verapamil & Diltiazem)
General Fx of CCBs on:
1. SA node
2. AV node
3. Cardiac myocyte
4. Coronary artery
5. Peripheral veins
6. Peripheral arterioles
- 1. SA: decrease automaticity (rhythmic firing)
- 2. AV: decrease conduction (velocity)
- 3. Cardiac myo: decrease afterload/TPR, decrease myocardial O2 demand **ANGINA
- 4. Coronary artery: vasodilation, increase O2 supply **ANGINA
- 5. Peripheral veins: minimal VD
- 6. Peripheral arterioles: vasodilation, decrease afterload, decrease myocardial O2 demand
1. SA: primary pacemaker
2. Atrial: expel blood
3. AV: secondary pacemaker
4. Purkinje fibers
- SA: Ica, Ik, If
- Atrial: Ina, Ica, Ik
- AV: Ica, Ik, If
CCB's on coronary arteries
some vasal tone always present...CCB=vasodilation=increase O2 supply
CCB's in peripheral arterioles
vasodilation=decrease resistance=decreased O2 required
CCB's in peripheral veins
little effect (low # Ca channels vs. arteries)
- venous return and preload stay the same
- **F-S: lower SV with same preload moves curve RIGHT
How are CCB's similar?
- * They all require entry from the inner side of the membrane
- * Binding is favored when the channel is in the depolarized state
Differences in CCB's
Verapamil and Diltiazem
also prefer to bind to the INACTIVE state (These are non-DHP's=CV)
- Therefore these are called "use-dependent" and means that they "promote the inactive state" (harder to move to active state)
- More Cardiac Effects than DHPs.
- ALL decrease afterload
- non-DHP's: - inotropic (contraction), -chrono/dromo (HR & Conduction), decrease afterload
- DHP's: decrease afterload only
Hemodynamic Fx of CCB's
- Dilation of peripheral arteries: relax, decrease afterload, decrease O2 demand
- Dilation of coronary arteries: relax, increase blood flow, increase O2 supply
Cardiac effects of CCBs
- Reduction of SA firing rate (dec. HR)
- Reduction AV conduction (prolong PR)
- Reduction cardiomyocyte contract (dec. CO)
***Most pronounced with Verapamil/Diltiazem
At SAME preload, what is effect of positive and negative inotropic drug?
- positive (Digoxin/B agonist)= move curve up
- negative (CCB's)= move curve down
no change in preload, just FOC
all are associated with drugs' MOA (contraction loss/relaxation)
ex: constipation due to loss of GI motility
lethargy/hypotension, bradycardia, av nodal block, decreased CO (with large decrease FOC)
Amlodipine & Felodipine are the ONLY agents that have QD dosing (long t1/2). All others require multiple dosing or SR.
Verapamil (and lesser Diltiazem) are CYP3A4!
- ALL: HT
- Angina: Amlodipine, Nisoldipine, Nifedipine, Verapamil, Diltiazem
- Raynaud's (circulatory): Some
- A/arrhythmia/migraine: Verapamil
"chest pain" esp. in womencharacterized by chest,jaw,shoulder,back,arm discomfort.Primary symptom of ischemic heart disease (aka myocardial ischemia)
results when heart experiences insufficient flow. Demand > SupplyProlonged ischemia = heart tissue damage
when heart pain transmits to spine and cortex, adjacent nerves can pick up signals
1. decrease O2 demand2. increase O2 supply3. 1&2 *VERAPAMIL
When does O2 demand increase?
1. increase HR2. increase in contractility3. increased venous (F-S:increase VR=Inc. CO)
What drugs to do we know that can decrease Oxygen demand?
- 1. Beta Blockers
- 2. CCB's (esp. verapamil and diltiazem)
- 3. NITRATES= dec. VENOUS RETURN!
What reasons force coronary arteries to become unable to supply adequate blood flow to heart?
- 1. atherosclerosis (tx: Statins)
- 2. vasospasm (tx: Nitrates)
- 3. microthrombotic events (tx: a/coag,a/plate)
3 classifications of angina
- 1. Stable Angina (classical,typical,angina on exertion)
- 2. Variant Angina (Prinzmetal's)
- 3. Unstable Angina (UA, "angina at rest")
- "angina on exertion"
- typically present at 70-75% blockage
caused by unpredictable, exercise independent vasospasms.
Organic nitrates: MOA 1
1. sheer stress causes eNOS to convert arginine to NO. NO activates guanylyl cyclase, which converts GTP to cGMP. cGMP dephosphorylates MLC-P to MLC, causing relaxation.
Organic Nitrates: MOA 2
NO diffuses freely across VSM membrane and binds to heme moiety on an enzyme called soluble guanylyl cyclase (sGC) and activates it. sGC converts GTP to cGMP, causing dephos of MLC-P to MLC, causing relaxation.
Low dose vs. High dose Nitrates
Low dose: primarily venous fx (opposite CCB!) & decrease O2 demand*increase venous capacitance*decrease venous return*little change in arterial BPHigh dose: also affects arteries (inc. O2 supply)*increased coronary artery blood flow
Drug tolerance to nitrates
denitrated to NO by mitochondrial aldehyde dehydrogenase (mtALDH). prolonged exposure to nitrates leads to damage of mtALDH. this decreases bioactivation of drug and necessitates a "nitrate-free" period **usually occurs w/in 48-72 hours
"nitrate-free" period and therapy
- *non-symmetrical dosing intervals (7,noon,5/ 8,2)
- *long acting QD in am, remove at night
- *do not use with PDEi=DECREASE BP!
3 preparations of nitrates
- 1. Nitroglycerin- SL, spray (bypass 1st pass); TD ointment (6-8 hrs then wipe off); TD patch (24hr, remove HS); ER cap; IV
- 2. ISDN- oral & chew tabs; longer acting than nitroglycerin
- 3. ISMN- oral tabs & caps; longer acting than ISDN **QD
- **CLARIFY ISDN vs. ISMN with DOCTOR
Special considerations with nitrates
- 1. Extensive liver metabolism of ISDN
- 2. Tolerance development (mtALDH)
- 3. Absolute CI with PDE-5i
- 4. SL preps extremely fast acting/short duration
- 5. Protect nitroglycerin from light, air, heat, moisture. USE ORIGINAL container. Relplace unopened (6 mo) and opened (2 mo.). HANDLE AS LITTLE AS POSSIBLE
- 2nd line nitrate as add on therapy for those unresponsive to B Block, CCB's, or nitrates alone. Similar to ion channel blocking of AMIODARONE.
- 3A4 metab and PGP substrate...USE CAUTION WITH VERAPAMIL
Direct Acting Vasodilators
- *Reserved for refractory HT/emergencies.
- *Hydralazine/ISDN has been shown to be very effective in Tx heart failure in African Americans.
- *Primarily affect arterial vasc.
- **Potent afterload reducers.
- *Nitroprusside= also venodilation.
- *May elicit significant SNS activation and reduce sodium excretion due to low renal BF and low renin **co-administer with B blocker and diuretic
Direct VD: Minoxidil
- Opens Katp channels in VSM, leading to hyperpolarization (**also a target for Diabetic drugs)
- **Potent VD "Last-line antihypertensive"
- AE: edema (use diuretic), tachycardia (B Blocker), significant hirusitism
Direct VD: Hydralazine
- MOA unkown. Maybe opening of K channels or inhibiting IP3 mediated calcium release.
- **reduces development of nitrate tolerance. Used in combo for advanced heart failure.High bioavailability. slow acetylators are susceptible. Lupus-like symptoms rare and reversible
Direct VD: Sodium Nitroprusside
- Activates GC, leading to cGMP and relaxation.
- *Potent arterial and venous dilator. Used in HT emergencies and SEVERE heart failure.
- *Contains cyanide..metabolized to thiocyanate and slowly excreted by kidney. TOXIC.
- Facilitate excretion with sodium thiosulfate (sulfur donor)
3 Major differenced between nitrates and nitroprusside:
NP: no bioactivation, arteries and veins, lower tolerance risk.
ON: requires bioactivation, veins only, needs "nitrate-free" period.
- PDE breaks down cGMP. PDE-5 is selective for penile area. PDE-5 inhibitors prevent breakdown of cGMP to promote vasodilation.
- *Sildenafil may inhibit PDE-6 in high doses (retina).
- ALL 3 are 3A4!