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Case 3: Pharmacology, A Dose is good when the Renal function of a patient…
Case 3: Pharmacology
Epidemiology of Cardiac FailureOutline the Epidemiology of Cardiac failure
- Chronic heart failure is common in 1-3% of the population and increases with age to 10%
- Chronic Heart Failure is, debilitating, Detectable, Treatable and has a major economic effect on Public Health System
- If Heart Failure is treated after a long time, there sill be a structural and functional abnormality
List the major causes of Heart Failure
- Hypertension
- Coronary Artery Disease
- Cardiomyopathy
- Rheumatic Heart Disease
Pathophysiology of Cardiac Performance: The Four Factors that drive Cardiac OutputOutline the Four Factors that drive Cardiac Output
- Cardiac Output = Heart Rate x Stroke Volume
- Heart Rate is controlled by the Autonomic Nervous System
- Bradycardia is an abnormally slow Heart Rate which results in an inadequate cardiac Output
- Tachycardia is an abnormally fast Heart Rate which results in an inadequate Cardiac output
- Tachyarrhythmia, which is an abnormally increased heart rate with ventricular fibrillations, results in a decreased Cardiac Output
- Stroke Volume is controlled by the following factors:
- Preload
- Preload refers to the volume of Blood in the Ventricle at then end of Diastole (Diastolic filling with Venous Blood)
- Works with Starling's Law
- Afterload
- Afterload is the pressure that the heart has to work against or overcome in order to eject blood.
- Resistance to Systolic Ejection
- Contractility
- Contractility controls the Stroke Volume therefore, it controls the Cardiac output
- Infarction/Ischaemia
- Arrhythmia
- Amyloid
Starling's LawExplain Starling's Law
- According to the Starling's Law the amount of blood leaving the heart (Stroke Volume) increases with an increase in the amount blood that enters the heart, as there is more blood to deliver.
- However, if the heart muscles are too stretched that the heart cannot contract properly, the Stroke Volume decreases despite an increase in the end-diastolic blood volume.
- The patient is said to be in Cardiac failure due to excessive Diastolic Filling
Physiological Responses to Cardiac FailureDescribe the Physiological Responses to Cardiac Failure
- Cardiac failure results in a decreased Cardiac Output and Blood Pressure
- Therefore, a decreased Cardiac output results in the activation of the Compensatory Mechanisms
- Activation of the Compensatory Mechanisms results in an Increased SVR and Plasma Volume
- Compensatory mechanisms are as follows:
- Activation of Renin-Angiotensin Aldosterone System (RAAS)
- Activation of the RAAS results in an increased Sodium and Water Retention
- Vasoconstriction in order to increase Systemic Resistance, and result in an increase in the Afterload and therefore, decrease the Cardiac Output
- Release of Norepinephrine
- Release of Norepinephrine results in Vasoconstriction and Tachycardia
- Thus making it difficult to have a normal Cardiac output
- Inflammatory mediators
- Inflammatory mediators such as the Tumour Necrosis Factor (TNF) and Endothelin are released
- Beta receptors
- Beta receptors may undergo Beta-Adrenergic desensitisation due to the increased release of Norepinephrine
- Hypertrophy, Ischaemia, and Arrhythmia
- Necrosis, Fibrosis, Apoptosis, Left Ventricular Remodelling (Dilation)
- Therefore, all of this may make the heart have an inadequate Cardiac Output
- As a result, the decreased Cardiac Output restarts the Compensatory mechanism cycle
WHO Guide to Good Prescribing (Normative Decision Analysis)Describe the Guide to Good Prescribing
- Define the Problem
- Set Therapeutic Objectives:
- Select Therapy
- Drug Therapy
- P-Drugs such as Generic Treatment Plan
- Patient Drugs which are Adapted Treatment Plans
- Practical Aspects of Prescribing:
- Prescription Writing
- Information, Instructions and Warning
- Monitor Therapy (Alter, Continue or Stop)
Guide to Good Prescribing:
- Define the Problem
- When defining the Problem there are a number of things a person needs to consider:
- De novo vs Chronic Heart Failure
- Is the Heart Failure acute or is it long standing
- Clinical Severity of the Heart Failure
- Precipitants or Causes of Heart Failure
- Such as: Coronary Artery Disease, Pericardial Disease, Valvular Disease, Electrical Abnormality and Medical Non-Compliance
- Precipitants of Cardiac failure can be used to treat the Cardiac Failure for better Treatment Outcomes
- Heart Rate and Rhythm
- It is important to find out if the patient has a Normal Heart rate or Tachycardia or Bradycardia
- Or if the Heart Rate Rhythm is Regular or Irregular Heart Rhythm
- As an Irregular Heart Rhythm is less likely to have an adequate Cardiac Output
- Blood Pressure
- It is important to know the Blood Pressure of the Patient as Hypertension is a cause of Cardiac failure
- And Hypotension is an indicate of a serous Inadequate cardiac output
- Comorbidities
- State of a Patient's heart is not unrelated to other factors such as Comorbidities
- Therefore, Renal disease, Iron Deficiency, Lung Disease and Diabetes may cause or exacerbate Heart Failure
Set Therapeutic ObjectivesList the Therapeutic Objectives
- Some of the Therapeutic Objectives include:
- Reduce Mortality
- Modify Disease progression
- Reduce symptoms in order to improve quality of Life
- Reduce Hospital admissions
- Treat Reversible Conditions (Such as Hypertension and Diabetes mellitus)
- Avoid/Correct aggravating factors (Such as severe Anaemia)
- Avoid unwanted drug interactions (Such as drug interactions that increase Arrhythmias)
Examples of Drugs which can precipitate or aggravate Cardiac failureList the Examples of drugs that can precipitate or aggravate Cardiac Failure
- It is important to note that the following list of Drugs that precipitate o aggravate cardiac failure may be need for another Comorbidity of the patient:
- Therefore, in such a case it important to use them mindfully and carefully and be aware if they are worth the risk or not:
- Oestrogen
- Steroids
- Oestrogen and Steroids can cause Sodium and Water Retention and therefore, aggravate Cardiac failure
- Therefore, they should be avoided
- Calcium-Channel Blockers
- Calcium-Channel Blockers slow down the Heart Rate and therefore reduce the Contractility of the Heart
- They are used in patients with Hypertension
- This is bad for a patient in Cardiac failure
- Beta-Blockers
- Beta Blocker slow down the Heart rate and reduce the Contractility of the Heart, therefore they can aggravate cardiac failure
- Beta Blockers are also used in cardiac failure as they have some benefits
- Non-Steroidal Anti-inflammatory drugs (NSAIDs)
- NSAIDs can cause Sodium and Water Retention and when used excessively for an extended period of time they can cause Renal Failure which aggravates cardiac failure
- Therefore, it is better to avoid them
- Excessive Diuretics
- Excessive Diuretics are a potential contributor to cardiac failure
- Excessive Diuretics are also used in the symptomatic treatment of Cardiac Failure
- However, if a Higher Dose is used then the patient may be pushed past the maximum point of Cardiac output to a point that the Filling Volume is decreased and the cardiac output is reduced
- Therefore. if the Diuretic treatment is reduced, the preload increases and the Cardiac output returns to an adequate level
- Drug Therapy
Describe and List the types of Drug Therapy that can be used in Cardiac Failure
- Cardiac Failure can be treated with Non-Drug Therapy and Drug Therapy
- Non-Drug Therapy includes General measures such as:
- Exercise training
- Flu immunization
- Reduction in Alcohol Consumption
- Cessation of smoking
- Correction of Anaemia
- Review of: Diet, Drug Interactions and Risk Factors
Drug Treatment for Cardiac FailureDescribe and List the Drug Treatment for Cardiac Failure
- There are 4 classes of Drugs that have shown to reduce Mortality in Cardiac Failure
- ACE Inhibitors
- ACE Inhibitors are the standard therapy for Cardiac failure whatever the ejection fraction may be
- An alternative of ACE Inhibitors if ACE Inhibitors are not tolerated by the patient is Angiotensin Receptor Blockers (ARBs)
- Beta-Blockers
- Beta-Blockers inhibit the Beat-Adrenergic response
- In order to prevent slowing down the Heart Rate and the reducing the Contractility and cardiac Output of the heart
- Beta-Blockers are initially given in a Low Dose and then up-titrated to maximally tolerated doses
- Beta-Blockers are not used in mild cases that can be managed using other drug therapies
- Spironolactone
- Spironolactone inhibits the effects of Aldosterone
- Isosorbide-hydralazine
- Isosorbide Hydralazine is a useful adjunct in patients
ACE-Inhibitors
- ACE inhibitors are the standard treatment therapy for patients with Cardiac failure, irrespective of the ejection fraction
Describe ACE Inhibitors
- Patients with cardiac failure have an increased Renin-Angiotensin Aldosterone activity due to:
- Hypotension which simulates an increase in Sympathetic activity
- Decreased Renal Perfusion which increases Renin
- As a result, Renin simulates the conversion of Angiotensinogen to Angiotensin I
- Then the Angiotensin Converting Enzyme (ACE) converts Angiotensin I into Angiotensin II
- As a result, Adrenal Gland absorbs Angiotensin II and uses to release Aldosterone
- Therefore, an increase in Angiotensin II has the following consequences which decreases Cardiac Output:
- Vasoconstriction of Blood vessels which increases Afterload
- Sodium and Water Retention by the Kidney which increases Preload
- Cellular Hypertrophy and Myocyte Apoptosis
- Brain will undergo Sympathetic activation and Vasopressin Secretion
- Therefore, ACE-Inhibitors inhibit the conversion of Angiotensin I into Angiotensin II
- ACE-Inhibitors have the following effects:
- Reduce mortality
- Reduce Hospital admissions
- Reduce symptoms and therefore improve quality of life
Angiotensin II Receptor Blockers (ARBs)Describe Angiotensin II Receptor Blockers (ARBs)
- Angiotensin II receptor blockers are an alternative drug treatment to ACE-Inhibitors used for cardiac failure
- They have similar precautions and contra-indications
- ARBs block the receptor to which the Angiotensin II binds to on the organs of the body
- ARBs results in Less Cough and Angiotensin II mediated Vasoconstriction
- BUT there is also no beneficial Bradykinin effects such as Renal Vasodilation, Endothelial protection
- ACE Inhibitors are better than Angiotensin II Receptor Blockers
- How ?
- 12% lower risk of Death
- 20% lower risk of Lethal Arrhythmias
- Particularly in patients on Beat-Blockers
Increased Sympathetic ActivityList the effects of the increased Sympathetic Activity during Cardiac Failure
- Increased Cardiovascular Sympathetic Activity results in the following:
- Increased release of Renin and other vasoconstriction substances that trigger Vasoconstriction and Tachycardia
- Myocyte Hypertrophy, Death, Dilation, Ischaemia and Arrhythmias
- Down-regulation of Beta-Receptor
Beta-Blockers (Carvedilol, Bisoprolol, and Metoprolol)Describe the effects of the Beta-Blockers as a treatment drug for Cardiac Failure
- Beta-blockers protect against Cardiotoxic effects of excessive sympathetic activity/ Catecholamines
- Decrease the Heart Rate resulting in:
- Lower myocardial energy expenditure
- Prolonged Diastolic filling
- Increased myocardial blood flow
- Vasodilating, anti-oxidants effects (carvedilol)
- The Long-term effects of Beta-Blockers are as follows:
- Mortality reduction in chronic heart failure and sudden death
- Improved Left Ventricular ejection fraction
- BUT not short-term hemodynamic improvement and may even worsen symptoms initially
- Beta-Blockers are added to Stable Grade II or III patients who are on ACE Inhibitors
- Treat congestion first
- Cautious introduction with up-titration to maximally tolerated dose (Cardiologist)
Spironolactone
- Spironolactone inhibits the effects of Aldosterone
Describe the effects of Aldosterone-Aldosterone is bad for a heart in cardiac failure
- The effects of Aldosterone are as follows:
- Increased Sodium and Water retention resulting in Oedema
- Left ventricular fibrosis and hypertrophy
- Reduced Potassium (K+) and Magnesium (Mg2+) resulting in Arrhythmias
- Reduced arterial compliance, and endothelial function resulting in Ischaemic Heart Disease
- Spironolactone is a competitive inhibitor of Aldosterone
List the effects of Spironolactone as a drug treatment used in Cardiac failure
- Adding Spironolactone to Diuretic and ACE Inhibitors in severe Heart Failure has the following effects:
- Reduced hospital admissions
- Reduced Symptoms resulting in improved quality of life
- Hyperkalaemia is uncommon (Plasma level of Potassium/ K+ is above the normal range)
Isosorbide-HydralazineDescribe the effects of Isosorbide-Hydralazine as a drug treatment for Cardiac Failure
- A fixed-dose combination of Isosorbide Dinitrate, a Vasodilator with effects on both Arteries and Snail
- Hydralazine hydrochloride predominantly arterial Vasodilator
- This results in a reduced Preload and Afterload
- Nitrates can alleviate Heart Failure Symptoms, but continuous use of Nitrates is limited, as a patient may develop Tolerance to Nitrates and the Nitrates become in effective
- Therefore, Nitrates are used for a Short-term
- Hydralazine may mitigate Nitrate tolerance
- Isosorbide-Hydralazine indicated for the treatment of the heart failure as an addition to standard therapy, with greater benefits seen in self-identified black patients in terms of:
- Improved Survival
- Prolonged time to hospitalization
- Improved patient-reported functional status
- There is little experience with Isosorbide-Hydralazine in patients with NYHA Class IV Heart Failure
Other Drug TreatmentOutline other drugs treatments used in Heart failure
- There are other drugs that can be used according to Clinical Judgement for heart Failure
- These drugs improve symptoms
- Diuretics
- Nitrates
- Iron for Anaemia
- There are other drugs that may be harmful but can be used with caution after due consideration
- These drugs improve the contractility of the Heart
- Inotropes
- Anti-arrhythmics (Other than Beta-Blockers and Amiodarone)
- Calcium-Channel Blockers
- Digoxin
DiureticsDescribe the Positive and Negative effects of Diuretics
- Positive Effects:
- Diuretics antagonise Sodium Retention
- Relieve symptoms especially in congested patients (Pedal oedema and Pulmonary oedema)
- Negative Effects:
- Diuretics can cause electrolyte abnormalities
- Diuretics can cause Renal dysfunction
- Diuretics can cause Gout, Diabetes mellitus (increase in Glucose), and Cholesterol
- Therefore, is it important to consider combining the different classes of Diuretics
DigoxinDescribe the Positive and Negative Effects of Digoxin
- Positive Effects
- Digoxin does not reduce mortality instead it reduces symptoms
- Digoxin reduces hospital admissions
- Digoxin improves exercise tolerance
- Negative Effects
- Digoxin has a narrow therapeutic range
- Therapeutic range is the concentration range of a drug in plasma where the drug has been shown to be efficacious without causing toxic side effects in most people
- Digoxin has a variable bio-availability
- Bioavailability refers to the proportion of a drug that enters the circulation and is able to have an active effect
- Digoxin has toxic side effects
- Digoxin risk may be exacerbated by other Drug interactions
- Factors which increase Digoxin Toxicity are as follows:
- Hypokalaemia
- Hypomagnesaemia
- Hypercalcaemia
- Quinidine, Verapamil and Amiodarone
- Cardioversion (Shock treatment given to arrhythmic patients)
NYHA ClassesOutline the accepted use of the drug treatment in each NYHA class
- ACE Inhibitors
- Diuretics
- Beta-Blockers
- Aldosterone Blockers (Spironolactone)
- Angiotensin II Receptor Blockers and ACE Inhibitors
- Beta-Blockers and Digoxin for Atrial Fibrillation
- Cardiac resynchronization and Bi-ventricular Pacing is used in Class 4
Monitoring Cardiac Failure TreatmentDescribe the monitoring involved in the Cardiac failure treatment
- Monitor response
- It is extremely important to monitor the response in 2-3 months post discharge as this is the vulnerable period
- Review adherence
- Make timely decision to continue, change or stop the treatment
- Re-assess comorbidities and concomitant medication
Take home message:
- Chronic Heart failure: ACE Inhibitors, ARBs, beta-Blockers and Aldosterone Blockers besides diuretics
- Acute heart failure: often needing therapy by IV Diuretics, Ionnotropes
- A Dose is good when the Renal function of a patient is not impaired
- A Dose is toxic when the Renal Function of a patient is impaired
- This is because drugs are eliminated by the kidney