CARDIO_PHARM

ANTI-LIPEMIC

(similar to simvastatin, pravastatin, atorvastatin, rosuvastatin)

STATIN

FIRST-LINE DRUGS

**Incr hepatic LDL receptor expression via “sterolstat”

• Inhb HMG CoA Reductase
• → deplete hepatic sterol pool

• Dose-related decr
• in LDL of 25-35%

(statins differ in potency)

• most potent :
• (decr LDL by >30-35%)
• 1.
• Simvastatin
• 2.
• Atorvastatin
• 3.
• Rosuvastatin
• 4.
• lovastatin
• ---------------------------------------
• PHARM

• Inhb sterol synth
• → decr intracellular sterol conc
• → incr synth of HMG CoA reductase & LDL receptors.

• Incr synth of HMG CoA reductase
• → compensates for inhb of the enz
• → only decr sterol synth by 20-25%

• Incr hepatic LDL receptors
• → incr plasma clearance of LDL & IDL

Incr in hepatic LDL receptor persists thru Rx

• Decr synth ApoB-100
• → decr hepatic synth of VLDL

• Incr plasma clearance of VLDL
• (via unknown mech)

• Other cardioprotective effects:
• 1. Reversal of endothelial dysfunc w/ improved ability to synth N.O.

2. Decr oxidation of LDL

• 3. Incr stability of chol plaques. Plaques → prod
• IL-6 at liver → prod acute phase prot (i.e., CRP)

4. Anti-inflammatory → decr in plasma conc of hs-CRP

THERA

(similar to simva, prava, atorva, rosuva)

Hyperlipidemia

• Dose-related decr in cholesterol in everyone at risk including Type II DM
• · Decr VLDL*

· Decr LDL*

· Decr TGs

· Incr HDL

• Statins do NOT decr plasma chol in genetic absence of hepatic LDL receptors
• (homozyg. fam. hypercholesterolemia)

• Incr in hepatic LDL receptor persists thru Rx
• --------------------------------------

TOX

• 1.
• Hepatic damage: Incr AST & ALT

2. Myopathy: musc pain & weakness

· Fatigue & progressive flu-like myalgia in arms & legs

• · Biopsy:myofibrils (-) for cytochrome oxidase
• & incr lipid stores → dysfunc of mito respir chain.

· Myositis: 10x incr plasma creatine phophokinase (CPK) ± myalgia (0.1% pts)

• · S/E incr when Rx in combo w/ gemfibrozil or
• niacin

· S/E incr when Rx in combo w/ CYP3A4 inhibitor

***pravastatin & rosuvastatin are NOT metabolized by CYP3A4

• 3. Fatal rhabdomyolysis:
• Cerivastatin removed fr market. Some pts also took gemfibrozil.

• 4. Fetal tox (Category X)
• = potential teratogen
• i.e. Do NOT give to pregnant ♀

ANTI-LIPEMIC

STATIN

NOT METAB BY CYP3A4

(similar to simvastatin, pravastatin, atorvastatin, rosuvastatin)

ANTI-LIPEMIC

STATIN

(similar to simvastatin, pravastatin, atorvastatin, rosuvastatin)

ANTI-LIPEMIC

STATIN

*NOT METAB BY CYP3A4

(similar to simvastatin, pravastatin, atorvastatin, rosuvastatin)

ANTI-LIPEMIC

(~same MOA as statins)

**Incr hepatic LDL receptor expression via “sterolstat”

Blocks protein-medt’d transporter which absorbs dietary chol from GI tract.

→ deplete hepatic sterol pool

• --Depletes the hepatic sterol pool in a different manner than statins, but has the same effect
• to incr HMG CoA reductase and LDL receptors

• Net effect (as monotherapy):
• · No change VLDL

· Decr LDL

· Decr TGs

* Incr HDL

ANTI-LIPEMIC

Rapidly absorbed & converted to actv glucuronide conjg w/in intestinal wall & conc’d in intestinal wall cells.

Extensive enterohepatic recirculation → t1/2 = 22h

~80% of p.o. dose elim in feces.

***

1. 50% decr of chol absorbed fr GI tract

→ decr delivery of chol to liver

• → incr HMG CoA
• reductase & LDL receptors via sterolstat

• → incr LDL uptake
• by liver

• → decr plasma
• LDL

2. Does NOT block absorption of fat-solb vits, TGs, estradiol & progesterone

3. Incr hepatic chol synth by 80-90% via induction of HMG CoA reductase but does not restore intrahepatic sterol pool to normal.

→ persistenc incr of hepatic LDL receptors

ANTI-LIPEMIC

THERA

Hyperlipidemia

1. Added to Rx w/ a statin when pts unable to decr LDL conc w/ statin alone

2. Co-admin allows a decr in statin dose w/o losing bene. effects of statins

• 3. Elim need to Rx w/ ion exchange resin to achieve further decr LDL
• ------------------------

TOX

• 1. combo w/ statin → incr risk of
• asymptomatic elev in AST & ALT but still < 2%

2. Does NOT incr statin S/E of myopathy

• 3. NO drug intxns b/c no effect
• on CYP1A2, CYP2D6, CYP3A4

4. Pregnancy category C (risk can’t be ruled out)

ANTI-LIPEMIC

• Ion exchange resins (anion)
• --bind bile acids (bile acid sequestrants)

(SAME AS CHOLESTYRAMINE, COLESTIPOL, COLESEVELAN)

**Incr hepatic LDL receptor production via “sterolstat”

• Swap Cl- for (-)charged bile acids:
• Bound bile acids are lost in feces

→ decr bile acid retuning to liver

→ decr intrahepatic sterol pool

→ induce tsc of HMG CoA reductase & hepatic LDL receptors

→ decr plasma LDL via incr hepatic LDL receptors

but prodtn of bile acids restored via incr hepatic LDL uptake & incr HMG CoA reductase

**Bile acid-binding resins do NOT decr plasma chol in genetic absence of hepatic LDL receptors

ANTI-LIPEMIC

ION EXCHANGE RESINS

Decr in plasma LDL limited by incr in hepatic chol synth.

*Dec delivery of chol to liver -> inc transcription of HMG CoA reductase & LDL receptors -> more uptake of LDL by liver -> dec plasma LDL

*Do NOT lower chol

• Net effect:
• · No change VLDL
• · Decr LDL (dose-related)
• · No change TGs
• * Incr HDL

Hyperlipidemia

Used to decr LDL in pts at risk (same groups as for statins)

• Ion-exchange resin
• 10-35% decr LDL

• Resin + statin
• ~50% decr LDL

• Resin + statin + niacin
• 70% decr LDL
• --------------------------

TOX

• 1. GI :
• -constipation
• -abdominal bloating
• -pain

• 2. May bind other drugs in GI tract →
• prevent absorption/decr bioavailability of:
• Warfarin
• Propanolol
• Tetracyclines
• Furosemide
• HCTZ
• Pravastatin
• Fluvastatin
• Thyroxine

Take other drug 1 hr before or 4 hrs after resin

• Colesevalan does NOT affect bioavailability of:
• Warfarin
• Digoxin
• Lovastatin
• Atorvastatin
• Simvastatin

**Colesevelan (Pregnancy B)

Cholestyramine (Pregnancy C)

SAME AS CHOLESTYRAMINE

ANTI-LIPEMIC

ION EXCHANGE RESINS

SAME AS CHOLESTYRAMINE

ANTI-LIPEMIC

ION EXCHANGE RESINS

• Colesevalan does NOT affect bioavailability of:
• Warfarin
• Digoxin
• Lovastatin
• Atorvastatin
• Simvastatin

**Colesevelan (Pregnancy B)

Cholestyramine (Pregnancy C)

MOA is unknown

Converted to NAD & NADP

• Net Effect:
• · Decr VLDL
• · Decr LDL
• · Decr TGs
• * Incr HDL
• --------------------------

PHARM

1. Inhb lipolysis in adipocytes

→ decr plasma FFA (free fatty acids)

→ decr hepatic synth of TGs

2. Decr hepatic synth of VLDL via:

· Decr hepatic TG synth → Decr VLDL synth

· Decr hepatic synth and esterification of FA → Incr degredation of ApoB100

· Actvn of lipoprotein lipase → Incr VLDL clearance

* Decr VLDL → Decr plasma LDL & Tc

3. Decr rate of catabolism of apoA-1 → Incr plasma HDL conc

· HDL resp depends on initial HDL value

· If [HDL] < 30 mg/dl → 5-10 mg/dl incr HDL

· If [HDL] > 30 mg/dl → up to 20-30 mg/dl incr HDL

Tx Incr HDL!!!

1. Primarily used as adjunctive therapy to incr HDL (b/c of high freq S/E)

2. Rx pts w/ elev TGs & low HDL (dyslipidemia)

3. Used to decr TGs, VLDL & LDL & incr HDL in pts w/ mixed hyperlipidemias (incr Tc & TGs)

• Contraindicated in pts w/
• --ulcer disease
• --type 2 diabetes mellitus

50% pts cannot tolerate S/E

1. Pregnancy C

• 2. Flushing & pruritis in face & upper body.
• Decr by 75% after 1-2 weeks. Also decr w/ 1 aspirin/day.

• 3. GI:
• · n/v
• · diarrhea
• · dyspepsia

4. Dry skin

5. Liver: incr AST & ALT (often remits if decr dose)

• 6. Incr plasma glucose conc or decr glucose
• tolerance in pts w/ subclinical type 2 DM

7. Symptoms of gout from incr plasma uric acid conc

Extended release niacin still causes flushing

Inositol hexanicotinate (new formulation of niacin) does NOT cause flushing or pruritis

ANTI-LIPEMIC

TX HYPERTRIGLYCERIDEMIA

STIM PPAR-a RECEPTOR IN LIVER, BROWN ADIPOSE TISS, SKEL MUSC, HRT AND KIDNEY

DEC PLASMA TG VIA DEC HEPATIC SECRETION AND INC CLEARANCE OF VLDL

--> INC OX OF FATTY ACIDS VIA INC PEROXISOMES

Actvn of lipoprotein lipase esp in skeletal muscle

REDUCED SYNTH OF ApoC-III --> DEC VLDL

INC ApoA-I & II --> INC HDL

• Incr release of SREBP
• → Incr LDL receptors
• → Decr LDL cholesterol

MOA -- ANIT-LIPEMIC - Actvn of lipoprotein lipase esp in skeletal muscle

Big decr VLDL & TGs!!!

• Bind PPARα → Incr clearance of VLDL
• → Decr TG

• Bind to PPARα causes:
• · Incr peroxisomes → Incr ox of FAs
• · Incr LPLase → Incr clearance of VLD
• * Decr ApoC-III → Incr VLDL clearance
• · Incr ApoA-I&II → Incr HDL

Hypertriglyceridemia (TGs)

1. pts w/ hypertriglyceridemia at risk for pancreatitis

2. single agent: →Decr TGs, VLDL, and LDL & incr HDL

• 3. Combo w/ statins → Decr VLDL, TGs, Incr
• HDL

• 4. Type 2 DM
• DM pts ~ on Statin + ezetimibe + gemfib/fenofib
• -----------------------------------

TOX


1. Pregnancy C

2. GI discomfort

3. myopathy (myositis flu-like syndrome w/ incr CPK). But combo statin + gemfibrozil has proven to be safe

4. Incr risk of gallstones

5. Avoid in pts w/ renal or hepatic disease

ANTI-ANGINAL

b-BLOCKERS

BLOCKADE OF CARDIAC b-ADREN RECEPTORS

PREVENTS CARDIAC STIM OF SNS

ALL b-BLOCKERS EQUALLY EFFECTIVE

• CARDIOSELECTIVE Dz PREFERED b/c LESS S/E ON PULM VENTILATION
• ------------------------

• PHARM
• 1. Decr HR
• 2. Decr dp/dt
• 3. decr DBP (afterload)
• 4. Incr blood flow to endocardium during diastole (incr ratio of endocardial/epicardial blood flow)
• --------------------------------

• TOX
• 1. Bronchoconstriction
• 2. Exacerbation of heart failure
• 3. Sudden withdrawal of therapy → may ppt an MI

CONTAIN / DONATE N.O.

ACTIVATES CYTOPLASMIC GUALYL CYCLASE

INC cGMP

ACT cGMP KINASE

ACT MLC PHOS-TASE

MLC-P TO MLC

RELAXATION OF VASC SMOOTH MUSC

ANIT-ANGINAL

• Nitrates
• PREFERABLY VENOdilate

TOPICAL

*Venodilation lasts >> arteriodilation

***

Common/major MOA:

1. Decr preload (venous return) →

2. Decr diastolic & systolic ventr wall tension

3. Incr diast. endocard. blood flow

4. Incr collateral blood flow

• 5. If decr afterload (DBP) → decr systolic
• intraventr press → decr O2 demand

***

VEC of arteries & veins produce N.O. → vasodilation.

Organic nitrates dilate b/c they donate N.O. tho pref dilate veins.

BUT: Lg doses can dilate arterioles → decr DBP → baroreflex-medt’d incr in sympathetic heart actvy

1. Decr preload & unchanged afterload: veins dilate w/ little or no effect on resistance arterioles

• 2. Decr wall tension during diastole & systole (due to decr LV volume):
• · Decr O2 demand
• · Incr O2 delivery (incr endocardial blood flow)

3. w/ selectv venodilation → decr CO

• 4. Inhb platelet agg
• * VEC tonically prod N.O. → prevents platelet agg
• * organic nitrates donate N.O. (relax VSM) → anti-platelet
• * Anti-platelets GOOD b/c CAD, which causes angina, also → MI

5. Incr epicardial (large arteries) blood flow (“coronary vasodilation”) but NOT 1o MOA for prevent/relieve angina

1. Angina!!!

• 2. CHF!!!!
• Venodilation → decr venous return (preload)

• 3. MI
• Minimize size of tissue damaged by infarct

• tolerance
• * ~ disappears if drug withdrawn for a short time
• * Can lessen tol by schedule
• ----Remove patch at night if pt low risk for isch
• ----Dose p.o. nitrates at 7 AM & 2 PM

----------------------------------

TOX

• 1. HEADACHE
• 2. ORTHOSTATIC HYPOTENSION
• (NOT w/ p.o. NITRATES

ANTIANGINAL -- NITRATES

P.O.

SAME AS NITROGLYCERINE

EXCEPT DOES NOT EFFECT PERIPHERAL RESISTANCE ARTERIOLES

SO PRELOAD FALLS BUT AFTERLOAD IS UNCHANGED

Tx HF + HYDRALAZINE

ANTI-ANGINAL NITRATE (see ntg)

Sublingual admin allows all absorbed NTG to reach heart via SVC

→ CO distrb to both arteries & veins

• Effects last < 1 hour:
• Arteriolar dilation lasts < venodilation
• ----------------------------------

PHARM

VENULE DEC IN O2 DEMAND >> BAROREFLEX MED'T ARTERIOLAR INC IN O2 DEMAND (inc hr & dp/dt)

• ACUTE hemodynamic effects:
• --Dilate both arterioles & venules
• --INC HR & dP/dT
• Arteriolar dilation
• → decr TPR &
• decr DBP
• → baroreflex-medt’d incr in
• eff sympathetic nerve actvy
• → incr HR & incr dp/dt
• → incr O2 demand

• Venule dilation
• → incr venous
• capacitance
• → decr venous
• return (preload)
• → decr diastolic
• wall tension
• → decr O2 demand &
• incr O2 supply
• (endocardial blood flow)

• Also: decr DBP (afterload) →
• decr systolic wall tension → decr O2 demand
• -----------------------------

TOX

• Decr DBP → faint/fall if pts don’t sit down before
• taking sublingual NTG

• DILTIAZEM
• VERAPAMIL
• AMLODIPINE

Ca++ channel blockers

Block L-type Ca++ channels in plasma mem of VSM in arterioles, AV node, SA node & myocardial cells

w/o Ca++ → musc won’t contract

***

L-type Ca++ channels:

· (voltage-gated), Open slowly

→ Ca­++ flows down gradient into cell

• → Intracellular Ca++ directly actv calmodulin &
• triggers release of more Ca++ from sarcoplasmic reticulum

→ Ca++-Calmod complex → actv myosin lt chain kinase

→ Pi myosin lt chain to allow intxn w/ actin

→ VSM contraction

· ch closes → refractory period

· 3 states: closed, open, inactv’d

• DILTIAZEM
• VERAPAMIL
• AMLODIPINE

Subclasses bind different sites on α1-subunit of L-type Ca++ channel → different pharm effects

Clinical doses ~ do NOT block Ca++ channels of sarcoplasmic reticulum.

Good GI absorb but hi 1st pass metab

***

• Block L-type Ca++ channels:
• 1. Decr HR

2. Decr AV conduction

3. Decr dp/dt (contractility)

4. Block ch in coronary vessels → dilate epicardial arteries & endocardial arterioles

5. Block ch in VSM of resistance arterioles → decr TPR → decr DBP

• 6. Do NOT dilate veins → No effect on
• venous return

• DILTIAZEM
• VERAPAMIL
• AMLODIPINE

1. Decr HR (V&D)

2. Decr dp/dt (V&D)

• 3. Decr systolic wall tension
• --V&D: via decr dp/dt
• --A: via decr DBP (afterload)

4. Dilate epicardial & endocardial arteries

5. Incr diastolic blood flow to endocardium (incr ratio endo/epi blood flow)

6. Incr collateral blood flow to myocardium

7. Effective on Prinzmetal’s angina b/c prevent vasospasm in epicardial arteries

• DILTIAZEM
• VERAPAMIL
• AMLODIPINE

· β-blockers (V)

· digoxin (V)

· class IA anti-dysrhythmics (V)

· grapefruit juice

· cimetidine (D)

• DILTIAZEM
• VERAPAMIL
• AMLODIPINE

1. Hypotension (all CCA)

2. GERD (all CCAs)

• 3. Incr risk of MI
• ~ due to excessive vasodilation → incr symp drive to heart

4. Bradycardia (V&D)

5. SA nodal failure or AV block (V&D)

• 6. Heart failure pts w/ systolic dysfunction
• (V&D)

• 7. Pedal edema (~A) (~20% pts)
• · NOT due to extracell fluid vol
• · Dilation of pre-capill sphinc → excess fluid filtration into interstitial space in ankles

• 8. Paradoxical angina (~A)
• · Cause unknown but poss...
• · Excessive arteriolar vasodiation → lowers DBP too much → decr coronary perfusion
• · “coronary steal” = dilates healthy arteries > atheroscl ones → shunts blood away from ischemic areas to healthy areas
• · Incr myocardial O2 demand from baroreflex-medt’d incr sympathetic tone

9. Constipation (V)

• V & D
• "VALENTINE'S DAY"

ANTI-ANGINAL CCA's

1* affect arterioles

*Decr DBP

→ baroreflex-med’t incr sympath actvy

→ No change/small incr HR, dp/dt, AV conduction, SV & CO

No depressant effect on ♥ actvy!

Given p.o.

t1/2 = 30-50 hours

Anti-anginal effects of V & D:

• *Decr O2 demand
• 1. Decr HR
• 2. Decr dp/dt
• 3. Decr systolic ventr pressure

• *Incr O2 supply:
• Dilate epicardial arteries & endocardial arterioles

• *Also:
• 1. Incr diastolic blood flow to endocardium (incr ratio endo/epi blood flow)

2. Incr collateral blood flow to myocardium

3. Decr systolic wall tension via decr dp/dt

4. ~ Decr CO

ANTI-ANGINAL CCA

1* affect arterioles

*Decr DBP

→ baroreflex-med’t incr sympath actvy

→ No change/small incr HR, dp/dt, AV conduction, SV & CO

No depressant effect on ♥ actvy!

Given p.o.

t1/2 = 30-50 hours

ANTI-ANGINAL CCA

• *Decr O2 demand:
• --Decr systolic ventr pressure

• *Incr O2 supply:
• --Dilate epicardial arteries & endocardial arterioles

*Also:

1. Dilate epicardial & endocardial arteries

2. Incr diastolic blood flow to endocardium (incr ratio endo/epi blood flow)

3. Incr collateral blood flow to myocardium

4. Decr systolic wall tension via decr DBP

ANTI-ANGINAL CCA

1. Hypotension (all CCA)

2. GERD (all CCAs)

• 3. Incr risk of MI
• ~ due to excessive vasodilation → incr symp drive

4. Pedal edema (A)

5. Paradoxical angina (~A)

Tx OF HF -- SYSTOLIC

• LOOP DIURETIC -- THICK ASCENDING LIMB
• NA/K/2CL --> SALURESIS

DEC ECF VOL

DEC VENOUS RETURN (preload)

DEC LV FILLING PRESSURES

***

ALLEVIATES CONG SYMPTS OF BACKWARD FAILURE

STILL ON SAME STARLING CURVE

Tx HF -- SYSTOLIC

DEC CONG SYMPTS

• BUT NO
• --INC SV
• --REV CARDIAC REMODELING
• --IMPROVE SURVIVAL

***

USE SMALLEST DOES POSS

DOSE 2-3 PER DAY b/c SHORT T1/2 AND REBOUND INC Na/H2O REABS

• *COMBO w K-SPARING DIURETICS TO PREVENT HYPOKALEMIA
• ------------------------------

HYPOKALEMIA

--COMBO SPIRONOLACTONE b/c ALSO BLOCKS ALDO REC --> PREVENTS CARDIAC REMODELING

ALDO INC COLLAGEN DEPOT IN HRT

ANTI-HT

-PRIL

1. Prevent Ang I→ Ang II

2. Block ACE (aka kininase II) → also prevents breakdown of bradykinin which is a vasodilator & → synth PGs**

***

· Initial decr BP is related to pre-Rx value of PRA

· Long-term resp does NOT correlate with pre-Rx PRA.

· No effect on BP in anephric pts

***

1. Decr plasma Ang II

2. Plasma Aldo maintained by ACTH & plasma K+ conc

• ANTI-HT
• -PRIL

*BALANCE VASODILATION*

1. Dilate resistance arterioles → Decr TPR → decr MAP

2. Incr compliance of Lg arteries → further decr SBP

Incr compliance due to ACEi prevent/reverse Ang II trophic effect on prot synth in Lg & small arteries

3. Decr SBP & DBP

4. Decr MAP

5. Uniform incr RBF via dilation of aff & eff arterioles. BUT GFR unchanged.

• 6. Decr Filtratn Fractn → No salt & H2O
• retention

7. Blood flow in cerebral & coronary bed well maintained.

8. Prevent remodeling caused by Ang II**

9. little or no change in CO (tho poss small decr in CO & SV via venodilation)

10. No change in HR BUT No impairment of baroreflex!!!!

1st line HTN drugs!

• 1. Monotherapy or combo w/ thiazide for incr efficacy.
• · single: decr BP in 50% pts
• · combo: decr BP in 80% pts

• 2. **DOC: pts w/
• · HF
• · LVH
• · DM
• · post-MI systolic dysfunc

• 3. **EVERY type 2 DM or HF pt should
• be on ACEi even pts w/o HTN → protects kidneys & prevents proteinuria

• 4. Also Rx:
• · Malignant HTN
• · renovascular HTN
• · HTN crisis of scleroderma

5. Long-term: reverses 15% of cardiac hypertrophy

1. “First dose” Hypotension, esp if pt also on thiazide

2. Renal insufficiency in pts w/ bilateral renal artery stenosis or stenosis of a solitary kidney

3. HYPERkalemia in pts taking K-sparing diuretic or K+ supplements

4. *Angioedema: not dose-related

5. *skin rash: dose related

6. ageusia & dysgeusia

• 7. *dry cough:
• · PGs potentiate cough reflex
• · dose-related, use 1 aspirin/day to prevent

• 6. *Pregnancy X: teratogen at all stages of preg.
• 1st: CNS or CV. 2nd, 3rd: oligohydramnios,
• calvarial hypoplasia, pulm hypoplasia, growth retardtn, neonatal anuria, fetal death & neonatal death

Instead, preg ♀: α-MD, atenolol & nifedipine

7. CV reflexes (baroreflex) maintained → Postural hypotension rare.

8. Prevent/reverse hypokalemia & adverse changes in plasma lipid profile produced by thiazides

9. Fatigue, weakness, & sexual dysfunc rare

CAPTOPRIL

ENALAPRIL

LISINOPRIL

ANTI-HT

-SARTAN

ARB: Ang II receptor antagonists

Competitively block Ang AT1 receptor

• All CV effects of Ang II caused by stim of Ang AT1
• receptors.

**Do NOT inhb bradykinin metab or incr PG synth

ANTI-HT

*BALANCE VASODILATION*

Incr compliance of small & large arteries by MOA indp of decr BP caused by these drugs

Other effects same as ACEi:

1. Dilate resistance arterioles → Decr TPR → decr MAP

2. Incr compliance of Lg arteries → further decr SBP

• Incr compliance due to ACEi prevent/reverse Ang II
• trophic effect on prot synth in Lg & small arteries

3. Decr SBP & DBP

4. Decr MAP

• 5. Uniform incr RBF via dilation of aff &
• eff arterioles. BUT GFR unchanged.

• 6. Decr Filtratn Fractn → No salt & H2O
• retention

7. Blood flow in cerebral & coronary bed well maintained.

8. Prevent/reverse vasc/cardiac remodeling caused by Ang II**

9. little or no change in CO (tho poss small decr in CO & SV via venodilation)

10. No change in HR BUT No impairment of baroreflex!!!!

1st line HTN drugs!

Monotherapy or combo w/ thiazide for incr efficacy.

• 1. HTN
• · shallow Dose-resp curve
• · Add small dose of HCTZ instead of incr ARB dose

• 2. Poss bene for CHF, but not yet approved
• -----------------------

TOX

1. Do NOT use in pregnant or breast-feeding ♀

2. NO dry cough

3. *Angioedema poss, esp in pts w/ past angioedema to ACEi

4. Hypotension poss

5. HYPERkalemia

-SARTAN

LOSARTAN

VALSARTAN

ANTI-HTs

Tx OF HT FAILURE -- SYSTOLIC

ALDOSTERONE REC ANTAG

1. Decr turnover of collagen in ECM of ventr → Prevents/reverses remodeling caused by Aldo

2. Improve survival

• Spironolactone:
• · improve clin status
• · decr symptoms, hospitalzns & death

• Eplerenone (when added to optimal therapy):
• --decr morbidity & mortality

• Decr “backward failure”
• · Reverse cardiac remodeling
• · Incr survival

• Small doses of sprionolactone block Aldo receptors but NOT incr risk for hyperkalemia if SCr < 2.5 mg/dl
• -------------------------------

TOX

• **Hyperkalemia (dose-related)
• · esp if pt also on ACEi other than captopril
• (shorter t1/2 = 2 hr)
• · Pts w/ HF have incr SNS activity & renal hypoperfusion → incr renin
• · Intrarenally-gen Ang II maintains GFR by pref constrict eff arteriole
• · ACEi block Ang II compensation^ → can impair renal func in some pt

→ Use captopril b/c short t1/2 only inhb Ang II synth for part of day

• **Spironolactone: partial agonist at andrgn, estrogn, progestone receptors → gynecomastia,
• breast pain, azoospermia, hirsutism & menstrual irregularity

Tx HF -- SYSTOLIC

• SAME AS SPIRONOLACTONE
• --ALDO ANTAGONIST

NOT PARTIAL AGONIST OF ANDROGEN, ESTROGEN, OR PROGESTERONE RECEPTORS

DOES NOT CAUSE GYNECOMASTIA, BREAST PAIN, AZOOSPERMIA, HIRSUTISM OR IRREG MENSTRATION

Tx HF -- SYSTOLIC

β-blocker

***Myocardium has β1, β2 & α1

Blocks β1 & β2 receptors

Blocks α1 receptors

***

1. Prevent/reverses remodeling of myocardium caused by excessive sympathetic stim

2. Prevent ventr dysrhythmias → Decr sudden death

• 3. Anti-anginal effects
• -----------------------------------

THERA


SYSTOLIC HF:

• · Incr SV
• · Incr EF
• · Reverse cardiac remodeling
• · Incr survival

1. Pts w/ class II, III HF & EF < 35%

• 2. Rx pts already taking ACEi & diuretic (&
• poss digoxin)

3. **dose: “start low, go slow”

• · β-blockade: Initial decr EF → Pts feel worse
• at first
• · After several months: Incr EF above pre-Rx
• values → pt feels better & incr exercise tol

4. Decr death from LV failure by 50%

5. **Use biggest dose pt can tolerate → dose-related bene effects

Tx OF HF -- SYSTOLIC

Direct (+) inotropic effect: GOOD

During systole: rapid incr & decr of intracellular free Ca++

Na+ conductance → opens voltage-senstv L-type Ca++ channels → SR releases Ca++ & also Ca++ --> CONTRACTION

• End of systole: Ca++ sequestered in SR
• & extruded from myocyte by Na+/Ca++ exchanger → decr intracell free Ca++

Na+/Ca++ exchanger driven by Na+ gradient estb by Na+/K+ ATPase

***

Digoxin binds a Pi aspartate on Na+/K+ ATPase → INHB

• → incr intracellular Na+
• → decr Na+ gradient
• → slows extrusion of Ca++ by Na+/Ca++ exchanger & incr total amt sequestered by SR

→ When “trigger” Ca++, more Ca++ released from SR → incr dpt/dt

***

1. INDIRECT: Acts w/in CNS → incr vagal efferents & decr sympathethetic efferents

2. DIRECT: Inhb Na+/K+ ATPase at doses above therapeutic window

Tx OF HF -- SYSTOLIC

*INDIRECT ♥ effect: GOOD

Acts in CNS →

• 1. Incr vagal efferents:
• · Decr HR
• · Decr conduction vel & incr ERP → Decr # signals thru AV node

2. Decr sympathetic efferents (anti-adrenergic actvy):

• --Decr automaticity
• --Incr ERP in myocardium

• *DIRECT ♥ effect: BAD
• Above therapeutic window

• 1. ***Inhb Na+/K+ ATPase:
• --Decr phase 4 membr potential diff (cell
• less electro (-) → closer to threshold voltage)

• --Automaticity (spont phase 4 depolzn) → PACs
• & PVCs

2. Incr intracellular Ca++ → incr probability of phase 4 automaticity

3. Incr intracellular Ca++ → incr possibility of delayed after-depolzn which trigger dysrhythmias

NOT for DIASTOLIC dysfunc!!!!

1. Rx HF asst’d w/ SYSTOLIC dysfunc when pt still symptomatic after Rx w/ ACEi & diuretic

2. **Rx HF in pts w/ A fib b/c digoxin→ incr vagal tone →

· Controls/decr ventr HR in presence of high atrial rate

· Incr ventr dp/dt

***

• therapeuticwindow is miniscule:
• 1-2 ng/ml. → monitered by radioimmunosassay

t1/2 = 24 – 48 hours

• · Excreted unchanged
• · **Clearance proport’l to GFR
• · Stored in skel musc → dose based on lean body mass.

Drug interactions

• 1. Decr digoxin abs fr GI tract:
• Cholestyramine
• Colestipol
• Antacids

• 2. **Spironolactone:
• --Decr digx renal clearance
• --Interferes w/ digx readioimmunoassay

3. Furosemide & HCTZ → HYPOkalemia

4. CCAs:V&D & β-blockers → bradycardia & decr AV conductn

ALL ELECTRICAL!

1. Sinus bradycardia (incr vagal)

2. AV block (incr vagal)

3. PACs

4. PVCs & late after-depolzns



Factors causing electrical S/E in ♥:

1. **Hypokalemia: Low extracell K+ favors Pi of Asp → incr digx binding to Na+/K+ ATPase

2. Hypercalcemia: Incr [Ca++]P “overloads” intracell storage sites

3. **Hypomagnesemia

Also:

• 1. Anorexia
• 2. Nausea
• 3. Abnormal yellow/green vision

Drug interactions:

1. Furosemide & HCTZ → HYPOkalemia

2. CCAs:V&D & β-blockers → bradycardia & decr AV conductn

ANTI-PLATELET

(COX-1 in platelets → synth TXA2)

Acetylsalicylic acid (aspirin) converted to salicyclate by hepatic 1st pass metab

Circulating salicylate REVERSIBLY inhb COX-1 & COX-2, but t1/2β = 2-3 h → platelet aggregn only impaired for 8-12 h

• @ hepatic portal blood: acetylsalicylic
• acid IRREVERSIBLY inhb COX-1 of
• platelets by acetylating actv site of enz

***

• B/c no nuclei, platelets cannot synth new COX-1 →
• platelets attacked by aspirin can NEVER again synth TXA2

Platelet life span = 9-14 d, but body makes new platelets every day → daily single dose nec for antithrombotic effect.

~160 mg/day completely inhb all platelet TXA2 synth in most pts.

***

If any aspiring esc hepatic 1st pass metab → acetylsalicylic acid IRREVERSIBLY inhb COX-1 in VEC (normally synth PGI2)

But VECs have nuclei → synth new COX-1 → PGI2 synth again after 6-12 h

ANTI-PLATELET

• *Incr bleeding time
• *No effect on aPTT
• *No effect on PT

• Huge dose (≥ 6 g/day) poss incr aPTT by inhb
• hepatic synth of clotting factors.

***

• **imbalance theory:
• Single small dose (325mg) produces a persistent antithrombotic effect b/c it IRREVERSIBLY inhb TXA2 production by platelets

w/o affecting PGI₂ synth by VEC

“No COX-2 in vascular endoth cells”

1. Decr incidence of 1st or 2nd MI in pts w/ unstable angina (325 mg/day)

• 2. Prevent 2* MI by 25% (greatest prophylactic effect during 1st few weeks post-MI)
• (325 mg/day)

• 3. Decr fatal & non-fatal MI 50% in ♂, > age 50, & No previous h/o MI
• (325 mg/every other day)

• 4. Decr stroke and/or death by 40% in ♂ w/ TIA
• (trans isch attack)

5. Also decr freq of TIA

6. Decr stroke in pts w/ atrial fib

7. Decr risk of MI during PTCA

8. Prevent immediate re-stenosis after PTCA

• 9. Decr incidence of thrombotic probs in pts w/ prosthetic heart valves, thrombocytopenia
• purpura & Kawasaki’s disease

• 10. Improve post-MI survival after thrombolytic
• therapy w/ plasminogen activators
• (e.g. tPA & streptokinase)

ANTI-PLATELET

• Blocks IIb/IIIa receptors (glycoprotein
• integrin receptor) which allow fibrinogen
• to bind platelets together

• → blocks platelet
• aggregation caused by any factor (e.g. collagen, TXA2, thrombin)

ABCIXIMAB -- MONOCLONAL Ab IRREV BINDS

• EPTIFIBATIDE & TIROFIBAN
• --COMPETITIVE INH

• ANTI-PLATELET
• --BLOCK IIb/IIIa

Given i.v.

1. Percutaneous coronary intervention (PCI): PTCA & stenting

• 2. Acute coronary syndrome (acute MI, unstable angina)
• --Chest pain
• --Abnormal ECG: depressed ST segment
• --Elevated cardiac enz
• --------------------

ADVERSE

BLEEDING

ANTI-PLATELET

Block the P2Y(12) purinergic (ADP) receptor on platelets

• → block platelet
• aggregtation

Ticlopidine: REVERSIBLE inhb

Clopidogrel: IRREVERSIBLE receptor inhibitor (permanently inactv platelet P2Y12 receptor)

ANTI-PLATELET

Platelet actvn & aggregn caused by ADP requires stim of 2 different purinergic receptors.

• 1. ADP stim of P2Y(1) receptor of platelets
• → actv phospholipase C → synth of IP3, release of Ca+ from SR & change in platelet shape.

2. ADP stim of P2Y(12) receptor of platelets → inhb actvy of adenyl cyclase → decr cAMP

--incr cAMP → inhb platelet actvn & aggregn by lowering free intracellular [Ca+]

• Blockade of either P2Y receptor → Inhb platelet
• actvn/aggregn

• TIC
• 1. neutropenia (1%),
• 2. thrombocytopenia,
• 3. agranulocytosis

• CLOP
• MUCH LOWER INCIDENCE OF NEUTROPENIA & AGRANULOCYTOSIS

ANTI-COAG & ANTI-PLATELET

Maintaining the electronegativity of damaged vascular wall --> PLATELETS ARE ELEC(-)

• IRREV inhb of clotting factors
• 2, 9-12

***

AT III weakly inhb actv’d clotting factors

actv’d clotting factors attacks spfc peptide bond on AT III → clotting factor IRREV bound

***

• Heparin binds AT III
• → AT III conformational change
• → AT III peptide bond more accessible

• Heparin (catalyst) incr rate of interaction by
• 1000x

1. Anti-platelet

May incr bleeding time; additive effect w/ that of aspirin

• 2. Releases lipoprotein lipase into circulation.
• --Lipoprotein lipase hydrolyzes TGs → glycerol & FFAs

--“clears” postprandial hyperlipemia caused by chylomicrons (rich in TGs)

Cleared by reticuloendothelial system

*Heparin resistance*

1. Occurs in pulmonary embolism

2. Genetic AT III deficiency

• 3. Acquired AT III deficiency caused by nephrotic syndrome (proteinuria), hepatic cirrhosis,
• DIC

• 4. Acute phase proteins can inactivate heparin
• -----------------------------

Incr dose → incr t1/2

100U (t1/2 = 1 h) vs 800U (t1/2 = 5 h)

• ***
• 1. INC aPTT bc CFII (thrombin) INH

• 2. No effect on PT (so anticoag actvy of warfarin
• can be meas in presence of heparin)

***

• ***ANTIDOTE: protamine sulfate
• --Binds heparin→ prevent heparin intxn w/ AT III
• --has some anti-coag actvy → do not admin >50 mg
• --Dose given via slow i.v. → immediate anti-heparin effects

1. Post-op DVT

2. DVT & pulm embolism

3. During PCI

4. Relieve chest pain in pts w/ unstable angina

5. Anti-coag for i.v. catheters, hemodialysis & cardiopulmonary bypass (big dose for bypass)

• 6. ***DOC: Anti-coag for Preg ♀ b/c
• --Does not cross placental barrier
• --No teratogenic effects
• --Does not cause premature labor or fetal death
• --Discontinue 24 h before delivery

• CANNOT be given p.o.
• i.v.
• s.c.
• bolus injection
• constant i.v. infusion

*Goal: Incr aPTT to 1.5-2.5x normal value

Given s.c. every 8-12 hrs during long-term Rx.

• spinal anesthesia
• ·
• lumbar puncture
• ·
• bleeding
• -----------

• S/E heparin & LMW heparin:
• 1. bleeding (less w/ LMW)
• 2. osteoporosis w/ fract in cont’s Rx for ≥ 3 mo
• 3. Inhb Aldo synth → Slight elev of plasma K+
• --Worse if pt also taking ACE-inhb

• 4. Reversible HIT (HepIndThtomb less w/ LMW)
• --IgG Ab bind to platelet factor 4-heparin complex → platelet actvn, aggregn & clot formation

Monitor platelet count.

Diagnosis: platelets <150,000 or < 50% baseline

Occurs in 1-5% of pts after 1-2 wks of Rx

• HIT asst’d w/ thrombosis, NOT bleeding: 20% pts lose a limb, 30% die
• --Incidence much less w/ LMW.
• --Pt w/ HIT use non-heparin anti-coag:·
• Danaproid
• Lepirudin
• Argatroban
• Fondaparinux

LMW HEPARINS "aid in flow"

• Bind to AT III
• --Primarily inhb actv’d factor 10 (Xa)

***

• Exert little effect against thrombin (IIa) b/c LMW
• heparin too short/small to bind both AT III & IIa simultaneously

*ANTIDOTE Protamine sulfate only partially reverses LMW heparin effects

LMW HEPARINS

• little effect on aPTT
• --INH FACTOR Xa

***Advantages of LMW heparin over unfractionated heparin:

• 1. Kinetics NOT altered by binding to plasma proteins, phase proteins, endothelial cells, or macros
• --removes one major cause of resistance

2. Incr s.c. bioavailability & t1/2

3. Cleared by kidney & NOT RES

4. Fewer anti-heparin Ab formed → less thrombocytopenia S/E

• 5. Decr hospital stay b/c pt can self-admin s.c.
• at home

6. **Given s.c. (q12h or qd) → produce a predictable, reproducible anti-coag effect w/o need for lab monitoring of hemostasis

BUT $$$$$ & not covered by Medicare

1. Prophylaxis of post-op DVT

2. Rx ischemic stroke

3. Acute coronary syndrome

4. Anti-coag during hemodialysis

ANTI-COAG

SMALL SYNTHETIC PENTASACCHARIDE

MIMICS HEPARIN SITE --> BINDS AT III

INDIRECT Xa --> REQUIRES AT III

NO EFFECT ON aPTT or PT

RENAL CLEARANCE

• NO ANTIDOTE
• --t1/2 = 17-21 hrs
• --inc in pts w renal probs

Admin s.c → 100% bioavailability

Produces predictable, stable anti-thrombotic effect

Fondaparinux > heparin

Rx Acute coronary syndrome.

• Similar risk reduction compared to heparin but less --bleeding
• --re-infarction
• --morbidity/mortality.

ANTI-COAG

• DIRECT Xa INH
• --NO AT III NEEDED

GIVEN P.O.

NO EFFECT ON BLEEDING TIME, aPTT, PT

Tx DVT (hip/knee replacement)

• CLEARED BY LIVER
• --DRUG-DRUG INTERACTIONS!

• NO ANTIDOTE
• --BINDS TO PLASMA PROTS so prob not cleared by dialysis either

MAJOR ADVERSE EFFECT IS BLEEDING

ANTI-COAG

DIRECT INH OF FREE & CLOT-BOUND THROMBIN (IIa)

INC aPTT 1.5-2.5 nL

ESSENTIALLY IRREV

AT III NOT NEEDED

CLEARED BY RENAL

EXTRACT FROM SAL GLAND OF MEDICINAL LEECH

• NO ANTIDOTE
• --t1/2 = 1.3 hrs
• --inc in pts w renal probs

NO DIRECT EFFECT ON PLATELET FUNC

ADMIN IV

Tx HIT

ANTI-COAG

DIRECT REV INH OF THROMBIN II

INH PLATELET AGG & TXA2 RELEASE IN PRESENCE OF FREE & CLOT-BOUND THROMBIN

• INC aPTT 1.5-3x nL
• --RETURN IN 1-2 hrs

SLIGHT INC IN PT BUT MORE w WARFARIN

NO ANTIDOTE

• CLEARED BY LIVER
• "ARG! LIVER ME TIMBERS!"

PRADAXA

ANTI-COAG

SMALL SYNTHETIC MOL

DIRECT COMPETITIVE REVERSIBLE INH OF THROMBIN (IIa)

INC aPTT

PROPHYLAXIS OF THROBOSIS IN NON-VALVULAR A.FIB

CONVERTED FROM ABIGATRAN ETEXILATE BY ESTERASES

t1/2 = 12-17 hrs

• CLEARED BY RENAL
• --INC t1/2 IF RENAL PROBS

• NO ANTIDOTE
• --REMOVED BY DIALYSIS

• ADVERSE
• --BLEEDING
• --GASTRITIS
• --DYSPEPSIA

ANTI-COAG

Warfarin inhb vit K epoxide reductase

Clotting factors 2, 7, 9, 10 made in liver req post-tsl γ-carboxylation of 9-12 Glu residues which is coupled to oxidtv metab of reduced vit K to its epoxide.

Reduced vit K is regen from vit K epoxide via vit K epoxide reductase →

→ depletion of reduced vit K → stops post-tsl modftn

***ANTIDOTES:

1. phytonadione (reduced vit K).

• --Given i.v., s.c., or p.o.Effect NOT immed (several hrs)
• --May take 24 hrs for full reversal of anti-coag effect
• --Repeated doses of vit K necess to produce nL hemostasis after overdose w/ warfarin.

2. fresh frozen plasma: provides fully-functional clotting factors

• 3. factor 9 concentrate: contains lots
• of clotting factors 2, 7, 9, 10

• Factor II (t1/2 = 40 h)
• Factor X (t1/2 = 60 h)

• Shortest t1/2 = factor 7 (6 h)
• → Anti-coag action of warfarin gauged by PT (INR)

• Therapeutic doses: No effect on aPTT.
• --Overdose: incr aPTT & PT.

Heparin does not nL affect PT (INR) → can meas warfarin actvy in presence of heparin

Only works in vivo.

• 99% bound to plasma proteins → many drug intxns
• involve displ fr plasma proteins

• CLEARED BY LIVER
• --CYP2C9 Induction → incr warfarin clearance & decr anti-coag actvy.
• --Inhb → decr clearance & incr action.

• Slow onset (2-3 days). Max effect at 5 days
• ---------------------

• *Cause for resistance to anti-coag effects:
• 1. Induction of CYP2C9

• 2. Hepatic dysfunc or nephrotic syndrome
• → Hypoalbuminemia → decr t1/2 of warfarin b/c more free drug availb in plasma for hepatic extraction & metab.

3. anion exchange resins (e.g. cholestyramine & colestipol) bind warfarin → prevent GI absorption

4. Incr’d intake of vit K

*Causes for incr anti-coag response:

1. Inhb CYP2C9

• 2. Destruction of gut bact w/ antibiotics (gut flora
• synth 50% of vit K used to synth clotting factors)

3. Cephalosporins partially inhb vit K epoxide reductase (not a clinical prob)

4. hepatic dysfunc → decr synth clotting factors

1. Prophylaxis of DVT after orthopedic surgery

• 2. Prophylaxis of thromboembolism in pts w/
• · Atrial fibrillation
• · Prosthetic cardiac valves
• · Rheumatic mitral valve disease
• · Unstable angina
• ----------------

• Goal to incr INR to 2-3
• (meas pts monthly after titrated)
• --INR > 3 necess in pts w/ prosthetic cardiac valve.
• --INR > 4 → Bleeding!!!

• *transition from hospital Rx w/ heparin to outpatient Rx w/ warfarin:
• -- Overlapping therapy necess for 4-5 days

-- t1/2 of factors 2, 10 → pt still at risk of thromboembolism if heparin discontinued after only 2 days on warfarin

-- Pt Rx self w/ s.c. LMW heparin to shorten hospital stay

• 1. Bleeding
• *Tx w PHYTONADIONE (reduced vit k)
• --iv sc po
• --may take 24hrs to reverse anti-coag effects
• --also give repeated doses of vit k
• *fresh frozen plasma
• *factor ix concentrate

2. Teratogenesis & fetal death (Category X)

• -- During 1st trimester → abnormal bone growth
• w/ nasal hypoplasia & stippled epiphyseal calcifications.

--Adversely affects vit-K-dependent synth of protein osteocalcin (for mineralization of bone)

--Poss CNS abnormalities.

--Hemorrhage → intrauterine or neonatal death

3. Cutaneous necrosis

FIBRINOLYTIC -- ACTIVATE PLASMIN

Serine protease cleaves a single peptide bond of plasminogen → form plasmin

Lysine residues on N-term of t-PA & plaminogen allow them to bind to fibrin in thrombi.

Bound to fibrin, t-PA incr enz actvy 200x → cleaves plasmin fr plaminogen → plasmin degrades fibrin & lyses thrombus

Plasminogen activator inhibitors (PAIs) 1 & 2 lim actvn of free plasminogen in plasma.

FIBRINOLYTIC -- ACTIVATES PLASMIN

UNMOD HUMAN t-PA PROD BY RECOMBINANT TECH

• t1/2 5-10 mins
• --SHORTEST

SAME PHARM EFFECTS AS t-PA

FIBRINOLYTIC -- ACTIVATES PLASMIN

Non-enz protein produced by Group A β-hemolytic strep

t1/2 = 40-80 mins

Lg doses poss nec in pts w/ Ab against strep prots from prior strep inf

• Binds near C-term of plasminogen → induces
• conf change that exposes protease activity near N-term of plasminogen

• Protease actvy cleaves plasmin from another
• plasminogen mol

Plasmin attacks thrombi or circulating factors V & VIII or fibrinogen

1. Estb reperfusion of coronary vessels after MI

• · streptokinase- & tPA-induced reperfusion
• → decr mortality by 30% after MI

• · Immediate PTCA (± intra-arterial stents) >
• thrombolytic therapy (drugs)

· Incr survival rate after MI by co-Rx w/:

• a. Aspirin & tirofiban
• b. β-blocker
• c. ACE-inhibitor
• d. Nitrate
• ------------------

2. Pulm embolism

3. DVTs

4. Ischemic stroke

FINBRINOLYTIC -- ACTIVATES PLASMIN

nL conditions: t-PA actvy so small → NO systemic fibrinolysis

• After i.v. alteplase or reteplase (recombinant human
• t-PA)
• → enz actvy so great
• → overwhelms endogenous inh of t-PA & plasmin
• → plasmin lose specificity for fibrin in thrombi
• → degrade fibrinogen & factors v & viii
• → systemic fibrinolytic state

• BLEEDING
• · Results fr non-selective lysis of thrombi involved in nL vascular repair

· Also fr uninhibited degradation of clotting factors 5 & 8 & fibrinogen

* Incidence = 1% (heparin = 2-4%)

• ANTIDOTE: AMINOCAPROIC ACID
• --LYSINE ANALOG
• --OCCUPIES BINDIN SITES ON
• PLASMIN(OGEN)
• t-PA
• ALTEPLASE
• RETEPLASE

PREVENTS BINDING TO FIBRIN IN THROMBI

ANTI-DYSRHYTHMIC

Class IA

*blocks Na & K channels

WEAKLY BLOCKS MUSC RECEPTORS

• Na BLOCKADE
• --SUPPRESSES PHASE 4 AUTOMATICITY IN FAST FIBERS
• --INC THRESH POTENTIAL FOR DEPOL
• --DEC CONDUCTION VEL --> WIDE QRS

• K+ BLOCKADE
• --PROLONGS APD w INC LENGTH OF ERP IN ALL CARDIAC TISS, INCLUD AV NODE --> INC PR SEG
• --DEC NUMBER OF IMPULSES THROUGH AV NODE bc ERP INC
• --DELAYED REPOL OF VENTS

*metabolized by acetylation in the liver --> converted to NAPA (n-acyl-procainamide)

*NAPA blocks K channels & contributes to the prolongation of the QT interval

• SHIP
• --SLOW ACETYLATOR

given iv

acute control of ventricular rate in pts w/ atrial fibrillation or flutter

slows AV conduction to dec ventricular rate

• *suppress PVCs
• ----------------------------

*seldom used for prolonged outpatient therapy due to toxicity

*hypotension w/ rapid iv injection

*Torsade de pointes

• *SLE like syndrome in pts who are slow
• acetylators (remember, it is the “P” in SHIP)

ANTI-DYSRHYTHMIC

Class IB

1. Blocks Na+ channels

2. Decr ERP & APD of fast fibers → ~ via inc of K+ current (phase 4)

3. Only affects ventricles!

• 4. i.v. only!
• ------------------------------

PHARM

“stuns” ♥ → less likely to resp to other drugs

• 1. Suppress ventr automaticity (PVCs =
• spont phase 4 depolzn) in partially depolzd tissue (ischemia, digoxin toxicity) w/ little effect on normally polarized tissue

• 2. 2-way blockade of conduction in
• retrograde transmission → Abolishes ventr re-entry dysrhythmias

3. Incr threshold potential to further suppress automaticity

4. No effect on AV conduction

~ No effect on EKG

ANTI-DYSRHYTHMIC

i.v. only! (extensive 1st pass metab)

• 1. Used selectively to suppress PVCs in pts
• immed after MI b/c prophylactic use post-MI incr mortality

2. Digoxin-induced PVCs

3. Ventr tachycardia in pts w/ healed MIs

• ~ Amiodarone replacing lidocaine for ventr dysrhythmias
• ----------------------------------------

ADVERSE

NEUROLOGICAL

~ after rapid i.v. injection

• 1. CNS depression
• · slurred speech
• · nausea
• · tremor
• · paresthesias

2. Seizures → Rx w/ diazepam

ANTI-DYSRHYTHMIC

CLASS II: b-BLOCKERS

1. Suppress catechol-induced automaticity*

2. Decr conduction vel & incr ERP of AV node*

• 3. Incr ERP in fast fibers when ERP shortened by
• stim of β-receptors

4. Decr rate of discharge of SA node

5. Incr PR interval

1. ***DOC: V tach in pts w/ congenitally prolonged QT interval b/c no effect on repolzn

• 2. Decr post-MI sudden death by 25-40% via
• preventing fatal ventr dysrhythmias (~V tach)

• 3. Prevent PVCs triggered by physical or
• emotional stress

4. Suppress tach caused by hyperthyroidism

• 5. Control (decr) ventr rate in pts w/ atrial
• tach (A fib or A flutter)

6. Suppresses AVNRT

• 7. Short t1/2 → esmolol control ventr rate
• in pts w/ A fib, A flutter or sinus tach during cardiac cath
• ----------------------------------

ADVERSE

1. (-) inotropic effect

2. Bradycardia

3. AV block

ANTI-DYSRHYTHMIC

• CLASS III: K+ CHANNEL BLOCKERS
• --INC ARP & ERP

BLOCK INWARD Na+ & OUTWARD K+ CHANNELS

• NON-COMPETITIVE a & b ADREN REC BLOCKADE
• -----------------------------------

PHARM

1. Block Na+ channels → suppress automaticity**

2. Block K+ channels → delay repolzn → incr APD & ERP in atria & ventr

3. Incr ERP in AV node→ decr transmission of depolzn thru AV node

• 4. Incr PR, QRS & QT intervals
• (incr QT tho seldom → torsades)

5. Decr rate of firing of SA node

Very large Vd due to avid binding to tissues throughout body → PURPLE MAN

t1/2 = 53 ­± 24 days

1. (DOC: suppress automaticity)

2. Cardioversion of acute A fib & A flutter → sinus rhythm

3. Decr vent rate in pts w/ persistent A fib**

4. Poss given i.v. to terminate life-threatening V tach & V fib

5. *Chronic therapy to prevent life threatening V tach & V fib (tho sotalol is DOC for recurrent)

AICD (automatic implantable cardioverter defib) > sotalol or amiodarone, esp pts symptomatic or low EF

~hybrid therapy: AICD + solalol b/c decr # shocks & sotalol does NOT affect energy necess for defib

• No Amiodarone w/ AICD b/c incr energy necess for defib by up to 50% → decr safety margin btwn
• defib energy & max energy output

Decr dose to avoid S/E → decr efficacy

1. Severe bradycardia

2. &/or AV block

3. Seldom causes Torsade de pointes

4. Min effect to suppr myocardial dp/dt in HF

Limiting factors in chronic therapy:

5. Pneumonititis leading to pulm fibrosis** (5-15%)

• 6. Corneal micordeposits → halos in
• peripheral vision

7. Photodermatitis (24%)

8. cutaneous deposits → slate gray, blue, or purple skin

9. Peripheral neuropathy w/ weakness of prox muscles

10. 37% iodide by wt → Hypothyroidism (prev T4 → T3) or Hyperthyroidism (I2 for T4 synth)

Drug interations:

11. Decr hepatic & renal clearance of many other drugs

ANTI-DYSRHYTHMIC

• SAME MOA AS AMIODARONE BUT
• --DOESN'T CONTAIN IODINE
• --DIFF USES

PREVENT RECURRENT A.FIB & A.FLUTTER

CONTROL VENT RATE IN Pts w PERSISTENT A.FIB or FLUTTER

NOT FOR V.TACH V.FIB**

• BLACK-BOX WARNING
• --SUPPRESS dP/dT IN Pts WITH HF
• --CONTRAINDICATED IN Pts w NYHA CLASS IV HF OR CLASS II-III w RECENT CARDIAC DECOMPENSATION LEADING TO HOSP

ANTI-DYSRHYTHMIC

• "PURE" CLASS III
• --LIKE d-SOTOLOL BUT NO b-BLOCKING ACTIVITY

DELAYS REPOL

• ADVERSE
• --TORSADE DE POINTES

ANTI-DYSRHYTHMIC

Combo Class II & III

1. β-blocker (class II)

2. block of K+ channels (c III) → delays repolzn

K+ out → repolzn or hyperpolzn

• Outward K+ rectifier current (IKr)
• → termination of plateau portion of cardiac AP in fast fibers of atria & ventr.

• D- & L-isomers: inhb rapid component of outward K+ repolzn current
• → delays repolzn
• → incr APD & incr ERP in atria, vents & AV node
• (→ prevents automaticity)

(only β-blocker where D-isomer is actv at all)

L-isomer: non-selectv, competv β-receptor blockade in both slow (SA & AV nodes) & fast fibers

ANTI-DYSRHYTHMIC

L-isomer:

β blockade in both slow & fast fibers :

1. decr HR

2. incr APD → incr ERP everywhere in heart

3. decr catechol-induced automaticity everywhere

D- & L-isomers:

Block outward repolzing K+ current:

1. addt’l incr in APD & ERP in fast fibers over & above that caused by β blockade

2. addt’l incr in ERP of AV node

3. delayed ventr repolzn → incr QT interval

• 1. ***DOC: prevent V tach/V fib
• --Chronic therapy to prevent life threatening V tach & V fib (less long-term tox < amiodarone)

2. Cardioversion of acute A fib & A flutter → sinus rhythm

• 3. Decr ventr rate in pts w/ persistent A fib
• ---------------------------

1. Torsade de pointes, esp when serum K+ is low

2. β1 block → Decr ventr dp/dt in heart failure w/ systolic dysfunc

3. β1 blockade → AV block

CLASS IV: CCA

BLOCK Ca++ CHANNELS IN SLOW FIBERS, esp AV NODE

• PHARM
• 1. Decr HR
• 2. Decr cond vel in AV node → incr PR interval
• 3. Incr ERP in AV node
• 4. Decr dp/dt

• THERA
• 1. Control/decr ventr rate in pts w/ A fib or A flutter

2. Converts AVNRT → sinus rhythm via blocking re-entry pathway in/near AV node

3. **Rx AVNRT = β-blocker or V&D

• ADVERSE
• 1. HT
• 2. SINUS BRADYCARDIA
• 3. HRT BLOCK

1. Acts centrally to incr efferent vagal nerve activity

2. Acts centrally to decr sympathetic outflow at serum conc w/in therapeutic window

3. Partial inhb Na+/K+ ATPase → Incr dp/dt via excess Ca++ release

• PHARM
• 1. Incr efferent vagal actvy:
• · Decr HR
• · Decr conduction velocity in AV node
• · Incr ERP in AV node

2. Partial inhb Na+/K+ ATPase by Incr dp/dt → incr SV

• THERA
• 1. **Control/decr ventr rate in pts w/ A fib or A
• flutter in presence of HF caused by systolic dysfunc

• 2. **Incr dp/dt in pts w/ HF from systolic dysfunc
• ADVERSE
• > therapeutic window:

1. Inhb Na+/K+ ATPase & incr intracellular Ca++

• → automaticity in fast fibers
• → PACs & PVCs**

2. Incr sympathetic actvy

3. Decr APD & ERP in presence of excessive intracellular Ca++ → delayed afterdepol

4. Sinus bradycardia

*AV block (incr vagal tone + direct depressant effect)

ANTI-DYSRHYTHMIC

1. Incr K+ conductance to hyperpolarize AV node

• 2. Inhb ability of sympathetic stim to incr Ca++
• conductance in AV node

t1/2 = only 10 seconds → actions short-lived

PHARM

t1/2 = only 10 seconds → actions short-lived

1. Decr conduction velocity in AVnode

2. Incr ERP in AV node

3. Heart STOPS momentarily → “re-boot” rhythm back to SA node

Given i.v. in ER

• 1. **Diagnosis of AVNRT
• (if rhythm doesn’t go away w/ admin of adenosine. V tach, if goes away → AVNRT)

• 2. Convert AVNRT to normal sinus rhythm
• (≥ 90% effective)

• 3. Stress test: Produce coronary vasodilation during technetium scan in pts who can’t exercise
• --------------------------------

ADVERSE

1. Transient asystole → heart STOPS

2. Short-lived Intense burning sensation in chest

3. Flushing

4. Dyspnea

ANTI-HYPERTENSIVE

THIAZIDE DIURETIC

MOA UNKNOWN

• FALL IN BP DEPENDENT ON A NEG Na BALANCE bc SALT INTAKE REVERSES ANTI-HT EFFECT
• -----------------------------

PHARM

• 1. prevent/reverse salt & H2O retention
• caused by other anti-HTN drugs

• 2. Init saluresis → decr ECF vol → init decr
• CO → decr BP

3. CO eventually returns to pre-Rx value. Decr BP due to decr TPR

4. ECF vol remains slightly decr (~5%) → persistent incr in plasma renin activity (PRA) & Aldo

5. Prolonged therapy reverses LVH by 5%

6. HR is unchanged or slightly incr

1st line HTN drugs!

1. Most freq used anti-HTN drug

2. Decr BP by -20/-10 mm Hg & takes 2-4 wks

3. Small doses work: Larger doses does NOT incr anti-HTN effect but incr risk of S/E

4. Modest salt restriction → allows small dose & lims K+ loss

5. Plasma Aldo rise 2o to incr PRA & Ang II→ 2o hyperAldo → hypokalemia

6. thiazides do NOT decr BP in pts w/ GFR < 30 (use metolazone)

• 7. Prevent/reverse salt & H2O retention caused by other drugs
• ---------------------------------------

ADVERSE

1. Hyperuricemia: ~ asympt but poss → gout

2. Hyperglycemia (Type II DM): thiazides directly inhb insulin secretion (low incidence)

• 3. HYPOkalemia
• · No evid that → dysrhythmia in LVH-only pts

· predisposes to digoxin toxicity (dysrhytmias)

• · hypoK+ → glucose metab disturbances (decr
• insulin senstvy)

· Also → muscle weakness & fatigue

· Lessen/prev by lower doses + modest salt restriction

• *Lessen/prev by co-Rx w/:
• - K-sparing diuretics
• - ACEi
• - ARB
• - Β-blocker
• - Oral K supplement

ACEi

*BALANCE VASODILATION*

1. Dilate resistance arterioles → Decr TPR → decr MAP

• 2. Incr compliance of Lg arts → more decr SBP
• --Incr compliance due to ACEi prevent/reverse Ang II trophic effect on prot synth in Lg & small arteries

3. Decr SBP & DBP

4. Decr MAP

• 5. Uniform incr RBF via dilation of aff &
• eff arterioles. BUT GFR unchanged.

6. Decr Filtratn Fractn → No salt & H2O retention

7. Blood flow in cerebral & coronary bed well maintained.

8. Prevent/reverse vasc/cardiac remodeling caused by Ang II**

9. little or no change in CO (tho poss small decr in CO & SV via venodilation)

10. No change in HR BUT No impairment of baroreflex!!!!

1st line HTN drugs!

• 1. Monotherapy or combo w/ thiazide for incr efficacy.
• · single: decr BP in 50% pts
• · combo: decr BP in 80% pts

• 2. **DOC: pts w/
• · HF
• · LVH
• · DM
• · post-MI systolic dysfunc

• 3. **EVERY type 2 DM or HF pt should
• be on ACEi even pts w/o HTN → protects kidneys & prevents proteinuria

• 4. Also Rx:
• · Malignant HTN
• · renovascular HTN
• · HTN crisis of scleroderma

5. Long-term: reverses 15% of cardiac hypertrophy

1. First-dose Hypotension, esp if pt also on thiazide

2. Renal insufficiency in pts w/ bilateral renal artery stenosis or stenosis of a solitary kidney

3. HYPERkalemia in pts taking K-sparing diuretic or K+ supplements

4. *Angioedema: not dose-related

5. *skin rash: dose related

6. ageusia & dysgeusia

• 7. *Dry cough:
• · PGs potentiate cough reflex
• · dose-related, use 1 aspirin/day to prevent

1. *Pregnancy X: teratogen at all stages of preg. 1st: CNS or CV. 2nd, 3rd: oligohydramnios, calvarial hypoplasia, pulm hypoplasia, growth retardtn, neonatal anuria, fetal death & neonatal death

Instead, preg ♀: α-MD, atenolol & nifedipine

8. CV reflexes (baroreflex) maintained → Postural hypotension rare.

9. DOES NOT CAUSE: hypoklaemia, hyperuricemia, hyperglycemia, or hyperlipidemia

10. Prevent/reverse hypokalemia & adverse changes in plasma lipid profile produced by thiazides

11. Fatigue, weakness, & sexual dysfunc rare

1st line HTN drugs!

Monotherapy or combo w/ thiazide for incr efficacy.

• 1. HTN
• · shallow Dose-resp curve
• · Add small dose of HCTZ instead of incr ARB

• 2. Poss bene for CHF, but not yet approved
• ------------------------------

ADVERSE

1. Do NOT use in prego or breast-feeding ♀

2. NO dry cough

3. *Angioedema poss, esp in pts w/ past angioedema to ACEi

4. Hypotension poss

5. HYPERkalemia

ANTI-HT CCAs

-pine → DHP (dihyropyridines)

CCAs to use for HTN

PRIMARILY EFFECT ARTERIOLES, AND DILATION CAUSES BARO-REFLEX RESPONSE

NET EFFECT --> DEC DBP w NO CHANGE OR SMALL INC IN HR, AV CONDUCTION, dP/dT, SV AND CO

• Block L-type Ca++ channels in plasma
• mem of VSM of arterioles

Dilates arterioles NOT venules

ANTI-HT CCAs

1. Decr BP: DHPs >> V&D

2. CCA esp DHP: Dilate preglom arterioles → incr GFR

3. Promote salt & H2O excretion → poss via direct inhb salt/H2O reabs in renal tubule

4. Decr proteinuria in Type II DM (BUT ACEi is DOC)

• 5. Dilates arterioles, NOT venules → decr TPR
• → decr BP

6. Decr SBP & DBP

7. Decr MAP

8. Incr compliance/relax Lg arteries → addt’l decr SBP

9. Slight incr CO (by DHPs only)

10. Slight tachycardia (by DHPs only)

11. No salt/H2O retention b/c direct naturetic effect at renal tubules

12. No effect on PRA

13. No effect on plasma Ang II

14. No effect on plasma Aldo

15. Unpredictable RBF & GFR effect.

1st line HTN drugs!

Extended release preps poss.

1. All CCAs effectv for HTN, but DHPs used when sole aim to Rx HTN.

Decr BP: DHPs >> V&D

2. DHPs 1st line for mild – moderate HTN!

• 3. Effectv for systolic HTN
• b/c decr SBP > decr DBP

• 4. Well-suited for pts w/:
• · Asthma
• · DM
• · Renal dysfunc
• · Gout
• · Hyperlipidemia

USED AS ANTI-HT CCAs

• 1. Excessive vasodilation
• · hypotension, dizziness
• · headache
• · pounding pulse
• · facial flushing
• · lower leg edema

Decr dose will help

Symptoms ~ improve w/ slow-release formula or DHPs w/ long t1/2

• 2. pedal edema (esp DHPs)
• · NOT due to incr ECF vol
• · Dilation of pre-capil sphincters → excessive
• filtratn of fluid into interstitial space in ankles

3. GERD

• 4. Paradoxical angina from “coronary
• steal” (see Anti-Anginal)

5. NO suppression of AV conduction or CO!!!!

b-BLOCKERS

DEC TPR BY UNKNOWN MOA

1st line HTN drugs!

• Add thiazide to β-blockers b/c
• 1. Further decr BP
• 2. Prevent salt/H2O retention

• ADVERSE:
• Decr renal perfusion pressure poss
• → incr Filtrn Fractn
• → slow salt/H2O retention
• → vol expansion lims anti-HTN effect
• → “pseudotolerance”
• -- Add thiazide to prev salt/H2O retention

ANTI-HT Tx

• α & β blocker
• 1. Blocks β1 in heart
• 2. Blocks α1 in arterioles & venules
• 3. Partial agonist at vasc β2

• *BALANCE VASODILATION*
• 1. Decr TPR → decr MAP

2. Decr basal HR: exercise-induced tachycardia is attenuated

• 3. Decr renal perfusion pressure → incr Filtrn
• Fractn → slow salt/H2O retention

4. CO unchanged (balanced vasodilation)

5. PRA unchanged

• 6. Plasma Ang II unchanged
• -----------------------------

THERA

Hypertensive emergency

• · Anti-HTN effect after i.v. injectn: smooth w/
• onset 2-4 min, peak 10-15 min & duration of 2-4 hrs

· HR unchanged/slight decr

· CO unchanged (balanced vasodilation)

· Poor lipid-solb → little effect on fetus in preeclampsia

• * After ctrl of BP w/ i.v. prep → p.o. labetol
• --------------------------------------

ADVERSE

• 1. Orthostatic hypotension
• 2. Headaches
• 3. Fatigue
• 4. Reduced sexual function

ANTI-HT Tx

Formerly 1st line for mild – mod HTN → but ~ diuretic nec & S/E lim use.

**DOC: pediatric HTN & preg ♀ HTN

• ADVERSE
• 1. Sedation
• 2. Dry mouth
• 3. Rebound HTN
• 4. Fatigue
• 5. Flu-like syndrome (drug fever)
• 6. (+) Coomb’s test
• 7. Hepatitis

ANTI-HT Tx

Highly lipid-solb → enters brain

1. α2 agonist → Decr symp outflow by stim post-synaptic α2 receptors in rostral VL medulla

2. Symp reflexes attenuated but NOT blocked

• PHARM
• 1. Standing: decr TPR→ decr BP
• 2. Seated: venodil → decr ven return → decr CO
• 3. Decr PRA
• 4. Decr Ang II
• 5. Decr renal perfusion pressure → incr Filtrn Fractn → slow salt/H2O retention

• THERA
• Usually combo w/ diuretic: mild – moderate HTN

*BUT progressive salt/H2O retention limits decr BP (pseudotolerance)

1. Sedation

2. Dry mouth

3. CNS: vivid dreams, restlessness, depression

• 4. CV:
• · orthostatic intol (orthostatic hypotension rare)
• · bradycardia
• · slowing of AV conduction

• 5. *Withdrawal syndrome
• Headache
• Apprehension
• Tremor
• Abdominal pain
• Sweating
• Tachycardia
• Incr BP from rebound incr sympathetic actvy

ANTI-HT (same hydralazine, minoxidil, diazoxide)

Arterial vasodilators: Unknown MOA

Relax (only) arteriolar VSM via decr availb of intracellular Ca++ for excitatn-contractn coupling

Arteriodilation → decr TPR → decr BP

• **Decr BP → baroreflex-medt’d incr symp to hrt, vasc & kidney
• --Incr HR
• --Incr dp/dt
• --Decr venous capacitance

NET: Lrg incr CO

***

drug: vasodil >> incr symp: constrict arterioles

• Renal β1 receptor stim
• → incr renin release
• → incr plasma Ang II
• → incr plasma Aldo
• → progressive salt/H2O retention

• Also salt/H2O retention via:
• --Decr BP
• --incr α receptor stim
• --incr Ang II receptor stim

ANTI-HT (same hydralazine, minoxidil, diazoxide)

Arterial vasodilators: Unknown MOA

Relax (only) arteriolar VSM via decr availb of intracellular Ca++ for excitatn-contractn coupling

Arteriodilation → decr TPR → decr BP

• **Decr BP → baroreflex-medt’d incr symp to hrt, vasc & kidney
• --Incr HR
• --Incr dp/dt
• --Decr venous capacitance

NET: Lrg incr CO

***

drug: vasodil >> incr symp: constrict arterioles

• Renal β1 receptor stim
• → incr renin release
• → incr plasma Ang II
• → incr plasma Aldo
• → progressive salt/H2O retention

• Also salt/H2O retention via:
• --Decr BP
• --incr α receptor stim
• --incr Ang II receptor stim

ANTI-HT (same hydralazine, minoxidil, diazoxide)

Arterial vasodilators: Unknown MOA

Relax (only) arteriolar VSM via decr availb of intracellular Ca++ for excitatn-contractn coupling

Arteriodilation → decr TPR → decr BP

• **Decr BP → baroreflex-medt’d incr symp to hrt, vasc & kidney
• --Incr HR
• --Incr dp/dt
• --Decr venous capacitance

NET: Lrg incr CO

***

drug: vasodil >> incr symp: constrict arterioles

• Renal β1 receptor stim
• → incr renin release
• → incr plasma Ang II
• → incr plasma Aldo
• → progressive salt/H2O retention

• Also salt/H2O retention via:
• --Decr BP
• --incr α receptor stim
• --incr Ang II receptor stim

ANTI-HT

ARTERIAL VASODILATOR: UNKNOWN MOA

"SHIP" acetylator

• 1. May degrade → form N.O.
• __or
• 2. Open K+ channels → hyperpol SMCs

RAPID onset of action

THERA (same for minoxidil)

1. Reserved for severe HTN resistant to combo Rx w/ 1st line drugs

• 2. NOT used as a single agent b/c tachycardia
• & ECF volume expansion

• Combo w/ β-blocker:
• · Prevents tachycardia
• · Lessens incr CO & myocardial O2 demand
• · Blocks sympathetic-medt’d renin release → prevents 2o hyperAldo

topical Minoxidil (Rogaine): Rx baldness

1. Tachycardia

2. Cardiac palpitations

3. Headache

4. Edema

5. Angina

• 6. **SLE-like syndrome (“SHiP”)
• · Fever
• · Arthralgia
• · Arthritis
• · H metab by N-acetylation
• → slow-acetylators at > risk
• · Remits after drug stopped but poss req Rx w/ corticosteroids.

7. Pyridoxine-respv polyneuropathy

• Actv metabolite = minoxidil sulfate (produced by liver)
• → incr K+ conductance
• →hyperpolarizes VSM

• Very SLOW onset (necess actv’d by liver)
• ---------------------------------

ADVERSE

• 1. Tachycardia
• 2. Edema
• 3. Angina pectoris
• 4. Global hypertichosis

ANTI-HT

ARTERIAL VASODIALATOR: UNKNOWN MOA

INC K+ CONDUCTANCE --> HYPERPOL VSM

• THERA
• --ONLY FOR HT EMERGENCIES
• --GIVEN IV MINI-BOLUS TO AVOID AVID BINDING TO PLASMA PROTs

• ADVERSE
• 1. Tachycardia
• 2. Edema
• 3. Angina pectoris
• 4. Hyperglycemia
• -- Directly inhb insulin release
• -- Type II DM Rx w/ p.o. hypoglycemic agents >> risk.

5. Relaxes uterine smooth musc

6. May arrest labor if given to treat eclampsia

ANTI-HT

Arterial & venous vasodilator

• 1. RBC’s liberates N.O. from nitroprusside
• · Dilates arteries & veins
• · Inhb platelet aggregn

• 2. Incr cGMP → relax VSM
• -------------------------

PHARM

1. Decr TPR→ decr DBP

2. Venodil → decr venous return → decr CO

• 3. Slight incr HR via carotid baroreflex
• in resp to decr BP

4. In pts w/ CHF: incr CO usually → hemodynamic saluresis

5. ~ not given long enough to HTN pts to cause salt/H2O retention

6. t1/2 = 30 sec → titration based on hemodynamic resp

• 7. Thiocyanate intoxication
• --Nitroprusside broken down to cyanide → combo w/ thosulfate & enz: hepatic rhodanese → thiocynate → renal excretion

ANTI-HT

1. ONLY give to SUPINE pts

• 2. HTN emergencies in hospital
• (HTN enceph, pulm edema, etc.)
• · Prepared fresh in sterile 5% dextrose in H2O (D5W)
• · Given slow i.v. infusion

3. Controlled hypotension during surgery

4. STOPS acute dissecting aortic aneurysm

5. Decr ♥ O2 demand after MI

• 6. Incr CO in CHF
• In pts w/ CHF: incr CO usually → hemodynamic saluresis

1. VERY dangerous → use as a last resort

2. Tachycardia

3. Headache

4. Palpitations

• 5. Thiocyanate intoxication
• · Anorexia
• · Naseua
• · Delirium
• · Hallucinations, psychosis
• · ~ After several days of Rx
• · ~ Asst’d w/ decr renal func
• · Earliest signs: mental disorientation & metab acidosis asst’d w/ incr dose

→ discontinue sodium nitroprusside & admin furosemide to improve renal func

Tx FOR MI

(Pain incr symp tone → incr BP)

• Decr sympathetic actvy by:
• 1. analgesic effects
• 2. Inhb carotid baroreflex
• ----------------------------------

PHARM

• *Decr sympathetic tone:
• 1. Decr preload & decr afterload → incr SV
• 2. Decr HR
• 3. Decr cardiac automaticity
• 4. Decr cardiac O2 demand
• -----------------------------

THERA

MI

• morphine ­± NTG → incr mortality in pts w/ non-ST-segment elevation acute coronary syndrome
• (nSTEMI; not transmural)

Tx OF MI

*Low dose = “renal” dose: D1

1. Stim D1 receptors in renal arterioles → vasodilation

• 2. Dilation of aff arteriole → incr RBF →
• · incr GFR
• · incr renal Na+ excretion

3. Unchanged/decr slightly DBP

• PHARM
• *Intermediate dose: D1 + β1

• 1. Incr dp/dt
• 2. Only small incr in HR
• 3. Incr SV/CO → further incr GFR

*Large dose: begins to stim vasc α1

• --Incr TPR
• --Incr DBP
• --Incr arterial impedance → decr SV/COV
• --enoconstriction → incr venous return & incr fillingpressure → incr wall stress (BAD)
• --REVERSE decr SV/CO (fr incr afterload )& incr filling pressure (fr venoconstriction)
• by:
• · i.v. dobutamine
• * i.v. sodium nitroprusside
• -------------------------

ADVERSE

Little effect on HR at small – intermed doses

BUT

Larger dose →

1. tachycardia (wastes O2 & worsens isch)

2. dysrhythmias

ANTI MI

Racemic mixture of (+) & (-) enantiomers

Both stim β1 & β2 receptors

Vasodilation only due to stim vasc β2

***

One partial α agonist

• Other α agonist → cancel out α effect
• --------------------------------

1. (+) inotropic via β1 → incr SV

2. Arteriodilation via β2 → decr TPR → decr DBP

• 3. Venodilation via β2 →
• --decr venous return
• --decr cardiac filling pressure

4. Incr GFR solely due to incr CO

• 5. Little effect on HR except hi doses
• → tachycardia & dysrhythmias
• ----------------------------

ADVERSE

• Little effect on HR except hi doses →
• · tachycardia
• * dysrhythmias

1. Dobutamine does NOT incr DBP (afterload)

2. Dobutamine is LESS likely to cause tachycardia

3. Dobutamine causes venodilation → decr venous return (preload) → decr ventr filling pressure

Pts may develop tolerance to (+) inotropic effects of both dopamine & dobutamine

• Rx HF asst’d w/ acute coronary syndrome = evolving MI
• "MONA"

• M: morphine
• O: O2
• N: NTG
• A: aspirin (sublingual)