What is blood pressure?

Equation

Is the pressure exerted on the walls of a blood vessel

BP= CO x PVR

Is the maximum pressure exerted by the blood against the artery walls. Corresponds to the contraction of the ventricles i.e systole.

Two Factors that regulate BP:

• Short term regulation: by nervous system and bloodborne hormones (by changing CO and PVR)
• Long term regulation: Alters blood volume via the kidney (RAAS system)

Brain helps to regulate BP through cardiovascular centre (cardioaccelerattory and cardioinhibitory centres) and the vasomotor centre (controls diameter of blood vessels).

Cardiovascular centre activity is modified by:

• Baroreceptors: detect changes in arterial pressure and stretch
• Chemoreceptors: detect changes in blood level of O₂, CO₂, H⁺,
• Higher brain centres: redistribution of bloodflow during excercise, changes of body temperature

• if pressure is high, Baroreceptors in carotid sinuses and aortic arch are stimulated. Increase impulses from baroreceptors to stimulate cardioinhibitory centre (inhibit cardioacceleratory centre) and inhibit the vasomoter.
• This leads to a decrease in sympathetic stimulation consequently reduction in HR, contractility and CO. Also a reduction in vasomotor fibres stimulate vasodilation causing a decrease in PVR and BP IS REDUCED

• Decreased number of impulses from the baroreceptors in the carotid sinus and aortic arch. This activates the cardio acceleratory centre (inhibits the inhibitory centre) and stimulates the vasomotor centre.
• This increases sympathetic stimulation. consequently incresing HR, Contractilitity and CO. The vasomotor fibres stimulate vasoconstriction causing an increase in PVR which causes an increase in BP

They detect changes in blood O₂, CO₂ and H⁺. If CO₂ levels increase or pH or O₂ falls, this increases impulses to cardioacceleratory centre which then increase CO.

They also send impulses tl vasomotor centre which causes vasoconstriction increase PVR.

This results in increase BP. This also speed up the return of blood to the heart and lungs.

Work via 4 different mechanisms to affect peripheral resistance and blood volume.

• adrenaline, noradrenaline
• Atrial natiretic Peptide
• Antidiuretic Hormone
• Angiotensin

The adrenal glans release adrenaline and noradrenaline when stressed.

• These enhance the sympathetic response by increasing HR and contractility, therefore increasing CO and therefore increasing BP.
• They also cause generalised Vasoconstriction, thus increase PVR and increasing BP

• Renin released from the juxtaglomerular apparatues in the kidney when there is a decrease in serum Na⁺ Concentration or renal perfusion.
• Renin acts on Angiotensinogen to release angiotensin 1
• Angiotensin 1 converts to Angiotensin 2 by angiotensin converting enzyme, ACE.
• Angiotensin 2 causes a potent rise in BP via:

• Pressor effects: Vasoconstriction, stimulation of noradrenergic sypathetic nervous system
• Volume effects: Stimulation of the adrenal glands to release aldosterone to promote salt and water retention.

Its done via a volume-pressure adaptive mechanism.

When BP drops Na and water is retained this leads to an increase in blood plasma volume increase in CO and BP.

When BP rises above normal there is increased renal excretion of Na and water and sp leads to plasma volume decreasing and a decrease in CO and Decrease in BP.

How do Thiazide diuretics Work in the treatment of hypertension?

examples: Bendroflumethiazide - 2.5mg OM

Indapamide - 2.5mg OM

Site of Action: Begining of the distal convoluted tubule in the kidney

MOA:

• Lower BP by inhibiting Na⁺ reabsorbtion.
• Increasing Na⁺ excretion and urine volume decreases plasma volume and SV that is associated with diuresis.
• Becaus CO = SV x HR, this can lower Cardiac output
• As BP≈ CO x PVR, this reduces BP
• The initial drop in CO produced by diuresis causes a compensatory increase in PVR
• But 4-6 weeks later, CO returns to pre treatment level (as diuresis stops) while PVR falls below its pretreatment level
• The reduction in PVR is responsible for the long term anti-hypertensive effects.

• High Dietary Na⁺ can reverse and low Na can potentiate diuretic effect
• Also relaxes vascular smooth muscle (dilation) and so reduce BP

• hypokalemia, hyponatreamia, hypomagnesaemia
• Hypercalcaemia, hyperuricaemia - caution with gout patients
• hyperglycaemia - diabetes
• hyperlipidaemia - increase in LDL, Increase in Trigs, Decrease in HDL
• Impotence- reversible on withdrawal

Bisoprolol, Atenolol - Cardioselective β₁

Propranolol - Non-selective β_{1 & 2}

B1 predominantly in the heart but come found in the kidney.

Stimulation of B1 produce an increase in HR contractility (sympathetic system adrenaline) and renin release. (stimulation of B2 cause vasodilation and bronchodilation)

MOA: 

• Heart: decreases HR and contractile force therfore decreasing CO
• Peripheral: Presynaptic B-adrenoreceptors to decrease sympathetic vasoconstrictor nerve activity
• Kidneys: (decrease renin and activity of RAAS and therefore decrease H₂0 and Na retention

What are the adverse effects of Beta blockers?

• bradycardia - tiredness and fatigue
• adverse effects on lipids (decrease HDL and Increase n Trigs)
• Bronchospasm
• cold hands and feet
• CNS effects - dreams and nightmares

• Lisinopril - 10mg OD
• Perindoril - 8mg OD

• Hyperkalaemia
• Acute renal failure
• first dose hypotension
• dry cough because of inhibitor of kinins
• switch to A2 receptor blocker
• Skin rash and angiodema (increase in bradykinin)
• Alter sense of taste

• Block Ca2+ entering cells in the myocardium and peripheral vascular smooth muscle.
• Reduce myocardial contractility depress the formation and propagation of electrical impulses within the heart and causes arterial dilation.

• Dihydropyridines:Amlodipine, Nifedipine
• Cause vasodilation of coronary and peripheral blood arteries with little effect on HR
• Phenylalkalamine: Verapamil
• Slow atrioventricular nodal conduction
• Reduces HR and thus CO
• Benzothiazipine derivatives: Diltiazem
• A rate limiting drug which reduces heart rate and atrioventricular nodal conduction but less than verapamil

• Adverse reaction os drugs therapy such as;
• beta-blockers, thiazides, ciclosporin, tacrolimus, oestrogen and steroids
• Dietary
• Diseases:
• Diabetes mellitus
• Hypothyroidism shows elevated LDL, TG and low level of HDL
• Chronic renal failure, nephrotic syndrome
• Alcohol increases hepatic TG synthesis

• To reduce plasma cholesterol, TG and to improve LDL;HDL ratio. ideally less than 3
• To prevent the risk of CV events in people who have no evidence of CVD
• To prevent further attacks in people who already have clinical evidence of CVD

• fruit and vegetable intake
• oily fish intake more than 2 portions a weak
• total choelsterol intake more than 300mg/day
• total dietary fat intake less than or equal to 30% total intake
• Saturated fats less than 10%

What's the pharmacological treatment for Dyslipidaemia?

• decrease entry of lipids into the blood
• increase the removal of lipids from the blood

• Statins - Simvastatin
• Fibrates - bezafibrate
• Bile acid binding agent - Cholestryamine
• Cholesterol absorption inhibitors - Ezetimibe
• Nicotinic acid and derivatives - Niacin
• Omegga 3 fatty acid - NOT recommended.

How do statins treat Dyslipidaemia?

What increases the risk of SE?

• Partial block HMG CoA reductase and inhibit cholesterol biosynthesis in the liver. 
• The fall in hepatic cholesterol synthesis leads to activation of hepatocytes LDL receptors thereby uptake of LDL from circulation.

• Shown to reduce plasma TG and increase in HDL. also reduction in overall CV events.
• Metabolised by CYP3A4 enzyme so increased risk of SE with erythromycin, grapefruit juice, azole, ciclosporin, amiodarone.

• They are generally well tolerated.
• SE - Skin reactions, headaches and GI disturbances.

Rhabdomylosis - Rare but can be fatal. Its a breakdown of muscle. this can lead to a release of myoglobin and is associated with renal damage.

Symptoms present as muscular pain or weakness with malaise, fever or dark urine.

How do Fibrates help in the treatment of Dyslipidaemia?

Example - Bezafibrate

Ciprofibrate

• Bind to peroxisome proliferator activated receptor alpha (PPARa) on hepatocytes
• Stimulates the synthesis of the enzymes of fatty acid oxidation in the liver and striated muscle thereby increase VLDL clearance
• Also decreases hepatic Trig secretion therefore beneficial for thos with blood TG

• Cholestyramine
• Colestipol
• Anionic exchange resins insoluble in water
• following oral intale they are not absorbed from the gut and bind to bile acid in intestine. this increases bile secretion
• The interuption in bile acid cycling leads to incorporation of endogenous cholesterol to form bile acids and there in also an increase in LDL receptor activity of the liver cell. 
• This favours the cellular uptake of cholesterol.
• Useful in treating patients with isolated raise LDL cholesterol but avoid in patients with hypertriglyceriaemia

• Ezetimibe
• Use in patients with primary hypercholesterolaemia with or without statins together with diet modification
• Inhibit the absorption of exogenous and biliary cholesterol in the GI tract through intestinal cholesterol transporter protein 
• This leads to a reduction in LDL cholesterol and total cholesterol and increase in HDL
• 
  

What is Iscahaemic Heart disease (IHD)?

And How might it be presented

It is a lack of oxygen and decreased of no bloodflow to the myocardium resulting from coronary artery narrowing or obstruction.

IHD may be presented as an acute coronary syndrome:

• Unstable angina
• ST-elevated myocardial infaction
• stable angina
• Iscahmia due to coronary artery vasospasm

What are Plaques?

-stable, unstable

Some are stable  and contain a small quantity of lipid and have a larger component of fibrous tssue. They obstruct the arterial lumen and impede bloodflow during exertions and cause chest pains because of oxygen demand is greater than the supply.

Other plaques are unstable and have much thinner fibrous tisse but a large quantity of lipids in the core aswell as a large number of inflammatory cells. They are prone to rupture which causes the lipid core to be exposed to the artery lumen resulting in activation of the platelets and thrombus formation.

What is stable angina?

and how is it presented?

Cased by fixed narrowing of the coronary vessels. This leads to predictable chest pain on exercise caused by an incresae in Oxygen demand.

Symptoms are usually precipitated through excercise, cold environment and relieved by rest.

They may also suffere a burning sensation over the sternum, which often radiates to the lower jaw, shoulder and arm. The chest tightens and causes shortness of breath (SOB). This sensation usually lasts from 30s to 30m

• Modification of risk factors
• symptomatic treatment
• to decrease chest pain and anxiety
• to incease excerices tolerance whilst avoiding side effects of treatment
• Modification of disease process
• To improve quality of life
• to prolong life/reduce risk of CV risks
• to prevent angina attacks

What is the pharmacological treatment for angina?

-symptomatic

-Modification of disease

• Symptomatic:
• Nitrates
• B-blockers
• calcium channel blockers
• potassium channel activators
• Other antianginal drugs - Ivabradine, Ranolazine
• Modification of disease
• Antiplatelets
• ACE inhibitors
• Statins

• Combine with thiol group (-SH) and form nitric oxide
• Nitric oxide activates cGMP which causes vasodilation
• Dilate the veins more than arteries
• In the context of angina they reduce cardiac workload.

• They have a low bioavailability
• Give orally to sustain systemic blood levels.
• Isosorbide Dinitrate - 30mg-120mg daily in 2-3 doses
• Isosorbide Mononitrate (ISMN) 20-120mg daily in 1-2 doses
• Other routes available
• Nitrate free periods
• Given sublingually - fast
• Sublingual Glyceryl trinitrate (GTN)
• onset of action 2-5mins
• use as soon as an attack has started o prophylactically
• Take every 5 mins up to 3 3 doses in total if chest pain persists.
• SE: Headache, flushing and dizziness

They decrease HR, contractility and BP which reduces myocardial oxygen demand and prevents symptoms. They are ideal in patients in which physical activity is the key cause of attacks.

Potentially reduce mmortality in patients with acute MI and heart failure.

Avoid co-admin with rate limiting calcium channel blockers andabrupt withdrawal has been associated with increased severity and number of angina episodes.

Dihydropyridines give rise to vasodilation and improve coronary blood flow, so preventing symptoms.

Verapamil, and Diltiazem decrease AV node conduction, so reducing cardiac workload.

• Nicorandil has several mechanisms:
• ATP - dependent potassium channel activation
• Nitrate like activity.
• Cause both arterial and venous vasodilation which reduces both pre- and afterload
• SE: headache, flushing, reflex tachycardia
• may be used as monotherapy or together with a beta blocker or calcium channel blocker.

• It is a heart rate lowering agent
• It inhibits pacemaker sodium and potassium current in the SA node ofthe heart. This leads to a reduction of cardiac workload.
• Monitor resting HR>50 bpm
• Licensed for treatment of angina in patients with normal sinus Rhythm when beta-blockers are contraindicated
• Metabolised by CYP3A4

• Its used as adjunctive therapy in patients who are inadequately controlled or intolerant of B-blockers or calcium channel blockers.
• It reduces calcium overload in ischaemic myocytes through inhibition of the late sodium current
• It does not affect HR, Contraction or coronary blood flow
• it can prolong QT interval -baseline nd follow up ECG
• It is largerly metabolised by CYP3A4. So avoid use with CP3A4 inhibitors e.g clarithromycin and grapefruit juice.

• Percutaneous Transluminal Coronary Angioplasty (PCTA)
• Increases blood supply to the heart rather than reducing the demand
• Coronary Artery Bypass Grafting (CABG)
• Allow Symptomatic relief and prolong survival in stable angina.

• Acute coronary syndrome (ACS)
• rupture of atheromatous plaque
• can occur at rest
• change in character, frequency, duration or precipitating factors in patients with previously stable angina
• treated urently as a risk of death
• Diagnosis by ECG

• Burning chet discomfort even at rest, severe onset angina or increasing angina that lasts more than 20mins
• Pian may be radiated to jaw, shoulder and down left arm
• May also present with nausea, vomitting and shortness of breath

• Immediate care: To remove pain, prevent deterioration and improve cardiac function.
• Management of complications: HF and arrythmias
• Secondary prophylaxis: Prevent further infarction/death; modification of risk factors

• ECG monitoring
• oxygen - improve O2 delivery to myocardium
• slow IV diamorphine -reduce pain and anxiety
• Metoclopramide 10mg IV antiemetic
• SL or IV nitrate for iscaemic pain
• Clopidrogel 300 and aspirin 300mg as antiplatelet therapy to limit further extension of the thrombus.
• Restoring pateny of the occluded artery:
• Percutaneous Coronary Intervention (PCI)
• give gylcoprotein IIb/IIIa inibitor + anticoagulant (heparin or low MW heparin) or alternatively bivalirudin alon or;
• Thrombolytic agent
• lyse thrombus  and restore blood flow + anticoagulant (heparin or LMW heparin OR Fondaparinux)

• Involves passage of a catheter into the coronary arteries and injects a contrast medium to visualise the coronary arteries (angiogram) this allows a definitive identification of the thrombosed artery
• Artery can be opened using ballon (angioplasty) or using metal mesh (stenting)
• Preffered option in patients with acute MI and procedure can be given within 90minutes

• Prior: Given Aspirin 300mg and clopidrogel 600mg to reduce the risk of peri-procedural thrombosis

• During: Give glycoprotein IIb/IIIa inhibitor adjunct to heparin or alternatively bivalirudin alone

• Post procedure: Give aspirin 7mg OD and Clopidrogel 75mg OD for 12 months to prevent stent thrombosis

• Antiplatelets -
• Aspirin
• Clopidrogel
• Prasugrel
• Ticagrelor
• Glycoproteins IIb/IIIa inhibitor -
• abciximab
• eptifibatide
• Anticoagulant -
• Heparin
• LMW Heparin
• Bivalirudin
• Thrombolytic Drugs -
• Alteplase
• Streptokinase

What is the Fibrinolytic system?

•  Rupture of the athersclerotic plaque causes platelet adhesion activation and aggregation
•  This leads to the activation of clotting factors, tissue factor, XIIa, Xa and IIa
• This leads to thrombus formation.
• Plasminogen is converted to plasmin via plasminogen activator
• The plasmin then degrades the thrombus to fibrin degredation products.

Aspriin inhibits the COX enzyme irreversibly by acetlyation. This reuces thromboxane (TXA2) prostacycling (PGI2) and prostaglandin synthesis

• TXA2 promotes thrombus formation
• PGI2 inhibits platelet aggregation 

• Aspirin (low dose) decreases the synthesis of TXA2 without drastically reducing PGI2 synthesis
• Clopidrogel - inhibits platelet aggregation by irreversibly blocking ADP pathway

Abciximab, tirofaban and eptifibatide

• Their aim is to restore patency of the occluded  artery.
• They inhibit all pathways of platelet activation
• Give to high risk patients to reduce risk of immediate vascular occlusion

Their aim is to break up thrombus and restore blood flow

• Activate plasmingogen to form plasmin which degrades fibrin and breaks up the thrombus.
• eg: Streptokinase, Alteplase, Reteplase and Tenecteplase.
• Given to patients to reduce mortality following MI
• Streptokinase: Binds with plasminogen to form a complex that becomes an active enzyme to convert plasminogen to plasmin
• Alteplase: tissue plasminogen activator naturally occuring enzyme that binds to fibrin and then starts to convert plasminogen to plasmin. It has a greater affinity than Streptokinase

• Antiplatelets
• Aspirin 75mg od
• Clopidrogrel 75mg
• Beta blockers
• rate limiting calcium channel blockers
• ACE inhibitors
• Nitrates
• Lipid lowering treatment

How do beta blockers help treat a STEMI?

• They reduce HR, myocardal contractiliity and blood pressure. They decrease the myocardial oxygen demand. The reduced HR increases diastolic time, thus improving ventricular filing and coronary artery perfusion.

They reduce the risk of life threatening ventricular and supraventricular arrhythmias due to sympathetic activation. There is a 23% reduction in total mortality 32% reduction in sudden death

• Should be offered to all patients especially those with evidence of left ventricle dysfuntion.
• Inititate with 24 -48hrs of MI as long as patient has been stabilised
• Angiotensin 2 blockers may be used if patients intolerant to ace inhibitors due to persistent dry cough.
• Use maximum dose if possible

Use aldosterone antagonsist for patientswith symptoms and signs ofheart failure and left ventricle systolic dysfunction.

Epeleron and spironolactone