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Cardiovascular Anatomy, Physiology and Pharmacology
BS913
Lecture 9: Drugs used in the treatment of cardiac diseases, effects, adverse reactions,
…
Martini, Figure 20.12
Revision Physiology …
Martini; Figure 20–12
The Conducting System
Action Potentials in Skeletal and Cardiac Muscle
Martini; Figure 20–15
Cardiodynamics
- Cardiac output
- End-diastolic volume
- End-systolic volume
- Stroke volume
- Heart rate
SUMMARY: Factors Affecting Heart Rate and Stroke Volume
Martini; Figure 20–24
Dynamics of Blood Circulation
Interrelationships between
- Flow
- Pressure
- Resistance
- Control mechanisms that regulate blood pressure and blood flow
Heart SNS PSNS
• inotropy + -• chronotropy + -
Vessels
• Pulm./coronary constrict dilate• most others constrict no effect
ANS effects on heart and vessels
How is Heart Rate Regulated?• Intrinsic pacemaker rate = 100 bpm• Autonomic Influences– SNS------> B1 receptor-------> Increased
HR– PSNS-> Muscarinic (Ach)--> Decreased
HR
• Stretch Reflex (Bainbridge): Increased filling------> Increased HR
• Drugs
- Anything that increases Ca++ availability in the heart muscle cell will increase Contractility.
- Anything that decreases Ca++ availability in the heart muscle cell will decrease Contractility.
What Factors Affect Contractility?
Cardiac conditions
- Hypertension
- Ischemic heart disease, Angina
- Heart failure; poor left ventricular function
- Arrhythmias
- Hyperlipidaemia
Common drugs administered to cardiac patients
- Nitrates
- ß-blockers
- ACE inhibitors
- Digoxin
- Diuretics
- Anti-arrhythmics
- Ca-ch. blockers
- Aspirin
- Warfarin
- Statins
- others
Cardiac medication: ß-blockers
- Body releases noradrenaline (sympathetic nervous system)
- Response to increased activity, danger, positive and negative stress:- increases HR and BP- bronchodilation
- ß-Blockers block effect of released noradrenaline
Cardiac medication: ß-blockers
- used for: - hypertension- angina- post MI- heart failure- arrhythmias- migraine
Cardiac medication: ß-blockers
- Effects and side effects:- bradycardia- hypotension- dizziness - tiredness, fatigue- cold fingers / toes- sleep disturbances- airway constriction- impotence
Cardiac medication: ß-blockers
- Should not be stopped suddenly
- can cause rapid rise in BP and HR
Cardiac medication: alpha-blockers
- Alpha receptors in blood vessels respond to release of noradrenaline vasoconstriction
- Alpha blockers block this effect
- Used for hypertension (usually combined with thiazid diuretics or ß-blockers)
Cardiac medication: alpha-blockers - Effects / side effects:
- rapid drop in BP after initial dose- postural hypotension- headache- palpitations
Cardiac medication: nitrates
- Act as vasodilator
- Coronary arteries: blood flow to heart muscle increased
- Great veins: reduces preload
- Great arteries: reduces afterload
Cardiac medication: nitrates
- Used for:
- Angina
- Heart failure
Cardiac medication: nitrates
- Effects and side effects:
- Facial flushing
- Headache
- dizziness
- Nausea
- Postural hypotension particularly after exercise
Cardiac medication: potassium channel activators
- Dilate the large coronary arteries and smaller resistance vessels
- Increase coronary blood flow
- Additional vasodilatory effect on systemic blood vessels
- Reduces pre- and afterload
Cardiac medication: potassium channel activators
- Used for: angina
- Effects and side effects:- Dizziness- Headache- Hypotension- Vasodilation- vomiting
Cardiac medication: Ca channel blockers
- Intracellular Ca is essential for contraction
- Ca channel blockers prevent influx of Ca into specific cells leading to inhibition of contraction
Cardiac medication: Ca channel blockers
- Effects of Ca channel blockers
- Dilate arteries in systemic circulation: reduced afterload
- Dilate great veins: reduced preload
- Relax coronary arteries
- Diltiazem / Verapamil: reduce contractility reduce oxygen demand of heart
Cardiac medication: Ca channel blockers
- Used for:
- Type 1:verapamil
- Acts mainly on conducting pathway; slows heart
- angina, hypertension, and arrhythmias
Cardiac medication: Ca channel blockers
- Used for:
- Type 2: Nifedipin etc.
- Acts mainly on smooth muscle fibres in arterial walls
- Angina and hypertension
Cardiac medication: Ca channel blockers
- Used for:
- Type 3: Diltiazem
- Combines action of type 1 and 2
- Angina and hypertension
Cardiac medication: Ca channel blockers
- Side effects:
- Facial flushing
- palpitations
- headache
- Ankle swelling
- Constipation (verapamil)
- Heart failure
Cardiac medication: ACE inhibitors
- Inhibits synthesis of angiotensin II, a very strong vasoconstrictor which also causes fluid retention
- Main effects are:
- Reduction of BP- Prevention of vasoconstriction, reducing
afterload and increasing cardiac output
- Reduction of fluid retention
Renin – Angiotensin system
Renin-Angiotensin-Aldosterone
Angiotensinogen AI AII AIII
Renin ACE
vasoconstrictionaldosteronesecretion
Cardiac medication: ACE inhibitors
- Used for:- hypertension- heart failure- post MI
Cardiac medication: ACE inhibitors
- Side effects
- dry, annoying cough
- Low blood pressure (start withlow dose and gradually increase)
- Skin rash; metallic taste
- Reduced kidney function in kidney patients
- Very rarely: angio-oedema
Cardiac medication: Angiotensin II receptor antagonists
- Block angiotensin II receptors
- Used for - hypertension
- Used as alternative to ACE inhibitors if they are not well tolerated
Cardiac medication: Angiotensin II receptor antagonists
- Side effects:
- Fatigue
- Hypotension and dizziness
- rash
- Taste disturbance
Cardiac medication: Diuretics
- Increase urine output by removing salt and water from circulation
- Reduction in circulating fluids
- Reduction in cardiac workload and BP
- Three groups: - loop diuretics - thiazide diuretics - potassium-sparing
Cardiac medication: Diuretics
- Loop diuretics: e.g Furosemid
- Used for: acute severe heart failure
- Very quick acting; large volumes of urine to be passed within one h
- Reduces effectively dyspnoe and ankle swelling
- Also used for hypertension
Cardiac medication: Diuretics
- Side effects- Loss of potassium which causes
- tiredness- muscle weakness, cramps- loss of appetite- ventricular arrhythmias
- Can cause diabetes and gout
Cardiac medication: Diuretics
- Thiazide diuretics
- Prevent sodium absorption in kidneys which is then lost in urine
- Reduce initially by loosing volume of blood, thus reducing BP
- Used for - mild heart failure - hypertension
Cardiac medication: Diuretics
- Side effects:
- Low potassium
- diabetes, gout
- Can increase lipids
- Impotence in high doses
Cardiac medication: Diuretics
- Potassium sparing: e.g. Amiloride, Triamterene
- Minimise loss of potassium
- Usually administered together with other more powerful diuretics
- Used for: - treating oedema in heart failure and cirrhosis
Cardiac medication: Diuretics
- Side effects:
- gastro-intestinal disturbances
- Dry mouth
- rashes
- Orthostatic hypotension
- hyperkalaemia
Cardiac medication: Antiarrhythmics
- Affect the conduction system of the heart
- ß-blockers
- Ca channel blockers
- Digoxin
- Amiodarone
Cardiac medication: Digoxin
- Reduces conductivity of the heart
- Increases myocardial contraction
- Controls HR by preventing rapid rates
- Used for: - supraventricular tachycardias - (heart failure)
Cardiac medication: Digoxin
- Side effects (excessive dosage):
- nausea, vomiting
- Loss of appetite
- Fatigue
- Slow pulse
- Ventricular arrhythmias
- Disturbance of vision
Cardiac medication: Amiodarone
- Increases refractory period
- Used for
- Atrial fibrillation
- Atrial flutter
- Often used with digoxin
- Other (ventricular) arrhythmias
Cardiac medication: Amiodarone
- Side effects:
- photo-sensitivity
- Metallic taste
- nightmares
Case 1: Philip
- Male, 30 yr, non-smoker, runner
- Was sent to a doctor
- Blood pressure was taken
- BP was 200 / 110 mm Hg
- Hypertension
- builder
- Nearly fell off the ladder because he felt dizzy and unwell
Case 1: Blood pressure
- Blood pressure: force of blood against walls of arteries
- Measured non-invasively with sphygmomanometer
- Measured by listening for Korotkoff sounds produced by turbulent flow in arteries as pressure released from blood pressure cuff
Blood pressure
Classification of Hypertension
Category
Normal <130 <85 Recheck in 2 years
High Normal 130-139 85-89 Recheck in 1 year
Hypertension
Stage 1 (mild) 140-159 90-99 Confirm within 2 mo
Stage 2 (mod) 160-179 100-109 Eval or refer 1 mo
Stage 3 (severe) 180-209 110-119 Eval or refer 1 week
Stage 4 (very sev) >210 >120 Eval or refer immediately
SBP DBPRecommended
Followup
Case 1: Hypertension …
- Serious condition - causes the heart to work harder - contributes to atherosclerosis
- Increases risk of - heart diseases - congestive heart failure - kidney disease - blindness - stroke
- “silent killer” because it has no warning symptoms
Differential Diagnosis of Hypertension
• Primary Hypertension (95%)• Primary Hypertension (95%)
• Secondary Hypertension, e.g. caused by – Contraceptive use– Renal disease– Renal artery stenosis– Cushing’s syndrome– Pregnancy induced hypertension
Risk factors for Hypertension
- Increases risk of (primary) hypertension- smoking - age (women > 65 yr, men > 55 yr) - obesity- diabetes - lack of physical activity- chronic alcohol consumption- family history- sex (men and postmenopausal women)
Treatment of hypertension
- Lifestyle changes- quitting smoking- weight loss- reduction of stress- dietary changes (less salt)- regular aerobic exercise
- Case “Phil”: normal weight, non-smoker, regular exercise training
- If not sufficient drug therapy required
Treatment of hypertension
- What kind of drugs would you choose?
- Consider age and “lifestyle”
Revision Alastair’s lecture
Blood pressure regulation
Case 1: Phil‘s treatment
- Diuretic
- Diuretic + ß-blocker
- BP decrease not sufficient
- BP decrease still not sufficient
- Diuretic + ß-blocker + ACE inhibitor
- BP decrease sufficient- Struggling with adverse effects
Treatment of hypertension
Treatment of hypertension
- Diuretics and ß-blockers are first-line drugs
- Mode of action in both cases unclear
- Several groups of drugs reduce BP by decreasing vasoconstrictor tone and hence peripheral resistance, e.g.
- ACE inhibitors
- Ca antagonists
Thiazid diuretics - initially:
BP falls because of a decrease in- blood volume - venous return - cardiac output
- gradually: cardiac output returns to normal
- however, hypotensive effect remains because peripheral resistance has decreased
Thiazid diuretics
- No direct effect on blood vessels
- Vasodilation seems to be associated with small but persistent reduction in body Na+
- Act on kidney inhibit NaCl reabsorption
- Excretion of Na+, Cl- and accompanying H2O is increased
Thiazid diuretics
- however, also K+ excretion increased
- Safe drug, orally active
- Act within 1-2 hoursDuration of 12 hours
- Adverse effects are important because drug may be taken for life
Thiazid diuretics: adverse effects
- Weakness
- Loss of libido, impotence
- Diarrhoea
- Tinnitus
- Metabolic side-effects:
Thiazid diuretics: adverse effects
- Metabolic side-effects:
- hypokalaemia: can cause arrythmias
- hyperuricaemia: May precipitate gout
- lipids: Increase cholesterol levels, at least during the first 6 months of administration
ß-adrenoreceptor antagonists
- initially:Produce a fall in BP by decrease in cardiac output
- gradually: Cardiac output returns to normal, but BP remains low
- Unknown mechanism “resets” peripheral vascular resistance at a lower level
ß-blockers: adverse effects
- Cold hands
- Loss of libido, impotence
- Fatigue
- Serious side effects:- provocation of asthma- heart failure- conductance block
- Tend to raise trigycerides and decrease HDL-cholosterol
ß-blockers: - Vary in lipid solubility and cardioselectivity
- All block ß1-receptors and are equally effective in reducing BP
- More lipid-soluble drugs: more rapidly absorbed, more first-pass hepatic metabolism, more rapidly eliminated
- Cardioselective ß-blockers may have sufficient ß2-activity to cause bronchospasm in patients with asthma
Vasodilator drugs:
- ACE-inhibitors:- Inhibit synthesis of angiotensin II which is powerful vasoconstrictor
- Ca antagonists:- tone of vascular smooth muscle is determined by cytosolic Ca2+ concentration- prevent influx of Ca and as result inhibit contraction- dilate arteries reduce BP
Case: Gerry
- 55 yr, sees his GP because of nose bleeding
- BP 180 / 100 mm Hg
- newly diagnosed with primary hypertension
- Lifestyle changes recommended and ß-blocker prescribed
- Second morning, very early he fell in the bathroom
Case: Gerry
- Massive problems with orthostatic hypotension
- What would you recommend?
Case: Paul
- healthy, successful modern pentathlete
- Took ß-blockers shortly before pistol shooting event
- Great results
- Change in follow-up of events: Now running event immediately after shooting and not the next day
- Great results in shooting but catastrophy in running
Case: Paul
- Can you explain this?
- What does it tell you about pharmacokinetic and –dynamic of ß-blockers?
Antihypertensive Therapy
Ischemic Heart Disease
• Etiology:– Coronary Atherosclerosis
• Risks:• Clinical Syndromes:– angina pectoris– myocardial infarction– chronic ischemic heart disease– sudden cardiac death
Angina pectoris
Pathogenesis of Atherosclerosis
Lipid accumulates in vascular wall
Macrophages infiltrate the wall and oxidize the lipids
Cell injury and release of local growth factors(Angiotensin II)
Plaque formation on intimal wall
Pathogenesis of Ischemia
Plaque Disruption or Breakdown
Tissue Thromboplastin Exposed
Platelet Aggregation and Clotting Cascade Activated
Thrombus Formation
Acute Ischemia
Demand > Supply: Angina
Perfusion pressurefixed stenosisoxygen content
SUPPLY
DEMAND
afterloadcontractilitypreload heart rate
How to increase supply? How to decrease demand?
StableAngina
Patho: Fixed stenosis Thrombus Thrombus>75% + lysis with occlusion
Pain: predictable unpredictable unpredictablerelieved by not relieved not relievedrest (3-5 min) rest rest (>15-30)
Serum Enz: not elevated not elevated elevated
UnstableAngina MI
Ischemic Syndromes
• Indicative Leads show:
• Ischemia: ST elevation or depression
T-wave peaking, flattening, inversion
Bigger than normal Q-waves
ECG Changes with Ischemia
Q
ST elevation
Decreased Myocardial Perfusion
Partially ischemic cells
Anaerobic metabolismand lack of ATP
No ATP
Ion leak across cell membrane
ST changes Dysrhythmias
Cell rupture and death
Q-wavesElevatedEnzymes
Totally ischemic cells
Sequela of Myocardial Infarction
Decreased Stroke Volume
IMMEDIATE HOURS WEEKS
baroreceptoractivation
SNS
SV, CO SV, COSV, CO
RAS activity
fluid retained
preload
Increased LVwall tension
ventricularhypertrophy
Compensatory Response to Decreased Stroke Volume
Copyright © 2000 by W. B. Saunders Company. All rights reserved.
Differential Diagnosis of Chest Pain
- Cardiac ischemia
- Chest wall trauma, costochondritis
- Pleural pain - pneumonias
- Pneumothorax
- Gastrointestinal (GERD)
Treatment of Cardiac Ischemia
• Stable angina– SL nitroglycerin– Platelet inhibitor (e.g. Aspirin)– beta blocker– add long acting nitrate (remove at
night)– add calcium channel blocker (not
verapamil)
Relief of Angina
Treatment of Cardiac Ischemia
- Medication to - increase myocardial blood
supply- reduce the amount of work
the myocardium performs
Treatment of Cardiac Ischemia
- Dilate coronary arteries- Slow heart rate- Reduce force of each contraction- Lower systolic BP
Treatment of Cardiac Ischemia- Increase supply (coronary flow):
- Ca antagonists- nitrates- revascularization procedures
(bypass surgery, angioplasty ..)
- ß-blockers (extend diastole)
Treatment of Cardiac Ischemia- Reduce demand:- decreased HR (ß-blockers)- reduced wall tension (nitrates,
Ca anatagonists, ß-blockers)
- reduced contractility (ß-blockers, Ca antagonists)
Case: Michael
- Male
- 36 yr
- 65 stone
- Heart failure
Case: Michael
- Symptoms
- fatigue
- oedema
- breathlessness
Heart Failure
• Def: Inability to effectively PUMP the amount of blood delivered to the heart
• Etiologies: Many– MI– hypertension– Valve Disease– Congenital Defects– Cardiomyopathy
Heart as a Two Pump System
rightheart
Leftheart
Tissues
arteriesveins
lungs
Left Heart Failure
Backward Effects Forward Effects
Increased pressure behind the pump
Pulmonary congestion
Low Cardiac Output
Right Heart Failure
Systemic VenousCongestion
Low Cardiac Output
Backward Effects Forward Effects
Principles of Heart Failure Treatment
GOAL: Optimize Cardiac Output and Minimize Cardiac Workload
- Management of Preload
- Management of Afterload
- Management of Contractility
Heart failure
Heart Failure Treatment
Diuretics: reduce circulatory volumedecreases preload and oedema
Vasodilators: e.g. ACE inhibitors decrease pre- and afterload
Digoxin: increase cytosolic Caincrease force of contraction
Drugs used to treat cardiac conditions: