Death And Destruction

Cell damage, cell death and apoptosis
15.9.06

Cellular injury: causes
• Hypoxia.
• Not the same as ischaemia.
• Physical agencies:
-trauma;
-burns/severe cold;
-radiation;
-electric shock;
-barotrauma.
• Infectious agents:
-cytopathic;
-toxins;
-immune-mediated.
• Other immune reactions:
-autoimmune;
-anaphylactic.
• Nutritional deficiencies/excesses.
• Genetic.

Chemical injury
• Direct eg. acids, alkalis.
-Mercury compounds, cyanide.
• Via toxic metabolites eg. paracetemol.

Cellular injury
• Most vulnerable points:
-mitochondria;
-membranes;
-protein synthesis;
-nuclear DNA.
• Mechanisms.
• Complex, but can be summarised as:
-free radicals;
-ATP deficit;
-mitochondrial damage;
-leaky membranes;
-loss of Ca2+ control.

Free radicals
• Free electron in outer orbit.
• End-point of many processes.
• Highly reactive, chain reaction.
• Generated by:
-respiration ie. metabolism;
-polymorphs;
-transition metal reactions.
• Unpaired electron in outer orbit.
• Very active and propagate.
• Eg. OH•, O2-•, NO2•, NO3-•.
• Implicated in:
-irradiation;
-inflammation;
-chemical and drug injury;
-carcinogenesis;
-ageing;
-paradigm: paraquet.

Cellular injury - outcome
• Minor - recovery.
• Major - apoptosis, necrosis.

Reversible injury
• ATP falls.
• Sodium pump fails.
• Cell swells.
• Anaerobic respiration uses up glycogen.
• If causes uncorrected, leads to…

Irreversible injury
• Severe swelling and disruption of organelles, particularly mitochondria.
• Lysosomes become leaky and enzymes damage cell.
• Can be detected in blood.

Apoptosis
• Dropping off (like leaves) - active process.
• Seen in:
-cell shedding (normal);
-atrophy;
-involution;
-embryogenesis;
-cell injury (insufficient to cause necrosis);
-tumours.
• Programmed cell death.
• Cell dismantled into apoptotic bodies.
• Phagocitised.
• No inflammatory reaction.

Phases of apoptosis
• Signal:
-TNF;
-nuclear cortisol receptors;
-p53-mediated after DNA damage.
• Control:
-fas-fas ligand (CD95 receptor);
-bcl-2 (mitochondrial function);
-increased mitochondrial permeability;
-opposed by bax.
• Effector:
-proteolysis - caspases.
• Removed by phagocytes.

Heart - reperfusion injury
• Free radicals quite low during ischaemia.
• Torrent produced on reperfusion.
• Mainly reactive oxygen species.
• Neutrophils involved (attracted by cytokines).

Treatment For Heart Failure

11.9.06

Common causes of chronic heart failure
• Myocardial dysfunction:
-hypertension - asymptomatic;
-IHD;
-cardiomyopathies eg. alcohol.
• Valvular heart disease:
-stenosis - congenital;
-incompetence.
• High output states.

Common causes of acute heart failure
• Acute myocardial dysfunction:
-cardiogenic shock after MI;
-myocarditis.
• Acute valve defects:
-rupture in infective endocarditis.
• Altered rhythm:
-fast - poor filling = low CO = shock;
-slow - low rate = low CO = shock.
• Massive pulmonary embolism.

Left, right or both?
• Distinguish left- and right-sided failure.
• Biventricular failure and left heart failure common.
• Isolated right heart failure less common ("cor pulmonale").

Prevention better than cure
• Detect and effectively manage high blood pressure.
• Smoking, diabetes mellitus and other vascular risk factors.
• Alcohol.

Symptoms of left heart failure
• Chronic:
-dyspnoea, orthopnoea and paroxysmal nocturnal dyspnoea;
-cough and wheeze;
-malaise.
• Acute:
-same, plus…
-symptoms of low blood pressure;
-cough - frothy, pink sputum - haemoptysis.

Signs of left heart failure
• Fine basal crackles.
• Third/fourth heart sound (or both - "gallop rhythm").
• Central cyanosis.
• Low blood pressure, if problem acute.

Symptoms of right heart failure
• Chronic (usually in presence of left heart failure):
-peripheral swelling (dependent parts).
• Acute (eg. after massive pulmonary embolism):
-hepatic pain.

Signs of right heart failure
• Pitting oedema of legs and sacrum.
• Raised JVP.
• Hepatomegaly.
• Ascites.

Prognosis and aims of treatment
• 5-year survival rate with left ventricular failure as bad as many cancers.
• Save life in acute circumstance.
• Relieve symptoms.
• Prolong life.

Differential diagnosis
• Left heart failure:
-asthma;
-pneumonia.
• Right heart failure:
-chronic liver disease.

Initial investigation
• Biochemistry and haematology:
-renal impairment, albumin, thyroid function and haemaglobin.
• Chest X-ray:
-cardiac size, presence of pulmonary oedema/effusions.
• ECG:
-cardiac size and evidence of muscle disease.
• Echocardiography:
-dimensions, valve function.

Drugs for heart failure
• Diuretics.
• Vasodilators.
• Inotropic agents.
• [Beta blockers.]

Loop diuretics: mode of use
• Potent naturesis and diuresis.
• Steep dose-response curve.
• Given IV for acute pulmonary oedema - symptoms may be ameliorated within 30 minutes.
• Given orally (often twice daily) in "maintenance" treatment of congestive cardiac failure.
• Eg. frusemide.

Adverse effects
• Severe dehydration.
• Hypokalaemic metabolic alkalosis.
• Hypomagnesaemia.
• Ototoxicity.
• Hyperuricaemia and gout.
• Decreased glucose tolerance.

Potassium-sparing diuretics eg. spironolactone
• Antagonists of aldosterone.
• Not usually potent enough alone.
• Usually + loop diuretic.
• Reduce mortality (+ACE inhibitor and loop diuretic).
• Adverse effects:
-hyperkalaemia;
-gynaecomastia.

Vasodilators: ACE inhibitors
• ACE converts A1 to A2.
• A2 = arteriolar constrictor.
• A2 increases adrenaline release from adrenal medulla.
• A2 causes aldosterone release (hence, salt retention).
• Lower preload and afterload by blocking synthesis of A2.
• Eg. enalapril.
• No parenteral formulation - used orally in chronic left/biventricular heart failure.
• Adverse effects include:
-renal failure (especially in renal artery stenosis);
-chronic cough;
-hypotension (especially with first dose).

Inotropic drugs
• Most commonly needed after large MI with "cardiogenic shock."
• Low blood pressure, poor renal/splanchnic perfusion; acute renal failure.
• High mortality rate.
• Eg. dobutamine.
• Given IV with very short half-life therefore infusion rate determines plasma concentration.
• Lower infusion rates increase contractility and CO.
• Higher infusion rates: arterial constriction (and tendency to reduced splanchnic perfusion).

Beta blockers
• Negatively inotropic - make CCF worse if used incautiously.
• But, have other actions too (including anti-arrhythmic).
• And reduce mortality in patients on treatment with diuretic and ACE inhibitor.
• Eg. carvedilol.

COPD And Breathlessness

11.9.06

NICE definition of COPD
• Characterised by airflow obstruction.
• Usually progressive.
• Not fully reversible.
• Does not change markedly over several months.
• Predominantly caused by smoking.

COPD
• Includes chronic bronchitis and emphysema.
• Characterised by airflow obstruction and little bronchodilator reversibility.
• Normal spirometry excludes diagnosis.
• Prevalence in UK ≈ 1.7% men, 1.4% women.
• 30,000 deaths annually in UK = 6% of all male and 4% of all female deaths.
• By 2020, projected to rank 5th as burden of disease worldwide (12th in 1990).

Impact on services
• >90,000 admissions to UK hospitals per year.
• 10% of all medical admissions.
• Nearly half of all COPD costs are hospital admissions.

Risk factors
1. EXPOSURE TO TOBACCO SMOKE.
2. Others:
• Occupational dusts and chemicals eg. coal dust.
• Specific genetic factors eg. alpha-1-antitrypsin deficiency.
• Indoor and outdoor pollution.
3. Predisposition:
• Recurrent bronchopulmonary infections.
• Socioeconomic status.
• Allergy and airway hyper-responsiveness.
• Lung growth - low birth weight and wheezy bronchitis.

How common?
• 10% females and 11% males have low FEV1 - Health and Lifestyle Survey (1987).
• 9% adult primary care population have abnormal FEV1 and respiratory symptoms - Primary Care Respiratory Journal (2001).
• 27% smokers aged 35-70 with chronic cough have FEV1 <80% predicted - BMJ (2002).
• 37% middle-aged adults who smoked continuously have FEV1 <80% predicted - Locke (2005).

Diagnosis
• Suggested by symptoms/history:
-chronic and progressive cough and/or wheeze and/or shortness of breath (usually exertional);
-impaired ability to exercise;
-significant smoking history.
• Confirmed by spirometry, not peak expiratory flow.
• Spirometry potentially differentiates asthma from COPD.
• If spirometry normal, not COPD.

Respiratory symptoms
• Dyspnoea - all diagnoses, but pattern important in asthma and IHV - episodic and at rest.
• Cough - asthma, ILD - dry; COPD, bronchiectesis - productive.
• Phlegm - COPD and bronchiectesis; frothy, pink with pulmonary oedema.
• Wheeze - any airway disease - asthma, COPD and bronchiectesis.
• Exercise limitation - all diagnoses - consequence of dyspnoea; deconditioning, obesity.
• Haemoptysis.
• Chest pain.

COPD/asthma - history
COPD Asthma
Smoker/ex-smoker Nearly all Possibly
Symptoms under 45 Uncommon Often
Chronic productive cough Common Uncommon
Breathlessness Persistent and progressive Variable

Importance of FEV1/PVC ratio
• Obstructive: ratio <0.7 - asthma/COPD/bronchiectesis.
• Normal: ratio >0.7, <0.8/0.85-ish - asthma/IHV/cardiac disease.
• Restrictive: ratio >0.8/0.85-ish - ILD/obesity.

Other invesetigations
• FBC - Hb and PCV.
• Alpha-1-antitrypsin level.
• ECG - R heart strain, P pulmonale.
• CXR.
• Full pulmonary function, +/- reversibility.
Plus maybe…
• Serial PEF +/- histamine challenge (asthma).
• HRCT (bronchiectesis and emphysema).
• ECHO (heart failure and R heart pressures).

Physiology
• Airflow obstruction.
• Dynamic airway collapse.
• Diffusion abnormality.
• VQ mismatch.
• Shunting.
• Dynamic hyperinflation.

Aims of treatment
• Relief of breathlessness and other symptoms.
• Improve exercise capacity.
• Improve sleep capacity.
• Reduce exacerbations.
• Hence, improve quality of life.

Current COPD treatment
1. All patients:
• Smoking cessation.
• Influenza and pneumococcal vaccinations.
• Short-acting bronchodilators as required.
• Pulmonary rehabilitation if exercise limited.
2. FEV1 <80% predicted:
• All of above, and if symptomatic…
• Long-acting bronchodilators.
• Theopyllines.
3. FEV1 <50% predicted:
• All of above, and if symptomatic…
• Inhaled corticosteroids/combination inhaled steroid/long-acting bronchodilator inhalers.
4. FEV1 30% predicted:
• All of above, and if symptomatic…
• Long-term oxygen therapy.
• Lung transplant.

Exacerbations
• Major cause of mortality and morbidity in hospital admissions.
• UK Audit - ≈ 15% COPD patients dead within 3 months of admission with COPD exacerbation.

Management of exacerbations
• Antibiotics:
-as local protocols;
-culture if failure to respond.
• Oral corticosteroids.

Acute management
• Bronchodilators.
• Corticosteroids.
• Antibiotics.
• Controlled oxygen.
• Ventilations - IPPV/NIV.
• Exercise.
• Home care.

Module 2.02

The Tardy Docker.
11.9.06 - 22.9.06.

Treatments For Acute And Chronic Ischaemic Heart Disease

4.9.06

Manifestations of ischaemic heart disease
• Sudden death.
• Angina pectoris (1% of entire population):
-stable;
-unstable.
• Myocardial infarction.
• Cardiac failure.

Stable angina - intermittent
• Mismatch of oxygen demand:
-exercise;
-increased ventricular wall tension.
• And supply:
-obstruction - fixed (atheroma), dynamic (spasm) or both;
-anaemia etc.;
-[aortic stenosis].

Treatment of acute attack in stable patient
• Rest.
• GTN - sublingually.
• If not responding quickly, seek help.
• Careful advice to patient about dealing with these episodes.

Chronic treatment of stable angina
• Deal with risk factors aggressively - smoking, hypercholesterolaemia, blood pressure etc.
-aspirin and statins.
• Drug treatment:
-nitrates;
-beta-blockers;
-calcium channel blockers;
-nicorandil.

Nitrates
• Cellular actions - via nitric oxide, nitrosothiols, activation of cGMP.
• Vasodilators:
-venous - decreased venous return, preload - decreased oxygen demand (major);
-arterial - decreased blood pressure, afterload and oxygen demand;
-coronary arteries - increased oxygen supply (minor usually, except in coronary artery spasm).

Adverse effects of nitrates
• Headache.
• Low blood pressure and tachycardia.
• Tolerance - depletion of -SH groups.

Examples and use
• GTN - sublingually (IV), first pass metabolism:
-acute attack/prophylaxis;
-congestive cardiac failure.
• Isosorbide mononitrate (ISMN):
-oral, prophylaxis, often modified release preparations.
• ISDN - oral and IV, angina and congestive cardiac failure.

Beta-blockers
• Block β-adrenoceptor:
-β1 v β2, selectively/nonselectively.
• Used in angina, hypertension.
• Slows the heart, especially during exercise:
-decreases oxygen demand;
-prolonged diastole (when coronary blood flow occurs);
-improves oxygen supply.

Uses of beta-blockers
• Angina.
• [Hypertension.]
• Cardiac arrhythmias.
• After myocardial infarction.
• Congestive cardiac failure.
• Anxiety.
• Thyrotoxicosis.

Examples
• Propanolol - nonselective, lipophilic - liver metabolism.
• Atenolol - selective, hydrophilic.
• [Carvedilol, bisoprolol in congestive cardiac failure.]

Adverse effects
• Bradycardia.
• Peripheral vasoconstriction.
• Bronchoconstriction.
• Rebound - "up regulation" - increased sensitivity to and amount of beta-receptors.
• Congestive cardiac failure.
• Fatigue, depression.

Calcium channel blockers
• Inhibit voltage-dependent calcium channel and decrease Ca2+ entry.
• Reduce smooth muscle contraction.
• Cause vasodilation:
-arterial;
-coronary;
-venous.
• Decreased force of contraction of heart.
• Used in angina and hypertension.

Examples
• Oral, prophylaxis.
• Three classes:
-bind to different, but related, receptor sites - different actions in different tissues;
-nifedipine (dihidropyridines) and relatives - vasodilation, angina, blood pressure;
-verapamil - supraventricular arrhythmias, angina, blood pressure;
-diltiazem - angina, blood pressure.

Adverse effects
• Nifedipine - headache, blood pressure decrease, heartburn, facial flushing, ankle swelling, dizziness.
• Verapamil - headache, dizziness, constipation, heart block, bradycardia.
• Diltiazem - constipation, ankle oedema, flushing, headache.
• All - congestive cardiac failure.
• Interactions - verapamil + beta-blockers - both slow heart, possibly to point of stoppage.

Nicorandil
• Potassium channel opener (mimics calcium channel blockers) and nitrate-like activity.
• Vasodilator.
• ?Other effects??
• Reserve drug for difficult cases.

Choosing a drug
• Aspirin, statins, GTN as required.
• Beta-blockers single best.
• If contraindicated or ineffective, ?calcium channel blocker, ?nitrate.
• Double/triple therapy common.

Invasive treatments
• High-risk patients.
• Patients not controlled with medication.
• Patient preference.
• For most part, no improvements in mortality, but improvement in symptoms.
• PTCA - percutaneous transluminal coronary angioplasty.
• PTCA with stent.
• CABG - coronary artery bypass grafting.

[ST elevation = "tombstone".]

Treatment for STEMI (ST elevation myocardial infarction)
• GTN sublingually.
• Aspirin.
• Pain relief - diamorphine + antiemetic.
• Thrombolysis (early angioplasty?)
-?followed by heparin.
• Antianginals if ongoing pain: beta-blockers and nitrates.

Thrombolysis
• All drugs activate thrombolysis by promoting formation of plasmin from plasminogen.
• Break down fibrin.
• "Golden hour."
• Up to 12 (?24) hours.
• Reduce mortality at 30 days from 12% to 9%.

Thrombolytic drugs
• Streptokinase - short infusion.
• Alteplase - infusion over 90 minutes + heparin.
• Tenecteplase - bolus +heparin.

Hazards
• Anaphylaxis/hypotension (streptokinase).
• Loss of effect, if antibodies.
• Bleeding - intracranial haemorrhage especially.
• Reperfusion arrhythmias.
• Contraindications:
-[prolonged CPR];
-history of bleeding, recent surgery;
-risk of bleeding.
• Excessive bleeding - antifibrinolytics - tranexamenic acid.

Treat complications
• Arrhythmias.
• Congestive cardiac failure.
• Others:
-physical;
-psychological - rehabilitation etc.

Clinical Interpretation Of The ECG

4.9.06

Atrial depolarisation + contraction = P wave.
AVN depolarisation = PR interval.
Ventricular depolarisation = QRS complex.
Ventricular repolarisation = T wave.

Iso-electric line represents resting potential of heart.
Positive deflections show electricity flowing towards lead and vice versa.

Assessing ECG
• Rate.
• Rhythm.
• Axis.
• P wave.
• P-R interval.
• QRS complex.
• S-T segment.
• T wave.

• Patient's details.
• Date and time.
• Condition of patient.

• 10 second rhythm strip - usually lead II:
-rate;
-rhythm:
§P wave;
§P-R interval.

Calculating ventricular rate
Eg. 1500 small squares = 1 minute.
R-R interval = 21 small squares.
1500/21 = 71 bpm.

Eg. irregular rate.
25 large squares = 5 seconds.
8 complexes in 25 large squares x 12 = 96 bpm.

Rate
• Tachycardia >100bpm.
• Bradycardia <50bpm. block =" P-R" i =" P-R" block =" No" fibrillation =" No">25% height of accompanying P wave;
-if wider than 1 small square;
-not seen if ischaemia damage does not involve entire thickness of ventricular wall.

Narrow complex tachycardia: impulse passes through AVN.
Broad complex tachycardia: impulse does not involve AVN.

Right bundle branch block
• Right ventricle activated belatedly by wave from left ventricle.
• Can be associated with right-sided cardiac problems:
-chronic lung disease;
-cardiomyopathy;
-atrial and ventricular septal defects.

Left bundle branch block
• Activity in left ventricle delayed.
• Usually indicates underlying cardiac pathology:
-coronary artery disease;
-acute MI etc.

ST segment
• Normal <3>

Module 2.01

The Gardener's Funeral.
29.8.06 - 8.9.06.

A new year, a new timetable. Ah, the joys of afternoon lectures and a ridiculously high attendance. Last? I don't think it will...