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84 Cards in this Set

  • Front
  • Back
Major groups of drugs for the treatment of CV disorders


CCB (angina, hypertension, arrhythmias)


Adrenergic Blockers: (Angina, hypertension, HF, arrhythmias


ACE inhibitors: hypertension, HF


Nitrates: angina


+Inotropic agents: HF


Others: diuretics, antithrombotics etc


Antiarrhythmic agents



Positive Inotropic Agents

force heart contraction - can actually accelerate the disease state but make the symptoms better
What is Angina

Anginais broadly defined as an imbalance between oxygen supply to oxygendemand in the heart.


- due to atherosclerosis in the coronary vasculature, vasospasms of coronary artery or both

symptoms of angina

severe ischemia results in pain describes as heavy an crushing



Type of angina


1. stable angina (aka fixed angina, classic angina, or typical angina


-Generally caused by advanced coronaryatherosclerosis.




2. Vasospastic angina (aka varied angina or Prinxmetal's angina) --> caused by spasms




3. Unstable angina: caused by formation of platelet thrombi in coronary vessels

General approaches for the management of Ischemic Heart Disease

1.Correction of lifestyle

2.Specific pharmacological approaches

3.Revascularization: PTCA (or PCI), CABG

4.Gene therapy (still consideredexperimental)


PCI (balloon angioplasty)

you put in a balloon inside the coronaryartery and then inflated. When theballoon is removed, stent is left in place.


The problem is that plaques can developon the side of the stent and inside the stent. There is a move to implant stants thathave drugs attached to them to prevent the accumulation of plaque


Major determinants of myocardial Oxygen demand

1. Wall stress

-intraventricular pressure

-intraventricular volume

-wall thickness

2. Heart Rate

3. Contractile Force


Major determinants of coronary blood flow

1. Coronary resistance

-neural factors (large epicardial vessels)

-intrinsic factors (resistance vessels)

2. Extravascular factors

-systole: negligible coronaryblood flow

-diastole: maximum coronary blood flow


Preload

Theamount of blood in the left ventricle at the

endof diastole (end diastolic volume, EDV). This is, in part, controlledby the amount of blood returning to the heart (venous return). the circulation.Can be reduced by drugs which dilate the venous side of
Afterload

Determinedby the mean arterial pressure

andcan be reduced by drugs which dilate thearterial side fthe circulation.

Reflex responses to Vasodilation

Many drugs are used as dilators – thereis a reflex mechanism that comes into play. Anything which reduced blood pressure will trigger these reflexes.


Consequences of decrease in renalperfusion.


Renin is also under the control ofsympathetic --- kidneys sense decrease in renal perfusion and trigger increasein renin release but also by the direct innervation by sympathetic system

general approaches to treat angina with drugs

-dilate coronary arteries (increase o2 supply)


-decreased HR and/or contractility ( decreased O2 demand)


-Decrease after load


-Decrease preload


-for Unstable Angina also antithromotic medications



Major Drug Groups used to treat ANgina

1.Drugs which inhibit myocardial O2demand

Nitrates

Beta adrenergic receptorblockers

Calcium channel blockers


2.Drugs which increase coronary flow

CCBs

Nitrates


3.Antithrombotic agents

Aspirin

Glycoprotein IIb/IIIaantagonists


Nitrates


-polyol esters of nitric acid


-undergo rapid hepatic biotransformation by glutathione-dependent organic nitrate reductase


-route of administration depends on the type of angina. For predictable angina, taken as a relief, for unpredictable ones; taken as a preventative

Cardiovascular effects of Nitrates

1. direct vasodilation --> redistribution of blood flow to ischemic regions of the endocardium


2. dilation or arterioles leading to a reduction in afterload


3. dilation of veins --> dec. preload (%wise greater than afterload)


4. Antiplatelet effect:

Mechanism of Action of nitrates

On top of thesmooth musclethereis a layer of cells called endothelial cells. In non-disease state, they protect the bloodvessels by generating nitric oxide. Thereare 3 nitric oxide synthases. Nitricoxide produced, enters vessel and all is good. People with heart disease almost always have damaged endothelial layeror completely removed. So in thosepatients those vessels do not have nitric oxide produced.


Nitrates come to the rescue because theybecome de-nitratedandrelease nitric oxide in the cell. SO ina way it is replacing the endothelial cells.


Mechanism of Action of nitrates

Calcium activates this enxyme LMCK– this kinase phosphorylates protein myosin light-chain(contractile protein) – it can interact with actin to cause contraction.


One of the functions of cGMP isto dephosphorylate myosine lightchain –contraction cannot occur and the blood vessel is allowed to relax.


cGMP can be broken down by a family ofenzymes “ “ - you don’t want cGMParound all the time.


Sildenafil works by inhibiting phosphodiesterasebecause now cGMPcannot be broken down and you have the same effect as nitrates. Patients who are being treated with nitrates,can have powerful additive effects if they are given viagra. Contraindicated drugs.

Calcium Channel Blockers for the treatment of Angina


three primary classes of CCBs




1.Benzene acetonitriles (verapamil)




2.Dihydropyridines (nifedipine)




3.Benzothiazepines (diltiazem)



Calcium Channel Blockers for the treatment of Angina

Irrespective of structure, all CCBs blockCa2+ entryby

blocking the slow inward calcium channel(ISI). However,

selectivity towards cardiac vsvascular tissues varies

Verapamil > Diltiazem > Nifedipine


Site of Action of CCBs


SA Node (decrease automaticity)


AV node (Decrease conduction)


Cardiac myocytes (decrease afterload & O2 demand)


Coronary arteries (increase vasodilation and O2 supply)


Veins: (minimal venodilation)


Arterioles: (inc. vasodilation, dec. afterload and O2 demand)



Effectiveness of CCBs in treating Angina

VASOSPASTIC ANGINA:

All are effective in reducing coronaryconstriction via a direct dilating influence. Improvement generally seen in>90% ofpatients with a large %age showing complete eliminationof anginalepisodes.




STABLE ANGINA:


All are effective: mechanism due to areduction


in oxygen demand via:


1.Decreased afterload


2.Decreased heart rate


3.Decrease contractile force




Unstable Angina: somewhat




Pure Dilator alone


Not ideal because it triggers all the reflex response to vasodilations and makes matters worse



Beta Adrenergic Receptor Blockers for the treatment of Angina

Use of these drugs (egpropranolol) based


solely on anti-sympathetic nervous systemeffects.

Mechanism by which Beta blockers work


(used on the demand side of the equation)


reduce cardiac function

1.Decreased heart rate (negative chronotropic effect) resulting in increasedend-diastolic volume (EDV*)

2.Decreased contractile force (negativeinotropic effect)


3.Decreased blood pressure






Beta Blockers

-also anti-hypertensors by unknown mechanism


-have to be careful. If you slow heart down, spends more time in diastole, and more time for right ventricle to fill up --> increased EDV -->increased O2 demand.




So just beta blockers on their own is not desirable

Combination therapy for the treatment of angina: Beta blocker + nifedipine (CCB)

-Nifedipine decreases afterload


-Beta Blocker prevents reflex sympathetic cardio-stimulation


-Result: reduction in O2 demand



Combination therapy for the treatment of angina: Beta blocker + nitrate

-Nitrate attenuates increased EDV produced by Beta blocker


-Beta blocker prevents reflex sympathetic cardiostimulation


-Result: added efficacy



Combination therapy for the treatment of angina: CCB + nitrate

Combined decrease of both preload andafterload;

however this combination can causeexcessive

vasodilation and thus reflex cardiostimulation

Combination therapy for the treatment of angina: Beta blocker + CCB + Nitrate

used in patients refractory to any other combination



























3 major patterns of LV hypertrophy

ConcentricLVH: pressure load leads to growth in cardiomyocytethickness

Eccentric LVH: volume load produces myocyte lengthening

Post MI LVH: stretched and dilated infarcted tissueincreases the left-ventricular volume with acombined volume and pressure load on thenon-infarcted zones

Fibrosiscontributes to all three patterns
Physiological Hypertrophy is an adaptive response to Growth signals

General approaches for the management of HF


Life style/dietary changes


Pharmacological


Surgical



Surgical treatment of HF

Heart transplant (only curative approach)

Leftventricular assist devices (LVADs)

Skeletalmyoplasty(limited improvement)

Ventricularreconstruction (experimental)

Celltransplantation (experimental)

Drugs used for the treatment of HF


1. + Inotropic agents


2. Preload/afterload reducers


3. Beta adrenoreceptor blockers



2. Preload/afterload reducers

genereally forchronic heart failure, not ideal. Theseare used mostly for acute heart failure. Anything with a pril is an ace inhibitor. They are widely used. Angiotension 2receptors have been introduced because ace inhibitors have this chronic coughas side effect



Positive Inotropic agents

-digitalis glycosides

-catecholamines

-xanthine derivatives


Beta adrenoreceptor blockers

carvedilol




For a long time they were contraindicatedbecause they thought the conditioned would be worse




Beta blockers may actually promotehealing of the heart



ACE inhibitors for treatment of HF

In a study they NYHA class 2 and three patients


They compared the effect of aceinhibitors and antagonist AT1


Both drugs reduced BP identically and yetthe patient receiving the ACE inhibitor much better. That proved that the effect of ACE inhibitormust be working by some other mechanism other than vasodilation


Sudden cardiac death is important. Take home message is that ACE inhibitors mustbe doing something else instead of vasodilation.


Mechanism of Action of ACE inhibitors or AT1 antagonist in HF

1. Vasodilating/afterload reduction


Angiotensin II: potent vasoconstrictor stimulatessympathetic nervous systemincreases aldosterone production


2.Preventionof myocardial hypertrophy and remodelling




Mechanism of Positive Inotrope such as DIgitalis

1. Inhibition of Sodium-Potassium pump --> reduced Ca2+ removal via Na-Ca exchange or reverse mode Ca influx via Na-Ca exchange --> Increase intracellular Ca2+ levels --> Positive Inotropic effect
Other Inotropic agents


-Catecholamines (dobutamine, dopamine) stimulate adenyl cyclase


-Phosphodiesterase Inhibitors (amrinone, milrinone) -- inhibit PDE 3 to prevent cAMP breakdown

Problems with + Inotropic Agents

1.Potential for toxicity (all,calcium-dependent)

2.Narrow therapeutic index (especiallyglycosides)

3.Increase cardiac work/oxygen demand

4.Low K (diuretic use) increases toxicity(glycosides only)


5.Although inotropes can improve quality of life, recentevidence suggests possible increased mortality


Beta Arenergic Blockers for Heart Failure

mild to moderate CHF


-6 months follow up


-dose dependent improvement in LVfunction


-73% reduction in mortality


-60% reduction in hospitalization rate


B-Blocker Treatment in HF


Propranolol, carvedilol, metoprolol


Effects:


-increase injection fraction


-improve symptoms


-decrease hospitalization


-decrease heart transplantation


-slows progression of HF and decreases mortality





B-Blocker Mechannism


-decreases sympathetic stimulation-


-decrease heart rate


-improve diastolic filling


-up regulation of B-adrenoreceptors

Propranolol

-not a specific B-blocker - blocks both Beta1 and 2. Patients with asthma shouldn't take it.
Improving Survival in CHF


Over the years there is a continuous decrease of mortality as different combination of drugs are used


From: (diuretic + digoxin) to (diuretic + digoxin + ACE-1) + (diuretic + digoxin + ACE-1 + B-Blocker) + (diuretic + digoxin + ACE-1 + B-Blocker + Candesartan)

Potential future treatment for HF


antiapoptopic agents


antioxidants


endothelin receptor antagonis


cytokine receptor antagonist


alternative medicines (traditional Chinese such as ginseng)


gene therapy (direct molecular targeting)


cell transplant therapy

Hypertension facts


-most common CV disease (25% of adult population)


-prevalence varies with age, sex, race


-usually asymptomatic


-diagnosis based on repeated measurements of elevated bp


-Approx. 90% unknown cause but generally associated with genetic inheritance, psychological stress, lifestyle

Classification of Hypertension







systolic/diastolic Pressure


<120/80 Normal


120-135/80-89 Pre-hypertension


>140/90 hypertension


140-159/90-99 stage 1


>160/100 Stage 2


Decision to treat the middle grey area dependent on other risks

Hypertension: general


any increase in BP above 115/75 mm Hg, increases CV risk, doubling with every rise in 20/10 mm Hg



Guidelines for treating hypertension


initial non-pharmacological approach warranted in all patients


1.Relief of stress


2. Dietary management (eglow dietary Na)


3. Regular exercise


4. Weightreduction (if needed)


5. Control of risk factors contributing to development of atherosclerosis




High Na+ intake increases risk of hypertension-related complications



Govt recommended intake of Na 2000mg/day


Doctors recommend 1500mg/day


can of soup has over 500mg alone




Redcution of averge dietary sodium from 3500 mg/day to 1700


1 million fewer hypertensives


5 million fewer physician visits for hypertension


1/2 billion savings in healthcare spendings


13% reduction is CVD




Goals of Ant hypertension therapy

•To optimally reduce cardiovascular riskby reducing the blood pressure to specified targets.

–This usually requires two or more drugs and lifestyle changes


–The systolic target is moredifficult to achieve however controlling systolic blood pressure is asimportant if not more important than controlling diastolic blood pressure


Principle of hypertensive therapy


BP=CO x PVR


hence all hypertensive drugs must act either by reducing CO or the peripheral vascular resistance



When to use pharmacological treatment for hypertension


-if bp is higher than 140/90


-If bp is higher than 130/80 and patient has diabetes and/or Chronic kidney disease

Targets for Antihypertensive therapy

*B-receptors of the heart: Propranolol and other B-blockers


*alpha-receptors of vessels: Prazosin and other a1-blockers


*Vascular smooth muscle: hydralazine, minoxidil, diazoxide, Verapamil and other CCBs, Fenoldopam


*Sympathetic ganglia: trimethaphan


*Kidney tubules: thiazides


*Vasomotor centre (brain): methyldopa, clonidine, Guanbenz, Guanfacine


*Angiotensin receptor of vessels: losartan and other AT1 blockers


*Kidneys: ACE inhibitors



4 primary anatomical Targets for blood pressure control


1. resistance vessels


2. capacitance vessels*


3. heart*


4. kidneys




*not a major target





Summary of site of Action of different classes of antihypertensive drugs


Centrally acting: Methyldopa, clonindine


(Not used much, lots of side effects)






Directly acting vasodilatators:


AT1 receptorantagonists (``sartans`)


α1 receptor antagonists (egprazosin)


Calcium channel blockers (egnifedipine)


Other vasodilatators (eg hydralazine,minoxidil)



Drugs acting on the kidneys


Diuretics


βreceptor blockers




Drugs acting on therenin-angiotensin system


ACEinhibitors


AT1 receptorantagonists


Directinhibitors of renin (Aliskerin)

















Aliskerin

Aliskiren –direct target renin àassociated with toxicity àcautionary warnings


By blocking an upstream effector likerenin has a lot of other side effects


Its still available but not widelyused. This drug came out 4-5 years ago





CCBs for hypertension

Major effect of calcium channel blockersis to dilate coronary arteries – some calcium channel blockers also have someadditional affects à mildaldosteroneffect, mild diuretic


Nifedipine –half life 7-8 hours is still considered a short acting


Major function – reduction in pressure –reduction in afterload


Beta blockers – propranolol first durg used– nonspecific – crosses BBB easily. Somestudies suggest that its centrally acting. Newer Beta blockers have less effect on CNS, and are specific and havebetter effect than propranolol. So thisidea that propranolol is acting centrally may not be true. Beta blockers reduce heart function and thatshould reduce blood pressure. But thereare studies that show that depressed cardiac function does not necessarily leadto decreased BP.


When you give beta blockers for a longtime, nerve endings reduce norepeinepherinrelease. This may be the mechanism, sothis is why it takes time for reduction in bp.


Reason why doctors don’t perscribe betablockers


-Lateeffect


-Unknownmechanism


-Otherside effects


CCBs for hypertension

Calcium channel blockers (CCBs = calciumantagonists) act largely by peripheral arterial dilation, with a lesserdiuretic effect. They also evoke counterregulatory mechanisms, dependent on stimulation ofrenin and formation of angiotensin, as well as on reflex release ofnorepinephrine. Such acute adrenergic stimulation with short-acting nifedipine(N) may precipitate myocardial ischemia in the presence of coronary disease .Currently only long-acting CCBs are used in the treatment of hypertension. Theinhibition of aldosterone release obviates overall fluid retention. D = diltiazem;SVR = systemic vascular resistance; V = verapamil.

Beta Blockers
Proposed antihypertensivemechanisms of beta-blockade. An early fall in heart rate (HR), stroke volume(SV), and cardiac output (CO) does not lead to a corresponding fall in bloodpressure because of baroreflex-mediated increased peripheral &alpha-adrenergic vasoconstriction, with a rise in systemic vascular resistance.Within a few days beta-blockade of prejunctional receptors on the terminal neuron withconsequent inhibition of release of norepinephrine (NE), which may explain whythe SVR falls to normal. The blood pressure now falls. In the case of vasodilatory beta-blockers, with addedalpha-blockade, there is an early decrease in SVR and a rapid fall in BP

Diuretics


Diuretics are widely used to treatHypertension and also for HF for the same reasons


The major effect is the loss of sodium –they act on the sodium regulatory systems in the nephron – wherever sodiumgoes, water follows. Lose sodium à losewater , lower blood volume à lowpressure


When Renin is activated then you getangiotensin 2 upregulation. So combination diuretics and ACE inhibitorswork well because the ACE inhibitors stop these reflexes to loss of sodium


Diuretics

If you take diuretics chronically, theblood volume comes back to normal and yet the hypertension is reduced. There is a disoacciationbetween blood volume and hypertension. Why is that? Nobody knows. SO itsnot a simple reduction in blood volume. There has got to be some other mechanism



Diuretcs

•The primary class (first line of choice)of diuretics used for the treatment of hypertension are the Thiazide Diureticswhereas others (eg Loop Diuretics or K+ sparingdiuretics) are less frequently prescribed although under some circumstancesthese may be advantageous over thiazides.


Site of Diuretic Action in the Nephron

Thiazide diuretics: Primarily byblocking

an electroneutral Na-Cl cotransporter (NCC)

in DCT producing moderate natriuresis.


Additional vasodilatation likelycontributes to

Antihypertensive effects

Loop diuretics: Primarily by inhibiting the

Na-K-Cl cotransporter in TAL

K+-sparing diuretics/aldosterone antagonists:

Primarily by decreasing Natransport

through epithelial Na channels (ENaC).Since

Na transport is coupled to Ksecretion, a K-

sparing diuresis results


Combination therapy for hypertension

-ACE inhibitor + Calcium channelblocker (CCB)


-ACEinhibitor + thiazide diuretic


-Angiotensinreceptor blocker (ARB) + thiazide diuretic


-ARB + CCB


-Beta adrenergic receptor blocker+ thiazide diuretic






A number of these combined medicationsare available as singletablet/capsule


Cardiac Arrhythmias

Can occur in anyone, even with anyonewith a normal heart.


Very verycomplex and can be caused by different mechanisms


Every single arrhythmic agent actuallyhas the ability to induce arrhythmia so they can be quite risk because theytarget some key ions channels in cardiac cell itself