2-16-10

ANTIHYPERLIPIDEMICS

Hypolipidemic drugs are used to treat....(3)

and

reduce the risk of mortality from....(2)

Hypolipidemic drugs are used to treat high chol, CAD, atherosclerosis

and

reduce the risk of mortality from heart disease and CVA.

metabolic syndrome:

4 conditions that promote CAD/heart disease

1) HTN

2) DM

3) hyperlipidemia

4) obesity

Major Lipoproteins:

1) Chylomicrons: formed where? from what? transporter of what?

2) VLDL: synthesized where? transporter of what to where?

3) LDL: formed from what?  Carried what to where?

4) HDL: carry what?  major functions?

5) Lp(a): what is it? related to what? risk factor of what?

Major Lipoproteins:

1) Chylomicrons: formed from GI wall (fat+bile).  Carries TG.

2) VLDL: synthesized in liver.  Carried TG to adipose tissue.

3) LDL: formed from VLDL.  Carried cholesterol to tissues.

4) HDL: carries chol, phospholipids.  Retrieves chol from artery/tissue and brings to liver (bile acids reabsorbed) & inhibits oxidation of atherogenic LPs.

5) Lp(a): atherogenic lipoprotein.  Genetically determined.  Related to LDL.  Risk factor for CAD.

Nml LDL level.

Goal level if pt has vascular disease.

Give LDL equation.

Nml LDL:HDL ratio

Incr risk if LDL:HDL is above...

Nml LDL level < 150mg/dL

Goal level if pt has vascular disease <100mg/dL

LDL = TC - HDL - (TG/5)

Nml LDL:HDL ratio = 3-3.5

Incr risk if LDL:HDL is above 3.5

These drugs bind bile acids, preventing GI reabsorption back into the liver (usually >90% bile acids reabsorbed).

What is the result of this action?

What is the drug class?

Name 3 drugs and their preparations/daily dosing.

Bile Acid Binding Resins:

Result is compensatory increase in bile acid synthesis from cholesterol (synth in liver).  Liver LDL receptors increased=LDL removed from plasma.

Cholestyramine - granular prep

Colestipol - tablets

Colesevelam - gel (less GI irritation)

all qd or bid before a large meal.

Adverse rxns are nausea, bloating, constipation or diarrhea.  They impair abs. of fat soluble vitamines (A,D,E,K).  They impair some drug abs (esp acidic compounds) like anticoags, diuretics, digitalis.

**Which drug in this class doesn´t impair absorption of vit or drugs?

Bile Acid Binding Resins:

Cholestyramine

Colestipol

**Colesevelam doesn´t impair absorption of vit or drugs

MOA: incr LDL receptors in liver forcing liver to import more LDL from blood, resulting in decr of plasma LDL and less cholesterol available for synthesis of VLDLs.

Name the drug class, administration, metabolism, excretion.

HMG-CoA Reductase Inhibitors (STATINS)

**Most important hypolipidemics**

Adm PO qd/bid in evening due to diurnal pattern of chol synthesis (liver sythesizes chol @ night....if you decr chol, liver craves it and upregulates LDL receptors).

Metab=1 pass thru liver = conc @ liver site of action.

Excretion=bile.

Name the two most potent statins, What is their half life?

Name 2 prodrug statins (must be metabolized first to active metabolite).  What other hypolipidemic combo are each of these drugs involved in?

Most potent:

Rosuvastatin and Atorvastatin (t 1/2 = 12-14 hrs).

Prodrug:

Simvastatin (in combo w/ ezetimibe)

Lovastatin (MEVACOR) (in combo with niacin)

Adverse Rxns:

-incr AST, ALT; hepatitis

-incr CK (myopathy, myositis, flu sx, rhabdomyolysis=renal failure)

-rash, pruritis, dryness

-carcinogenicity/teratogenicity (animals)

What class?

Contraindications

Statins

C/I: pregancy (b/c fetus needs chol)

Reduces blood chol by decr absorption in small intestines.  Major effect on LDL, min effect on TG and HDL. 

Used in combo with what drug to decr LDL an additional 12-18%.

Adm.

Ezetimibe

in combo with simvastatin to decr LDL addtional 12-18%.

Adm qd alone or with statin.

Adverse rxns:

-GI disturbances

-impaired liver function

-headache

-muscle/joint pain.

What drug?

What interferes with this drug's absorption?

Ezetimibe.

Adm 2hr before or 4 hr after bile resin drugs b/c they interfere with this drug's absoption.

Inhibits adipose lipolysis which decr free fatty acid supply to liver to decr VLDL synthesis, decr TG (50%), decr LDL (15-30%).  Also incr HDL (15-30%) and endothelial function (decr fibrinogen).

Used in combo with what drug to decr LDL & incr HDL.

Nicotinic Acid, Niacin, Vit B3

in combo with MEVACOR (lovastatin)

Adv Rxns:

-N/V/peptic ulcerations

-vasomotor flushing from PG release (tx with ASA)

-hepititis and rarely hepatic necrosis (incr transaminase)

-hyperglycemia/gluc intol (incr insulin resistance)

-hyperuricemia/gout in 20% of pts

What drug?

Name C/I's

Niacin (vit B3, nicotinic acid)

C/I's: peptic ulcers, liver disease, DM, pregnancy

activate PPAR-alpha nuclear receptor in liver which

a) increases apoprot A = incr HDL, decr LDL (5-20%)

b) decreases apoprot C = incr fatty acid oxidation in liver/muscle =decr in TG/VLDL production (50%).

Class and 2 drugs.

Fibrinic Acid Derivatives (for TG reduction).

fenofibrate

gemfibrozil

adv rxns:

-Gi disturbances

-cholecystitis

-hepatitis, incr liv enzymes

-myositis/myopathy*

*caution when used with what drugs?

Fibrinic Acid Derivatives (to decr TGs):

gemfibrozil, fenofibrate

*caution about myositis w/ statins*

2-16-10

ANTIANGINALS

Coronary flow is mainly autoregulatory and dependent on ___________: give examples.

Autonomic innervation of coronary arteries is mainly ___________.

Coronary flow is mainly autoregulatory and dependent on local metabolites like decr O2, incr: CO2, H+, lactate, adenosine.

Autonomic innervation of coronary arteries is mainly b2 receptors that mediate vasodilation.

Coronary Vessels:

1) What is the most potent vasodilator?

2) When treating angina, what is the difference between vasospastic and atherosclerotic vessels (mention coronary steal effect in your answer)?

1) ischemia

2) vasospastic vessels can be relaxed and dilated.  Atherosclerotic vessels do not dilate and the effect of vasodilator drugs by cause a ¨coronary steal¨effect: healthy vessels steal drugs away from diseased vessels.

_____ depends on venous return.  Venodilators, like _________, decrease venous return.

_______ depends on arteriolar dilation, like this class of drugs: _________

Preload depends on venous return.  Venodilators, like nitroglycerin, decrease venous return.

Afterload depends on arteriolar dilation, like this class of drugs: Ca Channel Blockers

Nitroglycerine

Isosorbide dinitrate

Isosorbine mononitrate

***We want the nitrate ion.

Nitrate -->nitric Oxide -->increases c-GMP to inactivate myosin and decrease inotropy.

c-GMP is metabolised by phosphodiesterase-5 (P5).

ED drugs (VIAGRA) are P5 inhibitors.

Nitrates + P5 inhibitors = EXTREME VASODILATION.

Drug class and administration.

Nitrates

ADM: PO is inactive due to first pass metabolism.  Administer sub-lingually for acute conditions.

Adv Rxns:

Calcium Channel Blockers for Angina Tx.

They block slow voltage-gated Ca channels to prevent infux of Ca in smooth muscle and cardiac muscle.

1) Which two drugs work in both cardiac and smooth muscle?  What happens with high doses/toxicity?

2) Which drug is a Ca, Na, and K blockers that is no longer sold in the US b/c of its implication in causing the ventricular arrythmia [Torsade de Pointes]?

3) Which class is primary an arteriolar vasodilator and has little effect on cardiac Ca channels?  What is it used for?

1) Which two drugs work in both cardiac and smooth muscle?

Verapamil (more potent) & diltiazem

-decr: afterload, HR, AV conduction.

-in high doses/toxicity: decr inotropy-->can cause CHF.

2) Which drug is a Ca, Na, and K blockers that is no longer sold in the US b/c of its implication in causing the ventricular arrythmia [Torsade de Pointes]?

Bepridil

3) Which class is primary an arteriolar vasodilator and has little effect on cardiac Ca channels?  What is it used for?

Nifedipine class: amlidipine & nicardipine

-no direct heart action

-used in Prinzmetal's vasospastic angina

CCB: Nifedipine class

Amlodipine & nicardipine

Used for the tx of Prinzmetal's (vasospastic) angina b/c it only has effects in smooth muscle, not heart.

Selective beta-1 blockers are indicated in the treatment of angina. 

They decrease HR, SV  & O2 consumption of myocardial cells.  They also cause decreased BP, resulting in a decreased ________.

1) Name a b1 selective blocker.

2) This blocks the reflex tachycardia caused by the other antianginals ______ & _______ .

3) caution when used with _____.  Why?

4) Not effective for what type of angina?

5) Name 3 adverse rxns.

They decrease HR, SV  & O2 consumption of myocardial cells.  They also cause decreased BP, resulting in a decreased afterload.

1) Name a b1 selective blocker. atenolol

2) This blocks the reflex tachycardia caused by the other antianginals nitrates & nifedipine (CCB in smooth muscle).

3) caution when used with verapamil (CCB) b/c it can be a cardiac depressant. 

4) Not effective for what type of vasospastic angina.

5)  adverse rxns: bradycardia, hypotension, CHF.

Types of HTN:

1) #1 cause.  begins at what age range?  cause?  Incr in sys or diastolic?

2) Malignant HTN is rare.  What is the # 1 cause?

3) This type of HTN is on the rise.  Common in geriatrics b/c of atherosclerosis of large vessels.  When do you treat?  What is the risk if you don't treat? What is a treatment challenge?

1) #1 cause of HTN: essential (primary).

40-50y/o.

Incr in diastolic BP.

2) Malignant HTN is rare.  # 1 cause:

neuroblastoma of adrenal medulla.

3) Systolic HTN: This type of HTN is on the rise.  Common in geriatrics b/c of atherosclerosis of large vessels.  Treat if systolic BP>170 or risk CVA. Difficult to solely target systolic BP.

1) CNS vasomotor area in medulla

2) vessels (vasodilation)

3) heart (decr HR)

4) reduce plasma volume

5) kidney: inhibit renin secretion (b1 antagonists) = vasodilation.

What is a common adv rxn of all antihypertensive drugs?

What is the #1 problem with HTN treatment?

Impotency.

Compliance (b/c of adv rxns).

Neurohumoral Modulators (for the tx of HTN)

1) name two classes and two drugs from each class.

2) Common adv/serious rxns, esp for pts on HTN diuretics

ACEi: enapril, lisinopril

ARB: losartan, valasartan

ADV: CARDIAC ARREST from hyperkalemia.

**Esp for pts on HTN diuretic who are on K supplements as well...be sure to stop K supplements before starting on ARB or ACEi.

What drugs cause a persistant cough due to increased levels of bradykinen which stimulated cough reflex?

If this cough affects quality of life of pt, what should you switch to?

ACEi (for HTN):

enalpril (low lipid solubility), lisinopril (high lipid solubility)

switch to ARB (losartan, valasartan)

ACEi: they preserve kidney function.

Lisinopril & enalpril.

1st line CHRONIC HTN drug

1) site of action

2) 2 functions

3) metabolism

4) excretion

5) Dosage (*what happens if you give more than recommended dosage?*)

*what is the other drug in this class that has no vasodilation and rather then hypercalcemia, causes hypocalcemia and can be given to sarcoidosis pts?*

hydrochlorothiazide (thiazide diuretic)

for CHRONIC HTN Tx

1) site of action: distal convoluted tubule

2) 2 functions: diuretic & mild vasodilator

3) metabolism: P450 liver system

4) excretion: urine, unchanged

5) Dosage <25mg/day.  (*>25mg= incr LDL, decr HDL*)

*furosemide  is a potent loop of henle diuretic that has no vasodilation and causes hypocalcemia, thus can be given to sarcoidosis pts.  Used more often in ACUTE HTN*

Adv rxns:

-hyperurecemia (gout, kidney calculi)

-hypokalemia (arrythmias) *must put on K supplement.

Diuretics:

Hydrochlorothiazide (works @ distal conv tubule)

Furosemide (potent loop diuretic)

This drug is infrequently used to treat HTN because of severe impotency.  It is also very sedating and can give false positive COMBS tests (for blood transfusions).

Drug, class, & MOA

Methyldopa: Central down-regulator of sympathetic tone.

MOA: replaces NE with inactive methyne.

Sometimes used in gestational HTN.

This drug was a 2st line anti-HTN drug, but rendered unsuccessful b/c of severe XEROSTOMA. Pilocarpine, a cholinergic agonist, was added to its preparation to increase salivation, but also a failure because of all the other shitty side effects of cholinergic agonists.

Drug, class, & MOA

Clonidine: Central down-regulator of sympathetic tone.

MOA: a2 stimulator, which blocks NE release.

other adv effects: hypotension, mild impotency.

This drug is a 1st line potent vasodilator for the tx of HTN.  You have to take it at night (at least initially) because of orthostatic hypotension (syncope).  These sx go away after a couple days.  Other adv rxn is tremors.

Drug, class, MOA

Prasozin (also terazosin): peripheral down-regulator of sympathetic tone.

MOA: selective a1 inhibitor.