The Cardiovascular System

• Sympathetic 
  • Fight or flight
• Parasympathetic
  • Resting and digesting
• Alpha receptors
  • Coronary arterioles
  • Viscera, skin, brain
  • Erectile tissue
  • Salivary gland
• B1 receptors
  • SA node
  • Atrial muscle
  • AV node
  • Ventricular muscle
• B2 receptors
  • Arteriole muscle

• A variety of cardiac and/or vascular diseases that usually stem from atherosclerosis.
  • Coronary, peripheral or cerebral arteries. 
• Caused 47% of all deaths in Europe.
  • 38% of all deaths in women >75
  • 37% of all deaths in men >75
• Responsible for 27% of all deaths in the UK
  • 25% of all deaths in men >75
  • 17% of all deaths in women >75 
• Risk factors (modifiable or non-modifiable)
  • Smoking
  • Obesity
  • Diet
  • Stress
  • Lack of exercise
  • Genetics
  • Ageing

• Arterial disease in which atheroscleotic plaques slowly develop in the luminal walls.
  • Plaques are composed of a necrotic core (lipids and cholesterol) surrounded by fibrous tissue and smooth muscle cells.
• Clinical symptoms usually occur in the later stages when blood flow becomes obstructed. 

• Cholesterol can be absorbed from the diet or produced by the liver.
• Lipids and cholesterol are not water soluble so are transported in blood as lipoproteins.
• Chylomicrons
  • Formed by intestinal mucosal cells to transport dietary fatty acids and cholesterol
  • Into the plasma via the thoracic duct
• VLDL
  • Transport triglycerides
  • Acted on by capillary lipoprotein lipase
  • In adipose tissue and muscle
• LDL
  • Formed from VLDL once fatty acids have been extracted
  • Rich in cholesterol
  • High levels promote atherosclerosis
• HDL
  • Takes excess cholesterol from cells and lipoproteins to the liver

• Endothelial cell dysfunction/damage
  • Often occurs around the area of turbulant blood flow
  • Affects PGI2 and NO synthesis and adhesion molecule expression.
• Monocytes can adhere and migrate into the arterial wall and form macrophages.
• Endotheial cells and macrophages produce free radicals that oxidise LDL
• Macrophages take up oxidised LDL
  • Forming 'foam cells' which release inflammatory cytokines
  • Foam cells coalesce and form fatty streaks
• Endothelial cells, foam cells, activated platelets etc release growth factors
  • Causing development of smooth muscle and a fibrous cap of connective tissue, forming a plaque.
• Plaques can rupture forming a point for thrombus formation.
• Hyperlipidaemias
  • Involve either raised cholesterol or triglyceride levels or both.

• Risk factors
  • Elevated plasma LDL levels
  • Low HDL levels
  • Hypertension
  • Diabetes
  • Smoking
  • Obesity
  • Physical inactivity 
• Can lead to 
  • Angina
  • Myocardial infarctions
  • Strokes
  • Peripheral vascular diseases

• Hypercholesterolaemia
  • Initial treatment is diet control, followed by drug treatment. 
  • High cholesterol = >6.5mmol/L
• Risk factors
  • High sat fat intake
  • Smoking
  • Lack of exercise
  • High alcohol consumptopn
  • Genetics
• Estimated around 50% of adults have raised cholesterol (>5mmol/L)

• HMG CoA reductase inhibitors reversibly inhibit hepatic HMG CoA reductase which is a key enzyme in the synthesis of mevalonic acid, a precursor of cholesterol.
  • Simvastatin
  • Atorvastatin
  • Pravastatin
• Cholesterol is synthesised in the liver. 
  • To compensate for the presence of statins the liver expresses more HMG CoA reductase
    • Statins also induce an increase expression of hepatic LDL receptors
      • Increasing the livers uptake of LDL, increasing plasma cholesterol clearance.

• GI problems such as constipations, diarrhoea and flatulance are common
• Nausea
• Rashes
• Muscle soreness and Rhabdomyolysis
  • Thought to be caused by the affects that statins have on muscle cellular systems
    • Gene expression
    • Mitochondrial function
    • Membrane stability
  • Reversible either by reducing dose or stopping administration.
  • Kidney toxicity can occur due to build up of muscle contents. 
• Contraindications
  • Pregnancy and breastfeeding
    • Cholesterol is required in development
  • Liver disease
    • Extensively metabolised by cytochrome P450
      • Dose reduction needed when drugs or foods that inhibit liver coenzymes are taken
        • Calcium channel blockers, amiodarone and grapefruit juice.
• Administered at night to control the peak cholesterol synthesis that happens in the morning. 

• Reduce plasma triglycerides and LDL and increase HDL
• Thought to work by stimulating lipoprotein lipase
  • Reducing triglyceride content of VLDLs and chylomicrons
• They also stimulate hepatic LDL receptor expression
• Side effects
  • Intestinal disturbances
  • Myositis like syndrome (inflammatory muscular degeneration)

• Bile Acid Binding/ Basic Anion Exchange Resins
• Bind to intesitnal bile acids, preventing their reabsorption.
  • This promotes the conversion of cholesterol into bile acids
  • Increasing hepatic cholesterol demand
    • Which increases hepatic LDL receptor expression and activity, enhancing plasma LDL cholesterol clearance.
• Colestyramine
• Colestipol
• Colesevelam
• Side effects
  • Intestinal effects such as bloating, abdominal discomfort and diarrhoea
  • Can intefere with the absorption of fat soluble vitamins (ADEK) and other drugs
    • Valporate, cardiac glycosides, diuretics, tetracycline and thyroid hormones.
• Other drugs/vitamins should be taken one hour before this or 4-6 hours afterwards. 
• Contraindication of complete biliary obstruction.

• Inhibit hepatic VLDL formation
  • Lowering plasma triglyceride levels by 30-50%
  • This will reduce LDL production
    • Loweing cholesterol levels by 10-20%
  • HDL levels are stimulated
• Side effects
  • Flushing
  • Dizziness
  • Headaches
  • Palpitations
  • Nausea
  • Vomiting

• Inhibits cholesterol absorption in the intestine
• Is used in combination with dietary measures and statins
• Leads to a decrease in the amount of intestinal cholesterol delivered to the liver
  • Complementary mechanism of action to statins
• Side effects
  • GI disturbances
  • Hypersensitivity reactions
  • Hepatitis 
  • Pancreatitis 
  • Myopathy
  • Rhabdomylosis

• Elevated arterial blood pressure above the expected range (140/90 - 160/95 mmHg)
• 'Primary'/'Essential' HT
  • Unknown cause
  • Small increases in sympathetic activity increase cardiac output and peripheral resistance, increasing BP.
• 'Secondary' HT
  • Of known cause such as kidney or endocrine issues.
• Asymptomatic but associated with 
  • Reduced life expectancy
  • Left ventricular wall thickening
  • Atheroma
  • Coronary heart disease
  • Stroke
  • Peripheral vascular disease
• Screening for and treating high blood pressure is important in prevention.

• Risk factors
  • Genetics
  • Ageing
    • Blood vessels lose flexibility
  • Gender
    • Men upto 45 are more likely to have hypertension than women.
    • Equal probability from 45-64
    • Women over 64 are more likely to have hypertension than men.
  • Lack of exercise
  • Poor diet
  • Obesity
  • Overconsumption of alcohol 
  • Smoking 
  • Stress
• Affects more than 1 in 4 adults, around 5 million are unaware they have it
• Arteriosclerosis involves the symmetrical thickening of the muscular medial layer of artery walls.
  • Usually in response to hypertension and can be reversed.

• Reductions in body weight, salt and alcohol consumption
• Smoking cessation 
• Step 1
  • Asian and Caucasian patients <55 are likely to have high renin HT
    • Drugs affecting the renin angiotensin system are a first choice
      • ACE inhibitors
  • Older asian, caucasian and any age afro-caribbean patients usually have low renin HT
    • Calcium channel blocker is a first choice
• Step 2
  • Combining one drug from each group if HT worsens 
• Step 3
  • Triple therapy where 3 drugs are used
• Step 4
  • Other agents such as spironolactone may be used. 
  • Combining beta blockers and diuretics may aggravate diabetes/
• Drugs that lower BP can be classified as vasodilators, beta blockers, centrally acting drugs and diuretics. 

• The renin angiotensin system is a mechanism that tries to maintain BP and sodium ion concentration.
• Renin is an enzyme
  • Released from the juxtaglomerular apparatus of kidneys
    • In response to a falling sodium ion concentration in distal convoluted tubules and falling renal perfusion pressure. 
  • Acts on angiotensin to form angiotensin I
    • An inactive precursor always present in the blood
    • As angiotensin I passes through the lungs, its converted to angiotensin II by the enzyme ACE.
      • Angiotensin II is a potent vasoconstricting octapeptide, which increases blood pressure. 
        • Also causes aldosterone to be released by the adrenal glands. 
          • Aldosterone is a mineralocorticoid that increases renal sodium ion reabsorption.
          • Water follows salt, so this results in increased retention of water, and so increased blood volume.
• If the RAS is inappropriately active, it can cause hypertension.
• Drugs that reduce angiotensin II production are used.
  • Captopril
  • Enalapril (prodrug)
  • Lisinopril
  • Ramipril

• Have little effect in normotensive individuals
• They affect capacitance and resistance vessels, decreasing blood pressure and cardiac workload
• Generally don't affect cardiovascular reflexes.
• Side effects
  • First dose hypertension
    • To overcome this patients are advised to take their first dose before bed so that if their BP does drop they are lying down or asleep.
  • Dry cough
    • Due to the accumulation of bradykin.
      • Peptide that can cause vasodilation and signs and symptoms of inflammation and pain.
      • Normally metabolised by kininases, which are similar to ACE.
      • ACE inhibitors can inihibit the breakdown of bradykin, which can accumulate around the lungs and cause a dry cough. 
  • Angioedema
    • Due to bradykin accumulation
    • Rare

• Potassium sparing diuretics
  • Potassium levels may have to be monitored to avoid hyperkalaemia
• Bilateral renovascular disease
  • Renal failure may occur due to a lowered afferent arteriolar tone reducing glomerular filtration
• Pregnancy
  • Avoid unless essential
  • May adversely affect foetal blood pressure and renal function
  • Reduced amounts of amniotic fluid and skill defects in neonate have also been reported.
• Blood pressure, potassium levels and renal function should all be monitored.

• Sometimes the coughing side effect of ACE inhibitors can become too much.
• The RAS can be affecred by antagonising AT1 receptors.
  • Although angiotensin II is still being produced it is not acting on it's receptors to produce an effect. 
  • Since kinases are not affected by ARAs they will still be active and bradykin will be broken down.
• Losartan
• Valsartan
• Candesartan
• ACE inhibitors are used first are they are effecive, less expensive and most patients can tolerate the side effects
• Side effects
  • Orthostatic hypertension, dizziness, headache, fatigue, hyperkalaemia and rash
• Cautions and contraindications
  • Renal artery stenosis, pregnancy, breastfeeding, aortic stenosis and potassium sparing diuretics.

• Vascular smooth muscle tone is determined by free intracellular calcium ion concentration.
• Increase sympathetic tone results in vascular alpha 1 adrenoceptor activation.
  • This stimulates phospholipase C and results in the production of the second messenger inositol triphosphate
    • This triggers calcium ion release from sarcoplasmic reticulum stores.
    • Calcium ions then bind to calmodulin which activates kinase to phosphorylate MLC
      • The enables smooth muscle to contract and vause vasoconstriction, which increases blood pressure.
• Voltage operated L-type calcium ion channels in the membranes of vascular smooth muscle cells
  • Causing more calcium ions to enter, increasing vascular tone.
• Calcium channel blockers can block these channels, reducing the amount of free cytoplasmic calcium ions.
  • Fewer calcium ions can interact with calmodulin, which reduces vascular tone.
  • This causes peripheral resistance to decrease, which lowers BP.

• Dihydropyridine type calcium ion channel blockers selectively affect vascular channels and can cause a generalised arterial vasodilation, but they have no cardiac actions.
  • Nifedipine
  • Felodipine (given od)
  • Amlodipine (given od)
• Veraoamil and diltiazem
  • Selectively affect cardial type L channels
    • Slows SA and AV node conduction, slowing heart rate
      • Shortens the plateau for cardiac cell muscle action potentials and exhibiting a negative ionotropic and chronotropic effect.
    • This makes them useful for ischaemic heart disease (angina, conduction disorders)
  • Diltazem tends to have an immediate effect
    • Acting on both peripheral arteries and the heart itself to reduce blood pressure.
  • Verapamil is more useful for it's predominant effects on the heart
    • Mostly used for arrhythmias or angina
• Slow heart rate and reduce the force of contraction.

• Nifedipine and amlodipine can cause hypotension if blood vessels dilate too much.
  • This can cause headaches, dizziness and flushing.
  • Can also cause reflex tachycardia as the heart will try to beat faster to increase blood pressure.
  • Peripheral oedema can be a problem as arteries dilate more than veins.
    • Arteries can now carry a larger volume of blood, but since the carrying capacity of veins isn't also increased, fluid may leak into tissues from capillary beds.
• Verapamil and diltiazem
  • Can cause hypotension
    • Due to direct action on the heart caused by reduced calcium ion conductance.
      • This will result in bradycardia and signs of heart block.
      • Congestive heart failure may be precipitated or exacerbated.
    • Verapamil commonly causes constipation
• Nimodipine
  • Commonly acts on cerebral arteries
  • Is used in the prevention and treatment of vascular spasm
• Susceptible to interactions due to metabolism by cytochrome P enzymes.
  • Antibacterials, antifungals, anticonvulsants, statins, theophylline and grapefruit juice.
  • B blockers should be used cautiously with diltiazem and not at all with verapamil.

• Inhibit a1 adrenoceptor mediated vasoconstriction
  • By antagonising vascular alpha 1 adrenoceptors
  • Results in vasodilation, reduced peripheral resistance and a fall in blood pressure.
• Prazosin
• Doxazosin (long acting)
• Administered orally.
• Side effects
  • Postural hypertension
    • Due to an impaired arteriolar vasoconstriction reflex upon standing up.
    • Blood delivery to the brain can be temporarily impaired as it may pool in the lower portion of the body.
• Additional effects
  • Improve symptoms of prostatism
    • Reducing bladder and prostate resistance, increasing urinary flow
  • Doxazosin slightly improves blood lipid profile
    • By lowering LDL cholesterol, VLDL and triglyceride levels
    • Raises HDL levels

• Reserved for hypertension that is resistant to other treatments. 
• Mechanism is unknown.
• May intefere with vascular smooth muscle inositol triphosphate
  • Reducing vascular resistance amd blood pressure.
• Can be given by oral or iv administration
• Side effects
  • Reflex tachycardia
  • Angina provocation
  • Headaches
  • Fluid retention
  • Idiopathic systemic lupus erythematosus. 

• Orally administered
• Potent vasodilator
• Only used for HT resistant to other drugs.
• Opens vasular smooth muscle potassium ion ATP channels
  • Causes hyperpolarisation 
  • Affected smooth muscle cells now find it hardeer to depolarise
    • This reduces calcium ion entry through L type channels
    • Causing reduced smooth muscle tone and vasodilation
• Side effects
  • Hirsutism
  • Sodium ion and water retention
  • Tachycardia
  • Cardiotoxicity
• Due to hirsutism, topical lotions are available for treating androgenic alopecia.

• Oral and iv administration
• Used to treat patients with resistant hypertension
• Acute mechinism
  • Cardiac output = heart rate x stroke volume
  • Sympathetic division of the autonomic nervous system activates cardiac B1 adrenoceptors
    • Antagonising these receptors will cause heart rate and cardiac output to fall, so blood pressure will be lowered.
    • With time, cardiac output begins to recover but blood pressure may still remain low due to a mechanism which may cause
      • Peripheral vascular resistance to be 'reset' at a lower level
      • Reduced renal renin release
      • Reduced sympathetic outflow from the CNS
• They vary in their receptor selectivity and lipid solubility.

• Non-selective
  • Propranolol
    • Wide spread B1-B2 blockade
• Antagonists
  • More selective for B1 adrenoceptors and are called cardioselective
  • Atenolol
  • Bisoprolol 
  • Metoprolol
• Carvediol is capable of producing non selective beta and alpha 1 blockade.
• Metoprolol and propranolol are more lipid soluble
  • Can penetrate the BBB more readily
• Atenolol, celiprolol and nadolol are more water soluble
  • Amide group in atenolol is responsible
• Decrease the heart rate and cardiac contractility, therefore decrease myocardial oxygen demand.
• Can be used in stable and unstable angina
• Avoided in prinzmetals angina as they can increase the risk of coronary spasms.

• Bronchospasm
  • Asthmatics should avoid
  • Can be used cautiously with lung function monitoring in patients with sever obstructive lung diseases.
• Fatigue
  • Likely caused by reduced cardiac output and reduced muscle perfusion
• Cold extremities
  • Loss of b adrenoceptor mediated vasodilatation, still occurs with cardioselective blockers.
• Sleep disturbances
  • More lipid soluble beta blockers can cross the BBB, intefering with dreams
  • Depression can also occur
• Male impotence
  • Centrally mediated
  • More common with lipid soluble beta blockers that cross the BBB
• Bradycardia and cardiac depression
  • Heart block can occur in patients being treated with antiarrhythmic drugs that impair cardiac conduction

• Non-selective beta blockers shouldn't be given to asthmatics due to potential triggering of bronchoconstriction
  • Can intefere with drugs such as salbutamol
• Caution required with cardioselective beta blockers as they lose their selectivity at higher doses.
• Hypoglycaemia
  • Glucose is released in response to adrenaline and the tachycardia symptom can cause diabetics to be warned to consume carbs.
    • Beta blockers blunt this response so hypo's may go unnoticed. 
  • Cardioselective beta blockers may be better as hepatic glucose release is mediated by B2 adrenoceptors.
  • Also impair glycaemic control by affecting carbohydrate metabolism.
• Peripheral vascular disease (PVD)
  • May worsen PVD by a combination of decreased cardiac output and unopposed alpha adrenergic drive causing vasoconstriction.

• Centrally acting a2 adrenoceptor agonists
  • Methydopa (oral)
    • Can be used to treat hypertension during pregnancy
  • Clonidine (oral and IV)
  • Moxonidine (oral)
  • Stimulate presynaptic a2 adrenoceptors in the vasomotor centre of the medulla oblongata
    • Reduces noradrenaline release, reducing sympathetic outflow and causing vasodilation.
    • Reduce heart rate and cardiac output.
• Side effects
  • Orthostatic hypotension

• Increase the volume of urine produced
• The water excreted will come from the blood, so circulatory volume will decrease.
• Can be used in the treatment of various cardiovascular problems.
  • Hypertension, heart failure, oedema, renal disease, glaucoma
• Oedema occurs when large volumes of blood accumulate in veins

• Thiazides
  • Bendroflumethiazide
  • Cyclopenthiazide
• Thiazide like diuretics
  • Indapamide
  • Chlortalidone
• Duration of action of 12-24 hours. 
• Usually administered in the morning to avoid sleep inteference caused by diuresis.
• Inhibit sodium ion reabsorption from the initial segment of distal convoluted tubules
• Also have a direct vasodilatory effect.
  • This can enhance and sustain their antihypertensive effect
  • May result from the reduced entry of calcium ions into vascular smooth muscle as a consquence of sodium ion depletion.
• Sodium chloride reabsorption is blocked by thiazides inhibiting the luminal symporter.
  • More sodium chloride remains in the filtrate, meaning more water will be excreted/

• Metabolic side effects
  • Increased serum cholesterol levels
  • Impaired glucose tollerance
  • Hyperuricaemia
  • Hypokalaemia
• Due to these effects they are no longer first line agents.
• Can be used in mild chronic heart failure
  • But are less potent as they work in the cortical diluting segment of the distal tubule where only 10% of sodium is reabsorbed.
  • They're described as 'low ceiling' agents as maximum diuresus occurs at low doses and does not increase with increasing dosage.
• Ineffective in moderate to severe renal impairment.

• Work in a similar way to Thiazides.
• Inhibit salt reabsorption in the Henle
  • By inhibiting sodium, potassium and chloride ion cotransport
  • This section has a very high capacity for reabsorbing salt, making these diuretics very potent.
• Mostly used to control oedematous symptoms
• Can be used to reduce peripheral and pulmonary oedema in heart failure.
  • Can also be used during renal failure.
• Not routinely used for HT but can be if a patient doesn't respond to thiazides.
• 'High ceiling' agents
  • The blockade of sodium reabsorption continues as dose is increased. 
• Optimum response is obtained by dividing the dosage.
• Higher doses are required in renal impairment.
  • Should not be administered too quickly to prevent ototoxicity.
• Can be administered orally, intramuscularly and intravenously.
  • Intravenous is commonly used in an emergency for fast drug delivery.
    • Produces a rapid effect in patients with heart failure who develop congestion in the GI tract which impairs the absorption of orally administered drugs. 

• Metabolic side effects
  • Hypokalaemia 
  • Hyperuriceamia
  • Hyperglyceamia
  • Hypotension
• Caution is needed with high doses as they may result in 
  • Dehydration
  • Electrolyte imbalances
  • Deafness
• Contraindications
  • Hypokalaemia 
  • Hyponatraemia
  • Anuria
• Caution is needed in patients taking cardiac glycosides
  • Due to the risk of hypokalaemia or hyponatraemia potentiating the glycosides effect and causing toxicity.

• Amiloride, triamterene, aldosterone receptor antagonists, spironolactone and eplerenone.
  • Not very effective when used alone.
  • Traditionally combined with thiazide or loop diuretics in order to prevent hypokalaemia.
  • Also used in the management of heart failure.          
• Work by reducing sodium ion reabsorption
  • This reduced the need for potassium or hydrogen ion exchange.
  • Since more potassium ions will now be retained, this prevents hypokalaemia.
• Decrease luminal membrane permeability by blocking sodium channels
  • Amiloride
  • Triamterene
• Competitively antagonise aldosterone's cytoplasmic receptor.

• Side effects
  • Hyperkalaemia
  • Hyponatraemia
  • GI distrubances
• Spironolactone and eplerenone may also cause gynaecomastia.
• Cautions
  • In combination with ACE inhibitors or ARAs carry the risk of causing hyperkalaemia
    • ACE inhibitors and ARAs reduce aldosterone secretion, meaning the latter part of the kidney is already being under stimulated by aldosterone.
    • Potassium sparing diuretics will add to this effect.
  • Should not be used with potassium supplements. 
• Combination products
  • Not usually needed in HT unless hypokalaemia is a problem.
  • Prefereable to prescribe each drug separately to allow for dose titration.
  • Combination products can be used if compliance may be a problem.
    • Co-amilofruse (amiloride and furosemide) 
      • Potassium sparing diuretic and loop diuretic.

• Risk factors
  • HT, high cholesterol, genetics, diabetes, obesity, lack of exercise, diet, smoking, ageing, gender
    • Men are more at risk than pre-menopausal women
    • After menopause women and men have similar risks.
• Leading cause of death worldwide.
• 70,000 deaths per year in the UK
• 2.3 million in the UK living with it
  • 60% male
• Most deaths due to this are a result of myocardial infarction

• Pain felt due to a disturbed blood flow to the myocardium
  • Pain is due to tissue release of potassium and hydrogen ions and adenosine
    • Adenosine accumulates in poorly perfused tissue.
• Symptoms
  • Range from mild to severe pain
  • Sweating
  • Fear
  • Pain radiates from the chest to the neck, jaw or down the arm
  • Often described as a heavy 'gripping' or 'crushing' pain.

• Classical stable/exertional angina
  • Predictable 
  • Coronary blood supply adequite at rest but is unable to meet demands during exercise or stress.
• Unstable angina
  • Likely to have a rapid onset
  • Pain occuring at rest and/or with increasing severity or frequency
  • Unpredictable symptoms that last longer than those of stable angina
  • May not respond to vasodilators
  • Caused by atherosclerotic plaques rupturing and platelets adhering, forming thrombi.
• Prinzmetal's variant angina
  • Caused by a coronary artery spazm
  • Often around the site of atheromatous lesions.
  • No obvious provocations and occurs mostly in the morning or at night
• Decubitus angina
  • Occurs when lying down
  • Associated with heart failure as blood redistributes to increase central blood volume.
• Nocturnal angina usually occurs in severe coronary artery disease and maybe worsened by dreams

• Treatment of angina attacks
• Reducing the frequency of angina attacks.
• Effect is to produce a general vasodilation via several mechanisms
  • Arteriolar vasodilation
    • Reduces peripheral resistance and cardiac afterload.
  • Coronary artery and collateral vessel vasodilation
    • Improves blood supply to cardiac tissue
  • Venodilation
    • Causing venuous pooling of blood
    • Less blood is returned to the heart, reducing cardiac preloading, reducing workload.
• An increase in free intracellular calcium ion concentration causes vascular smooth muscle cells to contract
  • NO causes a fall in calcium ion concentration, so blood vessels relax and dilate.
• NO stimulated guanylyl cyclase, forming cGMP
  • cGMP causes free intracellular calcium ions to be taken up into the sarcoplasmic reticulum.
    • This means fewer calcium ions are available to interact with calmodiulin, meaning smooth muscles relax and vessels dilate. 

• GTN is completely metabolised on first pass metabolism
• 0% bioavailablity when taken orally.
• Adminstered sublingually or as a spray
• Is effective for ~30 minutes
• IV injections and infusions are also available
• GTN is decomposed in the blood stream to give NO.

• Slows the heart rate
• Can be used as an alternative to beta blockers
• Works by affecting the pacemaker current in the SAN.
  • The cation channel that causes the current is activated by negative membrane potentials early on in diastole
    • This allows a mix of sodium and potassium ions to diffuse into the cell, causing an inward directed current, the pacemaker (If) current.
• Slows down depolarisation, reducing heart rate.
  • This also allows more time for blood to flow through the myocardium.
• Does not affect cardiac contractability unlike beta blockers and calcium channel blockers.

• Inhibits later inward sodium ion currents in cardiac muscle
  • Reduces intracellular calcium ion concentration/
  • Has a negative ionotropic effect
    • This reduces cardiac oxygen demand,
• Does not affect heart rate
• Following phase 0 of a cardiac action potential, most sodium channels are inactivated
  • A few do not close or close then reopen.
    • This occurs throught the plateau phase
    • Referred to as the 'late' sodium ion current.

• Can act as a nitrovasodilator
• By being a nitric oxide donor it can stimulate guanylate cyclase
  • This can activate calcium ion pumps on the sarcolemma to reduce intracellular calcium ion concentration
    • This causes smooth muscle relaxation and coronary vasodilation.
• Also activates potassium ion ATP channels
  • Which may provide a protective effect for the heart against ischaemia.

• Demonstrates that if a resting muscle is stretched, when it goes to contract, it will contract with greater force.
  • This increases the muscles workload.
• Preload - the volume of blood present in the chambers of the heart at the end of diastole
• Afterload - the volume of blood present in the chambers of the heart at the end of systole.
  • Largely determined by the resistance against which the heart has to pump to eject blood.

 SV ∝ Contractility x End Diastolic Volume

                     Peripheral Resistance

• Cardiac output is determined by both stroke volume and heart rate

CO = HR x SV

• Occurs when a coronary artery has become occluded (blocked)
• Death is common either due to cardiac mechanical failure or from dysrhythmia.
• If cardiac oxygen supply remains low following an event, cardiac myocyte apoptosis occurs.
• Therapeutic interventions are aimed at preventing or reducing the extent of isachaemic damage or the consequences. 
• Thrombotic antiplatelet drugs
  • To limit the extent or recurrance of thrombus formation
• ACE inhibitors
  • To reduce cardiac workload and prevent the development of vetricular systolic dysfunction.
• Beta adrenoceptor antagonists
  • Reduce sympathetic activity and dysrhythmias
• Strong opiods
  • Reduce pain and the fight or flight response
  • Given with antiemetics
• Insulin
  • In patients with high blood sugar
  • Evidence this improves outcome.

• Insufficient cardiac output produced, resulting in inadequite delivery of blood to the tissues of the body to meet its physiological needs.
• Can result from any structural or functional cardiac disorder that impairs the ability of the heart to function as a pump to support sufficient circulation.
• Characterised by
  • Reduced exercise tolerance 
  • Breathlessness
• Symptoms
  • Exertional dyspnoea, orthopnoea, PND, fatigue and ankle swelling.
• Heart failure with preserved ejection fraction (HFPEF)
  • Describes patients with no evidence of left vetricular systolic dysfunction (LVSD)
• A chronic condition but patients can experience rapid onset or a change in signs and symptoms.
• Systolic failure occurs when the left ventricle cannot eject adequitely.
• Diastolic failure occurs when the ventricle is slow to relax
• LV failure causes elevated pulmonary venous pressure and pulmonary congestion
• RV failure causes elevated systemic venous pressure and peripheral congestion
• Congestive means both sides have failed together, right usually follows left.

• Systolic
  • Caused by coronary artery disease usually following MI.
  • The left ventricle is dilated and fails to contract normally.
• Diastollic
  • Usually due to hypertension where there is left ventricular hypertrophy and failure of ventricular relaxation.
• Right sided
  • Usually secondary to left sided
  • Often associated with lung issues.
  • Symptoms include fatigue, breathlessness, anorexia and nausea
• Left sided
  • Heart disease, systemic hypertension, mitral/aortic valve disease and cardiomyopathies.
  • Symptoms include fatigue, exertional dyspnoea, orthopnoea and PND

• Congestive heart failure
• Arrises when right side failure is a result of pre existing left side failure.
• 1-2% prevelence in the western world
• 5-10 per 1000 people per year
• Prevelence predicted to increase as comorbidities rise and people begin living longer with the disease.
• Uncommon in patients under 50
• Over 50, prevelence increases with age.
• More common in men in younger age groups
  • As the most common cause, CHD, occurs earlier in men.
• Prevelence is equal between sexes in the elderly
• Cause of 5% of acute hospital admissions
• 50% of sufferers die within 4 years of a diagnosis.
• Main causes of death are progressive pump failure, sudden cardiac death and recurrent MI.

• Most common cause is the function deterioration of the heart or damage/loss of heart muscle.
• Other causes
  • Ischaemia 
  • Increased vascular resistance with hypertension
  • Development of a sustained tachyarrythmia.
  • Hyperthyroidism
  • Severe anaemia
• Most common cause of MI
  • Initiating cause in 70% of HF patients
  • Valve disease/dysfunction and cardiomyopathies account for another 10% each
• Management of underlying causes can alleviate symptoms.
• Mechanical valve defects may be treated with surgical insertion of prosthetic valves.
• Medicines such as cytotoxic, antiarrythmic agents and alcohol are also implicated.

• The failing heart tries to maintain cardiac output by increasing preload.
  • By increasing venous tone an retaining sodium and hydrogen ions.
• Resistance to filling and/or an inability to fully eject the preload results in pulmonary oedema.
• Increase preload initially causes the heart to dilate abnormally
  • Over time this further deminishes the ventricles ability to recoil.
  • Over time, and in response to hypertension, myocardial hypertrophy occurs.
    • Whist this initially helps, the increased mass ultimately increases workload and oxygen consumption.
• Low cardiac output results in a reflex sympathetic discharge and increased sympathetic tone
  • Exposing the heart to catecholamines.
  • This increases heart rate and force of contraction
  • Increases vascular resistance in order to maintain blood pressure.

• If blood pressure cannot be maintained and they kidneys are affected, the RAAS is activated.
  • Ths stimulates renin secretion and increases angiotensin II and aldosterone levels.
    • The resulting sodium ion and water retention will increase circulatory volume and blood pressue
    • Can also cause oedema formation and increase cardiac preload.
    • Raised levels of angiotensin II increase peripheral resistance, increasing afterload.
  • Noradrenaline stores in the heart depleat with time so the heart relies on circulatory catecholamines.
    • This results in a reduction of beta receptors in the heart.
• Natriuretic peptides act as homeostatic signals to maintain stable blood pressure
  • Also prevent excess sodium and water retention.
• These adaptations will initially maintain cardiac output
  • However, since the heart is already failing, the health of the heart is already in a decline and this adds to it.
  • Can lead to problems such as abnormal ventricular dilation and an increased morbidity and mortality.

• Can be attributed to the side of the heart affected and also a consequence of inadequite perfusion.
• In LVF, a build up of pressure in the pulmonary veins results in pulmonay oedema
  • Breathlessness, paroxysmal nocturnal dyspnoea (PND) and orthopnoea.
  • Can often complain of gaspin for fresh air and needing to open windows.
  • Can develop a frothy sputum which may be tinted with blood
• In RVF, the right side of the heart is unable to pump blood effectively and blood backs up into peripheral veins
  • Peripheral oedema that commonly occurs in the legs due to gravity.
    • Can occur in the gut and cause accumulation of fluid in the peritoneal cavity (ascites) and anorexia.
    • Can also occur in the liver causing tenderness and heaptomegaly.
  • Raised jugular venous pressure (JVP)
• Consequences of reduced peripheral perfusion
  • Fatigue, confusion, pallor, clod hands and feet and renal impairment/failure

• Ace inhibitors
• Beta blockers
  • Can protect a failing heart from overstimulation by the sympathetic nervous system.
  • Reduce cardiac output so can worsen symptoms of heart failure.
    • Started on low doses and titrated up to effective doses.
• Diuretics
  • Reduce the symptoms but don't prolong survival
• Aldosterone antagonists
  • Used in moderate to severe cases to reduce progression.

• Digoxin
  • Stimulates vagal activity which stimulates muscarinic receptors, slowing heart rate, atrioventricular conductance and increases the refractory period of the AV node.
• Digitoxin
  • Competes with potassium ions and stops the potassium sodium ion pump from working.
  • This reduces the sodium ion diffusion gradient, so fewer sodium ions enter the cell, meaning they are exchanged for fewer calcium ions.
  • More intracellular calcium ions cause a positive inotropic effect.
    • Reduces the symptoms of HF but makes the damaged heart work harder. 
• Normally, calcium ions are pumped out of myocardial cells which helps them to relac for diastole.
  • This is done via sodium calcium ion pumps.
• As sodium replaces calcium in the cell, due to the initially low sodium content, calcium ions are pumped out.
  • The low sodium content is caused by sodium potassium ion pumps.
• At toxic doses the increased intracellular calcium ion concentration opens potassium channels, increasing potassium conductance.
  • This shortens cardiac refractory periods, leading to ectopic beats and arrhythmias.
• Have a narrow therapeutic window, arrythmias can occur at twice the therapeutic concentration.
• Side effects include anorexia, nausea, vomiting and diarrhoea due to affecting gut smooth muscle and activating the CTZ.

• Sympathomimetic drug that stimulates alpha 1 adrenoceptors
  • This causes the activation of adenylate cyclase, which increases intracellular cAMP levels, which then activates protein kinase A to phosphorylate L-type calcium ion channels.
    • This increases their readiness to open, increasing calcium ion influx.
• It also stimulates vascular beta 2 adrenoreceptors, causing vasodilation.
• Administered by IV infusion in acute heart failure.
• Does not seem to increase mortality.
• Requires monitoring of blood pressure and heart rate.
• Usually given in a critical care setting
  • Can be given on coronary care units.

Drug

Precautions

ACE inhibitors/ARA: captopril, enalapril, ramipril, candesartan, valsartan, losartan

Monitor renal function, potassium levels and blood pressure. Risk of first dose hypotension

b-blockers: bisoprolol, carvedilol, nebivolol

Airway diseases and/or bradyarrhythmias, peripheral vascular disease. Avoid in acute HF until stable. Caution in diabetic patients as can mask the signs of hypoglycaemia.

Diuretics: furosemide, bumetanide, bendroflumethiazide, metolazone

Monitor renal function and check for low K^+, Na⁺ or Mg²⁺ levels.

Aldosterone antagonists: spironolactone, eplerenone

Monitor renal function and check for high K⁺ and gynaecomastia.

Cardiac glycosides: digoxin

Narrow therapeutic index. Caution in renal impairment, conduction disease and if on amiodarone. Bioavailability varies between formulations requiring dose adjustments to be made when changing formulations

Vasodilators: isosorbide dinitrate, hydralazine (these may be used in combination to reduce preload and afterload when ACE inhibitors are contra indicated e.g. due to hyperkalaemia or renal artery stenosis).

Monitor blood pressure

• Rhythm is normally controlled by the SAN which is governed by the autonomic nervous system.
  • SAN causes depolarization in surrounding tissue and the AVN.
• Arrhythmia can result from disturbances to depolarization, generation or conduction.
• Symptoms include
  • Palpitations, chest pain, breathlessness 
• They can occur intermittently or continuously
• Can develop in healthy hearts but is more often a result of heart disease.
• Two main classes:
  • Bradyarrhythmias - <60 bpm
    • Often asymptomatic
    • May occur as a result of increased vagal tone or heart block.
  • Tachyarrhythmias - >100 bpm
    • More symptoms tend to occur when arrhythmia is fast and sustained.
• Risk factors include heart failure, myocardial infarction, heart valve disease, endocarditis, recent heart surgery.
• Atrial fibrillation is usually more common in patients with hypertension or high alcohol consumption.
• Arrhythmias poses a risk due to the development of thrombi caused by stasis of blood in the chambers of the heart.
  • Clots can then move to cerebral arteries and cause ischaemic stroke.
• Patients with AF will be assessed and may be given an anticoagulent.

• Accelerated automaticity
  • Membrane depolarisation of cardiac cells is faster (occurs earlier) than normal so phase 2 is longer.
• Triggered activity
  • Myocardial damage results in oscilations of membrane potentials 'after depolarizations' which can reach threshold potentials and cause depolarisation.
• Re-entry
  • Normally as an action potential enters a ring of tissue it will split into two and travel around both sides of the ring and join up again at the exit
  • If an area of the myocardium us damaged it might not conduct normally but instead will conduct slowly or in one direction only.
    • Therefore by the time the action potential has passed though the damaged tissue, the surrounding tissue has recovered and can contract again which will result 
• Long term management 
  • Antiarrhythmic drug therapy, ablation therapy and medical device therapy.

• Some antiarrhythmic drugs have local anaesthetic activity
  • They block voltage-dependent sodium ion channels.
  • Others may block other ion channels.
    • This means these drugs can decrease pacemaker automaticity and increase refractory periods of atrial, purkinje and ventricular fibres.
• Class I drugs - use-dependent sodium ion channel blockers
  • Reduce the entry of sodium ions. 
  • Bind to either open or refractory channels
  • Use dependent means selective action at channels opening with high frequencies.
  • They delay the return of an activated channel back to it's resting state, so a second excitation following rapidly after an initial one will find more sodium ion channels unavailable. 
• Class IA
  • Block open voltage dependent sodium ion channels.
  • This slows down phase 0 of the cardiac action potential and lengthens the refractory period. 

• Class IB drugs (lidocaine)
  • Block inactivated voltage dependent sodium ion channels
  • Can treat ventricular arrhythmias following a myocardial infarction
  • In normal cardiac tissue they have little effect as it rapidly dissociates from sodium channels. 
    • In ischaemic areas membrane potentials are unstable and arrhythmias will inactivate many sodium ion channels.
    • Dissociation from channels is rapid to allow normal rates of firing.
  • They reduce the rate of rise for phase 0, shortening the action potential and slow impulse conduction.
• Class IC drugs (flecainide)
  • Dissociate very slowly from sodium channels.
  • Strongly depresses myocardial conduction 
  • Mainly used in the prophylaxis of atrial fibrilation
  • Reduces the rate of rise of phase 0 but has not effect on action potential duration.

• Class II (Beta blockers)
  • Reduce the risks of sudden death after myocardial infarction.
  • Can be used to treat arrhythmias associated with stress in which there is an increase in adrenergic activity.
  • Predominant action is on the SAN where they slow heart rate.
• Class III (amiodarone and sotalol)
  • Slow the repolarisation phase and increase action potential and refractory periods. 
• Class IV (Calcium ion channel antagonists)
  • Shorten phase two of the action potential
  • Verapamil blocks L type calcium ion channels and is also effective in treating the SAN, where conduction is dependent on calcium ion spikes. 
• Adenosine
  • Opens acetylcholine sensitive potassium ion channels by binding to A1 receptors.
    • The resulting hyperpolarisation in the AVN slows nodal conduction.
  • Has a short half life (8-10 seconds) so IV injections are used to treat acute supraventricular tachycardia.

• Amiodarone blocks sodium, potassium and calcium ion channels and antagonises alpha and beta adrenoceptors
• Has a long half life and large volume of distribution, meaning a loading dose is needed to reach a steady state plasma concentration in long term use. 
• An IV infusion can be used to provide an immediate effect where acute treatment is required, but ECG monitoring must be done.
  • Should be dissolved in dextrose solution rather than saline.
    • The use of saline can precipitate the hydrophobic molecule by salting out, meaning the salt will dissolve in favour of the hydrophobic organic molecule.
• Contains iodine which can result in the development of thyroid disorders so thyroid function must be continuously monitored.
  • Similar in structure to thyroid hormones. 
• Patients on it are susceptable to phototoxic skin reactions so must be told to shield from strong sunlight and use sun screens.
• Corneal microdeposits may cause glare which can affect night time driving and there is a rare risk of optic neuritis which can result in blindness.
• Other reactions sich as pneumonitis and hepatitis may occur.
  • Should be advised to report any new or progressive cough and shortness of breath
  • Should also have routine liver fucntion tests.