CARDIO_PHARM

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soren101
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110930
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CARDIO_PHARM
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2011-11-16 01:54:03
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CARDIOVASCULAR PHARMACOLOGY MS2
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CARDIOVASCULAR MS2
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  1. SIMVASTATIN MOA AND PHARM EFFECTS
    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
  2. SIMVASTATIN THERAPEUTIC USES AND TOX
    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 ♀
  3. PRAVASTATIN
    ANTI-LIPEMIC

    STATIN

    NOT METAB BY CYP3A4

    (similar to simvastatin, pravastatin, atorvastatin, rosuvastatin)
  4. ATORVASTATIN
    ANTI-LIPEMIC

    STATIN

    (similar to simvastatin, pravastatin, atorvastatin, rosuvastatin)
  5. ROSUVASTATIN
    ANTI-LIPEMIC

    STATIN

    *NOT METAB BY CYP3A4

    (similar to simvastatin, pravastatin, atorvastatin, rosuvastatin)
  6. EZETIMIBE MOA
    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
  7. EZETIMIBE PHARM
    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
  8. EZETIMIBE THERA & TOX
    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)
  9. CHOLESTYRAMINE MOA
    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
  10. CHOLESTYRAMINE PHARM
    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
  11. CHOLESTYRAMINE THERA AND TOX
    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)
  12. COLESTIPOL
    SAME AS CHOLESTYRAMINE

    ANTI-LIPEMIC

    ION EXCHANGE RESINS
  13. COLESEVELAN
    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)
  14. MOA & PHARM:
    NIACIN
    NICOTINIC ACID
    WATER-SOL B-COMPLEX VIT
    VIT B3
    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
  15. THERAPEUTIC USE:
    NIACIN
    NICOTINIC ACID
    WATER-SOL B-COMPLEX VIT
    VIT B3
    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
  16. TOXICITY:
    NIACIN
    NICOTINIC ACID
    WATER-SOL B-COMPLEX VIT
    VIT B3
    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
  17. MOA

    GEMFIBROZIL
    &
    FENOFIBRATE
    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
  18. PHARMACOLOGICAL EFFECTS

    GEMFIBROZIL
    &
    FENOFIBRATE
    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
  19. THERA & TOX

    GEMFIBROZIL
    &
    FENOFIBRATE
    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
  20. ATENOLOL
    &
    PROPANOLOL
    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
  21. BIOCHEM MOA FOR NITRATES AND NITROPRUSSIDE
    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
  22. NITROGLYCERIN MOA
    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 DBPbaroreflex-medt’d incr in sympathetic heart actvy
  23. NITROGLYCERIN PHARMACOLOGICAL EFFECTS (5)
    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
  24. NITROGLYCERIN THEREUTIC USES AND TOXICITY
    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
  25. ISOSORBIDE DINITRATE
    &
    ISOSORBIDE MONONITRATE
    ANTIANGINAL -- NITRATES

    P.O.

    SAME AS NITROGLYCERINE

    EXCEPT DOES NOT EFFECT PERIPHERAL RESISTANCE ARTERIOLES

    SO PRELOAD FALLS BUT AFTERLOAD IS UNCHANGED

    Tx HF + HYDRALAZINE
  26. SUBLINGUAL NITROGLYCERIN
    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
  27. ANTI-ANGINAL CCA MOA
    • 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
  28. PHARMACOLOGICAL EFFECTS OF ANTI-ANGINAL CCA's
    • 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
  29. THERAPEUTIC USES OF ANTI-ANGINAL CCA's
    • 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
  30. ANTI-ANGINAL CCA's DRUG INTERACTIONS
    • DILTIAZEM
    • VERAPAMIL
    • AMLODIPINE

    · β-blockers (V)

    · digoxin (V)

    · class IA anti-dysrhythmics (V)

    · grapefruit juice

    · cimetidine (D)
  31. ANTI-ANGINAL CCA's TOXICITY (9)
    • 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)
  32. PHAMACOLOGICAL EFFECTS OF DILTIAZEM AND VERAPAMIL (anti-anginal)
    • 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
  33. THERAPEUTIC EFFECTS OF DILTIAZEM AND VERAPAMIL (anti-anginal)
    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
  34. PHARMACOLOGICAL EFFECTS OF AMLODIPINE
    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
  35. THERAPEUTIC USES OF AMLODIPINE
    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
  36. TOXICITY OF AMLODIPINE
    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)
  37. FUROSEMIDE MOE AND PHARMACOLOGICAL EFFECTS
    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
  38. FUROSEMIDE THRAPEUTIC USES AND TOX
    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
  39. ACE INHIBITOR MOA
    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
  40. ACE INHIBITOR PHARMACOLOGICAL EFFECTS
    • 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!!!!
  41. ACE INHIBITOR THERAPEUTIC USES
    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
  42. ACE INHIBITOR TOX
    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
  43. ACEi ANTI-HT DRUGS
    CAPTOPRIL

    ENALAPRIL

    LISINOPRIL
  44. ARB MOA
    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
  45. ARB PHARMACOLOGICAL EFFECTS
    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!!!!
  46. ARB THERAPEUTIC USES AND TOX
    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
  47. ARB DRUGS
    -SARTAN

    LOSARTAN

    VALSARTAN

    ANTI-HTs
  48. SPIRONOLACTONE
    &
    EPLERENONE

    MOA & PHARMACOLOGICAL EFFECTS
    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
  49. SPIRONOLACTONE THERAPEUTIC USES AND TOX
    • 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
  50. EPLERENONE
    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
  51. CARVEDILOL MOA AND THERAPEUTIC USES
    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
  52. DIGOXIN MOA
    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
  53. DIGOXIN PHARMACOLOGICAL EFFECTS
    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
  54. DIGOXIN THERAPEUTIC USES
    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.
  55. DIGOXIN DRUG INTERACTIONS
    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
  56. DIGOXIN TOXICITY
    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
  57. ASPIRIN MOA
    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
  58. ASPIRIN PHARMACOLOGICAL EFFECTS
    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”
  59. ASPIRIN THERAPEUTIC USES
    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)
  60. ABCIXIMAB
    EPTIFIBATIDE
    TIROFIBAN

    MOA
    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
  61. THERAPEUTIC USES & ADVERSE EFFECTS:

    ABCIXIMAB
    EPTIFIBATIDE
    TIROFIBAN
    • 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
  62. TICLOPIDINE
    CLOPIDOGREL

    MOA
    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)
  63. TICLOPIDINE
    CLOPIDOGREL

    PHARACOLOGICAL EEFECTS
    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
  64. TICLOPIDINE
    CLOPIDOGREL

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

    • CLOP
    • MUCH LOWER INCIDENCE OF NEUTROPENIA & AGRANULOCYTOSIS
  65. MOA OF HEPARIN
    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
  66. PHARMACOLOGICAL EFFECTS OF HEPARIN
    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
  67. THERAPEUTIC USES OF HEPARIN
    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.
  68. HEPARIN AND LMW HEPARIN ADVERSE EFFECTS
    • 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
  69. ARDEPARIN
    DALTEPARIN
    ENOXAPARIN

    MOA
    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
  70. ARDEPARIN
    DALTEPARIN
    ENOXAPARIN

    PHARMACOLOGICAL 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
  71. THERAPEUTIC USES OF LMW HEPARINS
    1. Prophylaxis of post-op DVT

    2. Rx ischemic stroke

    3. Acute coronary syndrome

    4. Anti-coag during hemodialysis
  72. FONDAPARINUX
    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.
  73. RIVAROXABAN
    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
  74. LEPIRUDIN
    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
  75. ARGATROBAN
    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!"
  76. DABIGATRAN
    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
  77. WARFARIN MOA
    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
  78. PHARMACOLOGICAL EFFECTS OF WARFARIN
    • 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
  79. THERAPEUTIC USES OF WARFARIN
    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
  80. ADVERSE EFFECTS OF WARFARIN
    • 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
  81. t-PA MOA
    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.
  82. ALTEPLASE MOA
    FIBRINOLYTIC -- ACTIVATES PLASMIN

    UNMOD HUMAN t-PA PROD BY RECOMBINANT TECH

    • t1/2 5-10 mins
    • --SHORTEST

    SAME PHARM EFFECTS AS t-PA
  83. STREPTOKINASE MOA
    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
  84. t-PA
    ALTEPLASE
    STREPTOKINASE

    THERAPEUTIC USES
    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
  85. t-PA PHARMACOLOGICAL EFFECTS
    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
  86. t-PA
    ALTEPLASE
    STREPTOKINASE

    ADVERSE
    • 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
  87. PROCAINAMIDE MOA AND PHARMACOLOGICAL EFFECTS
    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
  88. PROCAINAMIDE THERAPEUTIC USES AND ADVERSE EFFECTS
    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)
  89. LIDOCAINE MOA AND PHARMACOLOGICAL EFFECTS
    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
  90. LIDOCAINE THERAPEUTIC USES AND ADVERSE EFFECTS
    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
  91. ATENOLOL
    PROPRANOLOL
    ESMOLOL

    MOA & PHARMACOLOGICAL EFFECTS
    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
  92. ATENOLOL
    PROPRANOLOL
    ESMOLOL

    THERAPEUTIC USES AND ADVERSE EFFECTS
    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
  93. AMIODARONE MOA AND AND PHARMACOLOGICAL EFFECTS
    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
  94. THERAPEUTIC USES OF AMIODARONE
    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
  95. AMIODARONE ADVERSE EFFECTS
    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
  96. DRONEDARONE
    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
  97. DOFETILIDE
    ANTI-DYSRHYTHMIC

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

    DELAYS REPOL

    • ADVERSE
    • --TORSADE DE POINTES
  98. SOTALOL MOA
    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
  99. SOTALOL PHARMACOLOGICAL EFFECTS
    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
  100. SOTALOL THERAPEUTIC USES AND ADVERSE EFFECTS
    • 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
  101. VERAPAMIL
    DILTIAZEM

    ANTI-DYSRHYTHMIC
    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
  102. DIGOXIN AS ANTI-DYSRHYTHMIC
    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)
  103. ADENOSINE MOA AND PHARMACOLOGICAL EFFECTS
    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
  104. ADENOSINE THERAPEUTIC USES AND ADVERSE EFFECTS
    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
  105. HCTZ MOA AND PHARMACOLOGICAL EFFECTS
    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
  106. HCTZ THERAPEUTIC USES AND ADVERSE EFFECTS
    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
  107. CAPTOPRIL
    ENALAPRIL
    LISINOPRIL

    PHARMACOLOGICAL EFFECTS AS ANTI-HT Rx
    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!!!!
  108. CAPTOPRIL
    ENALAPRIL
    LISINOPRIL

    THERAPEUTIC USES AS ANTI-HT Rx
    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
  109. CAPTOPRIL
    ENALAPRIL
    LISINOPRIL

    ADVERSE EFFECTS OF ANTI-HT Rx
    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
  110. LOSRARTAN
    VALSARTAN

    THERAPEUTIC USES AND ADVERSE EFFECTS IN ANTI-HT Tx
    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
  111. NIFEDIPINE
    AMLODIPINE
    FELODIPINE

    MOA
    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
  112. NIFEDIPINE
    AMLODIPINE
    FELODIPINE

    PHARMACOLOGICAL EFFECTS
    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.
  113. NIFEDIPINE
    AMLODIPINE
    FELODIPINE

    THERAPEUTIC USES
    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
  114. NIFEDIPINE
    AMLODIPINE
    FELODIPINE

    ADVERSE EFFECTS
    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!!!!
  115. ATENOLOL_______AS ANTI-HT Tx
    METOPROLOL
    PROPRANOLOL
    METOPROLOL
    TIMOLOL
    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
  116. LABETALOL
    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
  117. a-METHYLDOPA
    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
  118. CLONIDINE MOA AND THERAPEUTIC USES
    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)
  119. CLONIDINE ADVERSE EFFECTS
    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
  120. HYDRALAZINE MOA
    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
  121. MINOXIDIL MOA
    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
  122. DIAZOXIDE MOA
    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
  123. HYDRALAZINE PHARMACOLOGICAL EFFECTS & THERAPEUTIC USES
    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
  124. HYDRALAZINE ADVERSE EFFECTS
    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
  125. MINOXIDIL PHARACOLOGICAL AND ADVERSE EFFECTS
    • 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
  126. DIAZOXIDE PHARM, THERA, AND ADVERSE EFFECTS
    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
  127. SODIUM NITROPRUSSIDE MOA AND PHARMACOLOGICLA EFFECTS
    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
  128. SODIUM NITROPRUSSIDE THERAPEUTIC USES
    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
  129. SODIUM NITROPRUSSIDE ADVERSE EFFECTS
    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
  130. MORPHINE
    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)
  131. DOPAMINE MOA AND PHARMACOLOGICAL EFFECTS
    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
  132. DOPAMINE THERAPEUTIC AND ADVERSE EFFECTS
    *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
  133. DOBUTAMINE
    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
  134. ADVANTAGES OF DOBUTAMINE >> DOPAMINE
    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)

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