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lec#9 Pharma 16-10-2012 Dr.

Rawan

Ischemic Heart Disease


what do we mean by Ischemia? when there's a reduction in the blood flow that can be associated with organ damage. Ischemic heart disease mean that there's insufficient blood flow by the coronary arteries to the cardiac muscles due to narrowing to the coronary arteries, this narrowing starts from spasm or from formation of atherosclerotic plaque that may become more severe through platelet aggregation. Ischemic heart disease is mainly seen as chest pain. So myocardial ischemia Results when there is an imbalance between myocardial oxygen supply and cardiac oxygen requirements (oxygen demand). Mostly it may be occurs because of atherosclerotic plaque with in one or more branches of the coronary arteries, this will Limits the normal rise in coronary artery blood flow, and in response to increase in myocardial oxygen demand, this means that the pathophysiology of ischemic heart disease is in general there is an imbalance between oxygen supply and oxygen requirement or demand in which the supply is low associated with high oxygen demand or requirement .

Some Important notes " * Read this script carefully because the Dr was speaking shortly and said "very important" many times !! * You don't have to use the slides cuz everything is written here :) * You have to get ur seat number which are uploaded on our FB group !! Dr. is going to ask u to leave if u are not setting according to the list :D 1

Angina Pectoris (AP) ......................................................................


which means in Arabic "" Angina: strangling or suffocation. Pectoris: Chest. characterized by Intermittent chest pain specifically substarnal chest pain, sever acute pain caused by transient, reversible myocardial ischemia. The primary cause of angina is an imbalance between myocardial oxygen demand and oxygen supplied by coronary vessels , in another words there is an imbalance between oxygen demand (increased) alone or with oxygen supply (decreased). This imbalance may be due to: a decrease in myocardial oxygen delivery an increase in myocardial oxygen demand or both increase in oxygen demand is mostly seen during exercise or tachycardia reduction in oxygen Supply like in case of in anemia, coronary artery disease -----------------------------------------------------------------------------------------

Three major types of AP are recognized:


classification of angina is very important to know drug treatment 1) Typical (stable) AP or Atherosceloritic Angina : known as angina of effort it Precipitated by exertion and emotion e.g. once the patient go upstairs or make an exercise or effort or emotional stress chest pain will occur, in which this pain is Relieved by rest and sublingual nitroglycerin Caused by critical stenosis (limited blood flow) by atherosclerosis 2) Prinzmetal Angina it can occur at rest ,it is less frequently related to effort responds promptly to coronary vasodilators, such as nitroglycerin and calcium-channel blockers which are drugs cause vasodilatation of the coronary arteries, in which blockers specially non selective blockers will block 2 causing vasoconstriction which is danger to use so non selective blockers should be avoided. why? simply because the cause of the angina is vasospasm of the coronary artery and by using of blockers it will be more so the angina will be worse more and more. .
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Caused by CA spasm usually over atherosclerotic plaque that will limit blood supply to the cardiac muscle. 3) Unstable angina ( preinfarction angina ) chest pain can occur at rest, it is more frequently more severe and it's duration lasts longer comparing with the stable angina, in which the patient will not respond to sublingual nitroglycerine or it is less effective. it could be Provoked by less effort or emotion. it will carry a bad prognosis because it may progress to myocardial infarction (MI), it need hospitalization because it is associated with platelet aggregation leading to complete occlusion of the coronary arteries and needs more aggressive therapy to prevent death and progression to myocardial infarction. Caused by acute plaque lesion with superimposed partial thrombosis. ----------------------------------------------------------------------------------------------------

Clinical Presentation of Angina


in prognosis we depend on signs and Symptoms: the patient describe the pain as sensation of pressure/burning over or near sternum; often but not always radiating left jaw, shoulder and arm, chest tightness, shortness of breath. precipitating factors: this pain could be associated with exercise, cold environment, walking after a meal, emotional upset, stress, fright, anger all these may aggravate pain sensation. -----------------------------------------------------------------------------------------------

IHD (Ischemic Heart disease) Treatment


Short term goals: we need to prevent reduce and treat the symptoms of angina by limit exercise capability & impair quality of life Long-term goals: we are looking to prevent Cardiovascular events that may develop in the patient not fully treated Like development of : MI, arrhythmias and heart failure. and if it's possible to extend the patients life. Risk factor identification/modification risk factors play a major role in determining occurrence & severity of IHD they should be controlled. risk factors are additive classified as alterable or unalterable risk factors: * Unalterable risk factors we can't control :
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Gender: it's found that's it more common in males than in females but when the female reach the menopausal age the risk is comparable, why? due to the protective effect of the female sex hormones mainly Estrogen Age: by increasing the age the risk will be more Family history: like diabetes mellitus Environmental influences : like climate, air pollution * Alterable risk factors can be controled smoking HTN hyperlipidemia obesity psychosocial factors (stress) medications: some medication may precipitate angina development like sympathomimic drugs that will increase the heart requirement of oxygen.

Therapeutic Objectives:
Increase blood flow to ischemic heart muscle and/or Decrease myocardial oxygen demand Minimize the frequency of attacks and decrease the duration and intensity of anginal pain Improve the patients functional capacity with as few side effects as possible Prevent or delay the worst possible outcome like MI

"patient should be controlled as much as we can"


As you see in the figure above we have an imbalance between oxygen supply and demand in which the demand is higher than supply So we are working to correct this imbalance, some types of drugs we know from the hypertension lecture are effective in ether increasing the supply or decreasing the demand.

Q : what kind of drugs that are responsible to increase blood oxygen supply?
A : we want drugs that works mainly on the hear , we could: increase the supply by dilatation of the coronary arteries by Ca channel blocker, Nitrates (recall from dr.5alel lec. : given sublingually to bypass the first pass effect cuz if it's given orally 90% of the dose will be metabolized by the liver) (more HR more oxygen is needed, more CO more Oxygen is needed and more cardiac contractility more oxygen is needed) so we will reduce the cardiac oxygen requirement by reducing the heart rate and cardiac output and contractility using blockers and Ca channel blockers(recall from the previous lec.) reduce the preload (blood that return back to the heart, the venous return) this will lead to reduce the diastolic filling pressure reducing the CO by that we can reduce cardiac oxygen requirement. reduce the after load which could be reached by reducing the peripheral resistance mainly in the aorta and arterial side this means that the heart work will be less by that we can reduce the oxygen requirement. why short acting Ca channel blockers should be avoided in Angina? because they lead to create a reflex tachycardia which will worsen the condition ,so we are using other type of vasodilators in Angina to avoid reflex tachycardia.
the figure above summaries the drugs used to treat Angina and their side of action.

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ANTIANGINAL DRUGS

I. AGENTS WHICH O2 DEMAND & O2 SUPPLY A. NITRATES B. CALCIUM CHANNEL BLOCKERS II. AGENTS WHICH O2 DEMAND C. BETA BLOCKERS

A. NITRATES
Nitrates are generalized vasodilators but they found that there affect on the veins more than the arteries, because veins are more sensitive than arteries to the action of Nitrates, so they can dilate the coronary arteries by that they will increase oxygen supply to the cardiac muscles. they are used for the treatment of angina and prophylaxically to prevent further attacks; depending on the rout of administration; for ex. if there is acute attack of angina i will use sublingual nitrates in which they have brief duration of action within 1 -3 min they begin their effect, but for long term duration as prophylactic i will select other routs Like Oral, IV or topical application (using batches .)

Mechanism of Action of Nitrates


1. Coronary artery dilatation Administrated nitrates convert to Nitrates which change to Nitric oxide, nitric oxide is a vasodilator increases an accelerates the formation of cyclic guanosine mono-Phosphate (cGMP) this will increase dephoshporelation of the myosine in the light chain of the muscle by that the Vascular smooth muscle relax ether in the coronary arteries or in the blood vessels in the body, SO as result coronary arteries dilatation will lead to decrease coronary bed resistance which will be effective in vasospastic or prinzmetal angina by that this will increase coronary blood flow this will lead to increase oxygen supply. 2. Reduction of peripheral arterial resistance Nitrates also can reduce the peripheral resistance so they reduce the after load due to reduction of the resistance of the Aorta --> this will decrease the blood pressure --> decrease the work load of the heart by
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that this will reduce oxygen requirements. 3. Reduce venous return decrease preload Nitrates also can reduce the venous return due to dilatation of the veins this is the main effect because as we said before that the veins are more sensitive to nitrates than arteries --> this will reduce the left ventricular volume (diastolic filling pressure) --> this will reduce the preload --> so there will be reduction in the work load of the heart by that this will reduce the oxygen consumption or demand.

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Antianginal Agents: Nitrates


Nitroglycerin (GTN), Isosorbide dinitrate if they are given PO (orally) large first-pass effect will occur. they are Used for symptomatic treatment of ischemic heart conditions (angina) in which the Sublingual or transdermal (a drug is administered in a batch where the drug releases slowly through the skin to the systemic circulation) administration of these agents avoids the first-pass hepatic effect.

ROUTES OF ADMINISTRATION of nitrates:


1. Sublingual route rational and effective for the treatment of acute attacks of angina pectoris. rapid onset of action (1-3 min) and ability to by pass the liver. 2. Oral route to provide convenient and prolonged prophylaxis against attacks of angina. 3. Intravenous Route useful in the treatment of coronary vasospasm and acute ischemic syndrome. used to treat severe recurrent unstable angina.
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4. Topical route mainly transdermal in a form of batches, used to provide gradual absorption of the drug for prolonged prophylactic purpose. ** Oral route & Topical route are used for prophylactic control of angina to prevent secondary or other anginal attack.

Adverse Effects, mostly occur due to generalized vasodilation:


Throbbing headache, mainly in the temporal side due to vasodilation of the cerebral vessels. Flushing of the face , also due to vasodilation. Dizziness especially at the beginning of treatment, due to hypotension. Postural Hypotension, due to vasodilation which will induce reflex tachycardia as acompancatory mechanism. Reflex tachycardia

Antianginal Agents: Beta Blockers


Mechanism of Action They are effective in the treatment of angina because they reduce the heart rate they can reduce cardiac contractility this will reduce the work load on the heart by that reducing the oxygen consumption or oxygen requirement. On the same time they can increase the oxygen delivery to the heart How? coronary flow occurs mainly during diastole, if i reduce the heart rate i can increase the diastolic period by this it may increase coronary blood flow to the cardiac muscles Therapeutic Uses of beta blockers: Antianginal , Antihypertensive, and Cardioprotective effects, especially after MI. we talked about them in previous lec.

Antianginal Agents: Calcium Channel Blockers


verapamil :it is a cardioselevtive drug. diltiazem : it has intermediate effect both . nifedipine : it is smooth muscle selective.

Mechanism of Action
Vasodilate coronary arteries lead to increase in oxygen supply. Cause peripheral arterial vasodilation wich lead to Reduce afterload. Reduce myocardial contractility (verapamil and diltiazem) (negative inotropic action) lead to decreased myocardial oxygen demand.

NOW we finished the first part of the lec. "Angina"


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Heart Failure .............................................................................................................


it is a chronic progressive disease that characterized by high mortality rate , that is defined as the hearts inability to pump sufficient blood to meet the bodys metabolic needs. Can occur from any disorder damaging the pericardium, heart valves,

myocardium, or ventricle function. once we say heart failurewe mean an Outdated term congestive heart failure BUT it is inaccurate because patients may present without congestion.
PRECIPITATING CAUSES OF HEART FAILURE:

Thyrotoxicosis, Arrythmias, Chronic alcohol intake, Systemic hypertension, Myocardial infarction and Valve disorders.
** this topic on slide 32 is just to know dr will not make a Q on them.

Classifying Heart Failure *Anatomically: Left versus Right


Left Heart Failure associated with pulmonary congestion, Dyspnea or shortness of breath ,Decrease

exercise tolerance, Cough and Orthopnea in which there is shortness in breath once the patient ling flat. Right Heart Failure associated by peripheral edema, Decrease in exercise tolerance, Hepatomegaly, Ascites (fluid accumulation in the abdomen)

*Physiologically: Systolic versus Diastolic,


described if there is systolic dysfunction in another words there is impairment in ejection OR diastolic dysfunction or there is impairment in relaxation in filling part of the heart.

*Functionally: How symptomatic is your patient? The most common symptoms of CCF includes
shortness of breath, edema and fatigue. shown in the pic--> What are the symptoms of heart failure? FACES... Fatigue Activities limited Chest congestion Edema or ankle swelling Shortness of breath
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COMPENSATORY RESPONSES DURING HEART FAILURE: the problem with heart failure that the heart not capable to pump sufficient blood so there is low cardiac output, once there is low cardiac output as u remember there will be a compensatory mechanism that will occur in order to increase the cardiac output which are mainly two mechanisms: neuronal and hormonal. Neuronal : by the stimulation of the sympathetic nervous system that lead to increase the heart rate, increasing cardiac contractility which will be helpful in increasing the cardiac output. Hormonal: there is low cardiac output and low renal blood flow will activate Rennin angutensin system --> leading to Na & water retention in addition to vasoconstriction may be helpful in increasing the cardiac output. these compensatory mechanisms initially they will increase the cardiac output, but persistent decline in cardiac output in heart failure in long term activation of compensatory response will lead to functional, structural and biochemical molecular change so they will worsen the condition not improve it, SO the first goal in treatment is to try to stop or abolish these compensatory mechanisms because with time they will worsen heart failure.
the figure beside is cleared and explained in the next few paragraphs

reduction in the cardiac output --> activation of the sympathetic nervous system will lead to increase force of contraction, heart rate, preload and after load all of these contribute to increase the cardiac output "initially" also reduction in the cardiac output -> activation of rennin angutensin system --> increasing rennin --> this will lead to increase in preload by increasing Na & water retention which leads to increase blood volume, also increasing in the after load because of vasoconstriction due to angiotensin II formation leading to increase in the peripheral resistance, also RAS will lead to remodeling effect on the heart that is the main worse in the condition in which there is type of apoptosis to the functional cardiac muscles as slow progression replaced by connective tissue.
**SLIDES #37 & #38 dr. read them cuz they have been discussed :)

Compensatory Responses in HF :
achycardia & increased contractility primarily results from NE release Fluid retention & increased preload
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o decreased CO leads to reduced perfusion of other organs including the kidneys o activation of renal-angiotensin-aldosterone system (RAAS) o Na+ & H2O retention increase preload to increase CO Vasoconstriction & increased afterload Ventricular hypertrophy & remodeling o key component of pathology progression. o remodeling affects the heart at molecular & cellular levels. o major focus for therapeutic interventions therapies that reverse modeling, decrease mortality, slow disease progression. At the END we can say that heart failure associated with LOW CARDIAC OUTPUT on the same time there is an INCREASE IN THE CARDIAC WORK LOAD due to the compensatory mechanism. So our aim in the treatment is to INCREASE THE CARDIAC OUTPUT and/or ABOLISH THE WORK LOAD ON THE HEART by inhibiting the compensatory mechanism with DRUGS >> which is simplify in the next figure ,, ENJOY LOL :D

The Donkey Analogy

SLIDES #39 #40 #41 #42 Dr is reading from the slide, here they are:

Diagnosis
No single test available to confirm HF diagnosis HF diagnosis often based on symptoms or chest X-ray to see presence of cardiomegaly. Perform history & physical to identify disorders or behaviors that may cause/worsen HF Medication history we should focus on ethanol, tobacco,, dietary/herbal supplements, NSAIDs, antineoplastic agents they are cardio toxic
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Treatment Goals
improve quality of life relieve/reduce symptoms prevent, minimize hospitalization slow disease progression, prolong survival

Treatment of CHF
Treat Precipitating Factor(s)!!!! Adjust Heart Rate Decrease Preload Decrease Afterload Increase Contractility so we are looking mainly to decrease the work load on the heart by abolish the agents mentioned above by different mechanisms.

HF Management
Determine etiology &/or precipitating factors treat underlying disorders identify, treat risk factors eliminate/minimize precipitating factors pharmacologic & nonpharmacologic therapy patient/family counseling - signs, symptoms - importance of appropriate medication use, compliance close monitoring, follow up

Approaches:
when we begin the treatment we should Reduce workload of heart by: 1.ask the patient to Limit activity level, reduce weight and control hypertension 2. Restrict sodium take lower salt diet 3. Give diuretics which can reduce the blood volume by removal of retained salt and water and they are helpful in congestion or edema ether pulmonary or peripheral edema. 4. Give angiotensin-converting enzyme inhibitors and they are the corner stone of the treatment of heart failure in which they decreases afterload and retained salt and water ;eading to reduce the work load on the heart. 5. Give digitalis they are group of drugs their source from a plant effective on increasing cardiac contractility (positive inotropic effect on depressed heart) 6. Give vasodilators we can decreases preload & afterload
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TREATMENT
Drugs with mortality benefit ACE inhibitors, -blockers potassium sparing diuretics (ex.spironolactone) in NYHA class III & IV heart failure Vasodilators (hydralazine & nitrates in African Americans) Drugs for symptomatic relief diuretics and digoxin

This figure show you the site where the drug act, you don't have to read if you understood the pathophysio of HF.

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Beginning with the Drugs:

ACE Inhibitors
they are the cornerstone of HF pharmacotherapy example: captopril, enalapril, they end with the suffix pril, in which they Prevent RAAS (rennin angiotensin system) mediated response rhat will worsen the myocardial function.
In addition to 1) improving symptoms, they 2) slow progression of HF & 3) prolong survival. Also effective for 4) preventing

HF development, 5) reducing CV risk,, ,mainly they are the first choice if they are not contraindicated.

Diuretics
MOA: They blood volume so symptoms of volume overload by reducing Na & water retention. They are used to relieve pulmonary & peripheral edema they Do not alter disease progression or prolong survival, they are just symptomatic

Loop diuretics
E.g. Furosemide used in acute pulmonary edema This group is more powerful than Thiazides
Pay attention to every single statement !!

Thiazide diuretics
are effective in mild cases only.

K+ sparing diuretics
ex. spironolactone the main aim is help in reducing the hypokalemia due to these diuretics. Decrease mortality, reduce hospitalization rate, improve symptoms

Uses: Diuretic in combination with K+ loosing diuretics


if hypokalemia develops it will Increase digitalis toxicity, so the addition of spironolactone is helpful to reduce the risk of hypokalemia development in which this will reduce the risk of digitalis toxicity when we are using digoxin.

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-Blockers
Logically beta blockers reduce the heart rate and reduce

the cardiac output although in heart failure there is a low low cardiac output THIS MEANS THAT Beta-Blocker will worsen the heart failure, but they found that certain type of -blocker carvedilol, metoprolol, bisoprolol are effective in the treatment of CHRONIC STABLE HEART FAILURE in which they reduce the progression of chronic heart failure. the patient should be stabilized by drugs then -blockers given by certain situation, NOT all patient capable or can tolerate -blockers. -blockers are helpful to reduce mortality and decrease the associated symptoms with heart failure. so they will reduce the sympathetic out flow or activity. they are not a class effect, not all -blockers show benefit, -blockers can be used in stable HF
patients in the absence of CIs or history of intolerance decrease HF progression improve survival mixed effect on symptom improvement

Vasodilators
DRUGS USED TO TREAT CONGESTIVE HEART DISEASE .. Reduce the preload (through venodilatation), or reduction in afterload (through arteriolar dilatation) or both that will lead to Decrease the load of the myocardium. ex: Nitrates: nitric oxide donors lead to venodilation & decreased preload Hydralazine: direct vasodilator leads to decreased SVR, increased SV, CO Amlodipine is a Ca channel blocker effective in CCF prazosin is alpha 1 antagonist effective in vasodilators can be used in CCF

1st line if unable to tolerate ACE inhibitors/ARBs due to renal insufficiency, hyperkalemia, hypotension. Require frequent dosing. Adverse effects: headache, dizziness

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positive INOTROPIC AGENTS


they are group of drugs which are responsible to increase cardiac contractility because in HF there is a reduction in cardiac contractility, there is just one new class for us which is the digitalis glycosides (Cardiac glycosides).

Cardiac glycosides (DIGITALIS)


digoxin is the most common one, it has no significant difference in mortality.
it is just used for symptomatic control by: decreasing morbidity.

How Ion movements during the contraction of cardiac muscle??? see the figure below

1- cardiac muscle as a muscle depend on Ca ions to initiate contraction, these Ca ions enter the cell by the Voltage-Sensitive slow Ca channel these Ca ions will be stored in the saecoplasmic reticulum by that this will initiate the contraction process. 2- If there is a sufficient in Ca ions inside the myocardial muscle this will initiate cardiac contraction. 3- after contraction Ca ions should be removed in which part of it will return back to the saecoplasmic reticulum and part of them will leave the cell by Na/Ca Exchange. in which Na in (from outside the cell to inside) and Ca out. 4- then Na balance is restored by Na/KATPase pump which is an energy dependent pump in which Na out and K in.

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NOW: Mechanism of action of cardiac glycosides

How digitalis Induce cardiac contractility ???


they will be responsible to increase Ca concentration inside the myocardial cells in which contractility increase when Ca ions increase,HOW? 1-Digitalis inhibits Na/KATPase pump which will lead to increase the intra cellular Na because of the inhibition of Na/K exchange. 2- Increasing in the intra cellular Na will be restored by Na/Ca exchange by moving the Na out and Ca in 3- this will increase the intra cellular Ca inside the cardiac muscles then As we increase the Ca we increase cardiac contractility. Summary of MOA:

Inhibition of Na/K ATPase pump increase intracellular sodium concentration eventually increase cytosolic calcium. It restores the vagal tone and abolishes the sympathetic over activity. Inhibit the monovalent action transport enzyme coupled Na+, K+ ATPase & increased intracellular Na+ content increases intracellular Ca2+ through a Na+ - Ca2+ exchange carrier mechanism. Increased myocardial uptake of Ca2+ augments Ca2+ release to the myofilaments during excitation invokes a positive inotropic response

Uses:
1.HF : in just symptomatic control, increasing heart contractility by increasing intra cellular Ca. 2. Atrial fibrillation: their use now is limited but it is preferred to use in HF if it is associated with kind of cardiac arethmia known as atrial fibrillation (when there is irregular atrial contraction ex 300
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beat/min! and part of them pass through the AV node irregularly ), the vagomimetic properties of digoxin may be used prophylactically in supraventricular arrhythmias , including AF. vagomimetic properties (they have an action similar to parasympathetic nervous system they will slow cardiac firing this will slow the heart rate )

S/Es
Digoxin has narrow therapeutic index so it's unsafe it should be monitored Cardiac adverse effects: ventricular arrhythmias, when given in high doses which is a life threatening situation sinus bradycardia, it is a life threatening situation GIT: Vomiting, Anorexia. it is the first sign seen due to digitalis toxicity CNS: Confusion Coloured vision. the domenet colors are yellow and green Adverse effects more common in select patients : renal dysfunction, because 60% of this drug is eliminated by the kidney which will lead to accumulation of the drug in the plasma or the blood which will increase the chance of drug toxicity elderly interacting drugs hypokalemia , by increasing the sensitivity of Na/KATPase pump to digoxin this will increase the toxicity , using of K sparing diuretics is importamt to reduce the risk of hypokalemia , because if there is hypokalimia the risk of digoxin toxicity is high hypomagnesia hypercalemia hypothyroidism

in the treatment using of digitalis toxicity we should Treat cardiac arrhythmias, electrolyte abnormalities especially correction of K level.

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the last group which we talked about it in ANC drugs is the :

Beta1- adrenoceptor agonists


it is Other +ve Inotropic agents, stimulation of bete 1 in the heart we can increase cardiac contractility there are two examples: 1. Dopamine 1 stimulant contractility of heart

also Stimulate Dopamine in renal blood vessels dilation renal blood flow. 2.Dobutamine it is a selective beta1 agonist,similar to Dopamine but has no effect on the Kidneys or dopamine receptors KEEP IN YOUR MIND : that both Dopamine and Dobutamine is used in acute severe heart failure in which the patient is hospitalized because they are given pratrally un available orally the have a high risk to develop cardiac arrethmia (arrethmogenic drugs)

if there is any mistake let us know about it please,

THE HAPPY END


Done by : Baraa'h Al-Salamat

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