cardiovascular anatomy, physiology and pharmacology bs913 lecture 9: drugs used in the treatment of...

Cardiovascular Anatomy, Physiology and Pharmacology

BS913

Lecture 9: Drugs used in the treatment of cardiac diseases, effects, adverse reactions,

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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: