CVD Flashcards
What’s the Pathophysiology and pharmacology of hypertension?
Hypertension, also known as high blood pressure, is a chronic medical condition characterized by elevated blood pressure in the arteries. The pathophysiology of hypertension involves several factors, including increased peripheral vascular resistance, increased blood volume, and abnormalities in the renin-angiotensin-aldosterone system.
Peripheral vascular resistance refers to the resistance encountered by blood flow in the small arteries and arterioles. In hypertension, there is an increase in peripheral vascular resistance due to the narrowing of the blood vessels, which can be caused by factors such as endothelial dysfunction, smooth muscle cell hypertrophy, and increased sympathetic nervous system activity.
Blood volume plays a role in hypertension as well. An increase in blood volume can lead to higher blood pressure. This can occur due to factors such as excessive salt intake, kidney dysfunction, or hormonal imbalances.
The renin-angiotensin-aldosterone system (RAAS) is a hormonal system that regulates blood pressure and fluid balance. In hypertension, there can be abnormalities in this system, leading to increased levels of angiotensin II, a potent vasoconstrictor, and aldosterone, a hormone that promotes sodium and water retention.
Pharmacologically, there are several classes of medications used to treat hypertension. These include:
- Diuretics: These medications help reduce blood volume by increasing urine production, thus lowering blood pressure.
- Beta-blockers: These medications block the effects of adrenaline on the heart and blood vessels, reducing heart rate and blood pressure.
- Angiotensin-converting enzyme (ACE) inhibitors: These medications block the production of angiotensin II, leading to vasodilation and decreased blood pressure.
- Angiotensin receptor blockers (ARBs): These medications block the action of angiotensin II on its receptors, resulting in vasodilation and lower blood pressure.
- Calcium channel blockers: These medications block the entry of calcium into smooth muscle cells of blood vessels, causing relaxation and reducing peripheral vascular resistance.
- Direct renin inhibitors: These medications block the action of renin, an enzyme involved in the production of angiotensin II, leading to decreased blood pressure.
- Alpha-blockers: These medications block the action of norepinephrine on alpha receptors, resulting in vasodilation and lower blood pressure.
It is important to note that the choice of medication depends on various factors such as the severity of hypertension, presence of other medical conditions, and individual patient characteristics. Treatment may also involve lifestyle modifications, such as dietary changes, regular exercise, and stress management techniques.
List all the calcium channel blocker drugs?
Dihydropyridines:
Amlodipine
Felodipine
Isradipine
Lercanidipine
Nicardipine
Nifedipine
Nisoldipine
•Non-dihydropyridines:
Diltiszem
Verapamil
Dihydropyridine (DHP) CCBs tend to be more potent vasodilators than non-dihydropyridine (non-DHP) agents, whereas the latter have more marked negative inotropic effects.
Dihydropyridines (DHPs) have greater selectivity for vascular smooth muscle with little direct effect on the myocardium; non- dihydropyridines (non-DHPs) have less selective vasodilator activity and have a direct effect on the myocardium.
CCB mechanism of action?
Interfere with the inward displacement of calcium ions through the slow channels of active cell membranes in the peripheral blood vessels and/or heart.
Increases peripheral vasodilation dihydropyridines.
Increases coronary vasodilation all but especially verapamil and diltiazem.
Decreases rate and force of cardiac contraction (verapamil and diltiazem)
•*•CCBs, or calcium channel blockers, are a class of medications that interfere with the inward displacement of calcium ions through the slow channels of active cell membranes in the peripheral blood vessels and/or heart. This action leads to several pharmacological effects.
Firstly, CCBs can increase peripheral vasodilation, particularly the dihydropyridine subclass. This means that these medications relax and widen the blood vessels in the periphery, resulting in a reduction of peripheral resistance and a decrease in blood pressure.
Secondly, CCBs can increase coronary vasodilation, although this effect is more pronounced with certain CCBs like verapamil and diltiazem. By dilating the coronary arteries, CCBs can improve blood flow to the heart muscle and alleviate symptoms of angina.
Lastly, CCBs can decrease the rate and force of cardiac contraction. This effect is more prominent with verapamil and diltiazem, which are known as non-dihydropyridine CCBs. By inhibiting the influx of calcium ions into cardiac cells, these medications reduce the contractility of the heart, resulting in a decreased heart rate and a decrease in the force of contraction.
Overall, CCBs have diverse pharmacological effects that make them valuable in the management of various cardiovascular conditions, such as hypertension, angina, and certain arrhythmias.
Therapeutic use:
Dihydropyridines eg Amlodipine 1st line step 1 choice in >55yrs of black African or African Caribbean populations of any age (non-diabetic)
Verapamil must not be use in combination with beta-blacker due to risk of severe bradycardia and heart block.
Amlodipine:
Side-effects:
Abdominal pain, nausea,
Palpitations, flushing, oedema, headache, dizziness, sleep disturbances, fatigue.
Dose:
10mg twice daily increases according to response up to 40mg twice daily (for twice a daily M/R preparations eg Adalat Retard)
20-30mg once daily increassed according to response up to 90mg once daily (for once daily long acting M/R preparation eg AdalatLA)
NB: short acting Nifedipine is not recommended due to an association with increased of CV events.
Diltiazem
Contraindications:
Severe bradycardia, heart shock
Cautions:
LVF
Side effects:
Bradycardia, heart block, palpitations, dizziness, hypotension, malaise, g.i., oedema.
Dose:
90mg twice daily increased according to response up to 180mg twice daily (for twice daily M/R preparations eg Tildiem Retard)
200-240mg daily increased according to response- maximum depends on preparations (for once daily long acting M/R preparation eg Tildiem LA)
Verapamil
Contraindications: bradycardia, heart block, LVF (Left ventricular failure) Left ventricular failure occurs when there is dysfunction of the left ventricle causing insufficient delivery of blood to vital body organs.
A heart block is when the electrical impulses that control the beating of the heart muscle are disrupted. The most serious type of heart block known as a complete, or third degree, heart block will have symptoms, but often those with less serious heart block can have symptoms too.
Side-effects:
Constipation, bradycardia, heart block, g.i., flushing headache, dizziness, fatigue, ankle oedema
Dose:
240-480mg daily in 2-3 divided doses.
List the diuretics drugs?
Thiazides:
Eg
Bendroflumethiazide
Chlortalidone
Cyclopenthiazide
Indapamide
Metolazone
Xipamide
Potassium-sparing & Aldosterone antagonists:
Amiloride
Triamterene
Spironolactone
Thiazides mechanism of action?
Thiazides:
Eg
Bendroflumethiazide
Chlortalidone
Cyclopenthiazide
Indapamide
Metolazone
Xipamide
Inhibit sodium reabsorption (inhibit Na+/Cl- co-transporter) at the beginning of the distal convoluted tubule
Induces Diuresis decreases circulating volume this decreases cardiac output
Also have direct vasodilatory action
Act within 1-2hrs of oral administration, max effect 4-6hrs & duration of action of 8-12hrs
• Thiazides are a class of diuretic medications that have a specific mechanism of action and pharmacological effects.
The primary mechanism of action of thiazides is the inhibition of sodium reabsorption at the beginning of the distal convoluted tubule in the kidneys. They achieve this by blocking the Na+/Cl- co-transporter, which is responsible for the reabsorption of sodium and chloride ions from the urine back into the bloodstream. By inhibiting this transporter, thiazides increase the excretion of sodium and chloride in the urine, leading to diuresis or increased urine production.
The diuretic effect of thiazides results in a decrease in circulating volume, as the excretion of sodium and water increases. This reduction in circulating volume subsequently decreases cardiac output, which is the amount of blood pumped by the heart per minute. By reducing cardiac output, thiazides can help in the management of conditions such as hypertension and edema.
In addition to their diuretic effect, thiazides also possess direct vasodilatory action. This means that they can cause relaxation and widening of the blood vessels, leading to a decrease in peripheral resistance and a subsequent reduction in blood pressure.
Thiazides are usually taken orally and start to act within 1-2 hours of administration. Their maximum effect is typically observed within 4-6 hours, and their duration of action lasts for approximately 8-12 hours.
Overall, thiazides have a multifaceted pharmacology that includes inhibition of sodium reabsorption, induction of diuresis, reduction in circulating volume and cardiac output, and direct vasodilatory action. These characteristics make thiazides effective in the treatment of conditions such as hypertension, congestive heart failure, and certain types of edema.
Dose:
2.5mg in the morning
Maximal bp lowering occurs at 2.5mg dose and therefore higher doses are unnecessary when treating hypertension (and will increase risk of side effects)
Side effects
Postural hypotension
Renal impairment
Mild gastrointestinal effects
Impotence
Electrolyte disturbances:
Hypokalaemia
Hypomagnesaemia
Hyponatraemia
Hypercalcaemia
Hyperuricaemia and gout
Hyperglycaemia and impaired glucose tolerance
Altered lipid profile
Therapeutic use:
Inexpensive
Do not perk if GFR<20ml/min
Can be used in combination with other antihypertensive agents (step 2 of NICE guidelines)
Use in combination with potassium-sparing diuretics if hypokalaemia is a a problem.
Potassium-sparing diuretics?
Potassium-sparing & Aldosterone antagonists:
Amiloride
Triamterene
Spironolactone
Amiloride
Mechanism of action:
Inhibit sodium proton exchanger which affects sodium reabsorption in the distal tubule and collecting ducts potassium loss is indirectly decreased.
Dose:
5-10mg
Side-effects:
Hyperkalaemia
Postural hypotension
Mild gastrointestinal effects
Dry mouth
Rashes
Confusion
Hyponatraemia
Therapeutic use
Very weak diuretic in own
Almost always used in combination with thiazides or loop diuretics to conserve potassium and prevent hypokalaemia.
AI:
Potassium-sparing diuretics are a class of medications that have a unique pharmacology and are primarily used for their ability to conserve potassium while promoting diuresis. Here is an overview of their mechanism of action, dosage, side effects, and therapeutic use:
Mechanism of Action:
Potassium-sparing diuretics exert their pharmacological effects by inhibiting the sodium proton exchanger in the distal tubule and collecting ducts of the kidneys. This inhibition interferes with the reabsorption of sodium, which indirectly reduces potassium loss. By blocking the sodium reabsorption, these diuretics promote the excretion of sodium and water while conserving potassium.
Dosage:
The usual dosage range for potassium-sparing diuretics is 5-10mg. However, the specific dosage may vary depending on the individual patient’s condition, response to treatment, and the presence of any other medical conditions. It is important to follow the prescribed dosage as directed by a healthcare professional.
Side Effects:
Some of the common side effects associated with potassium-sparing diuretics include:
- Hyperkalemia: Since these diuretics prevent potassium loss, there is a potential risk of elevated potassium levels in the blood.
- Postural hypotension: This refers to a drop in blood pressure upon standing up, which can cause dizziness or lightheadedness.
- Mild gastrointestinal effects: These may include nausea, vomiting, or stomach discomfort.
- Dry mouth: Some individuals may experience a sensation of dryness in the mouth.
- Rashes: Skin rashes or allergic reactions may occur in some cases.
- Confusion: In rare instances, potassium-sparing diuretics may cause confusion or mental changes.
- Hyponatremia: This refers to low levels of sodium in the blood and can occur rarely as a side effect.
Therapeutic Use:
Potassium-sparing diuretics are considered to be relatively weak diuretics on their own. They are typically used in combination with other diuretics, such as thiazides or loop diuretics, to enhance diuresis while preventing the loss of potassium. This combination therapy helps to maintain potassium balance and prevent hypokalemia (low potassium levels) that can occur with other diuretics.
In summary, potassium-sparing diuretics work by inhibiting sodium reabsorption, which indirectly decreases potassium loss. They are used in combination with other diuretics to prevent hypokalemia and are generally well-tolerated, although they can have side effects such as hyperkalemia, postural hypotension, and gastrointestinal effects. It is important to discuss the appropriate dosage and any potential side effects with a healthcare professional.
Aldosterone antagonists
Spironolactone
Mechanism of action:
Inhibits affect of aldosterone on distal renal tubule
Results in decreased sodium absorption and decreased circulating volume
Also causes decreased potassium secretion hence also potassium sparing.
Dose: 25mg daily
Side effects:
Hyperkalaemia
Hypotension
Renal impairment
Gynaecomastia
Therapeutic use:
Add on for resistant hypertension
Step 4 but only if K+ <4.5mmol/L due to risk of Hyperkalaemia.
Angiotensin converting enzyme inhibitors ACEIs
Captopril
Enalapril
Fosinopril
Imidapril
Lisinorpil
Moexipril
Perindopril
Quinapril
Ramipril
Trandolapril
Mechanism of action:
Block the action of angiotensin converting enzyme ACE and thus prevent the conversion of angiotensin-I to angiotensin-II.
Prevents the vasoconstrictive effect of angiotensin II and also prevents its stimulation of Norwich of aldosterone.
Contraindications:
Hypersensitivity & angioedema
Renal artery stenosis
Pregnancy
Side effects:
Hypotension (especially first dose in patients on diuretics)
Renal dry cough common due to blocking breakdown of bradykinins
Angioedema (rare but important- more common in people of black African Caribbean origin)
Hyperkalaemia
Blood dyscarasias
Therapeutic use:
First line step-1 therapy for younger patients <55yrs and patients with diabetes type-1 & type-2
Drug of choice to treat HT in patients who also has CCF or is post MI
Dose:
•Enalapril 5mg daily increased as required to 20mg OD maintenance
•Ramipril: 1.25mg daily increased as required at intervals of 1-2 weeks to 2.5-5mg daily maintenance
Lisinopril:
Initially 10mg OD; usual maintenance 20mg OD maximum 80mg per day
•Perindopril: Erbumine more commonly prescribed salt initially 4mg OD for 1month dose to be taken in the morning, then, adjusted according to response; maximum 8mg per day
Ariginine: initially 5mg OD for 1 month, dose to be taken in the morning then adjusted according to response maximum 10mg per day.
AI:
•ACE inhibitors (angiotensin-converting enzyme inhibitors) are a class of medications commonly used in the treatment of hypertension, heart failure, and certain kidney conditions. Here is an overview of their pharmacology, contraindications, side effects, and therapeutic use:
Mechanism of Action:
ACE inhibitors work by blocking the action of angiotensin-converting enzyme (ACE), which is responsible for converting angiotensin I to angiotensin II. By inhibiting this enzyme, ACE inhibitors prevent the formation of angiotensin II, a potent vasoconstrictor. This leads to vasodilation and helps lower blood pressure. Additionally, ACE inhibitors reduce the production of aldosterone, a hormone that promotes sodium and water retention, thus further lowering blood pressure and reducing the workload on the heart.
Contraindications:
There are several contraindications for the use of ACE inhibitors, including:
- Hypersensitivity and angioedema: Individuals who have a known hypersensitivity or history of angioedema (swelling of the deeper layers of the skin) to ACE inhibitors should not use these medications.
- Renal artery stenosis: ACE inhibitors are contraindicated in patients with renal artery stenosis, a narrowing of the arteries that supply blood to the kidneys.
- Pregnancy: ACE inhibitors are not recommended during pregnancy, particularly during the second and third trimesters, as they may cause harm to the developing fetus.
Side Effects:
Some common side effects associated with ACE inhibitors include:
- Hypotension: A sudden drop in blood pressure, especially during the initial dose, may occur, especially in patients who are also taking diuretics.
- Dry cough: ACE inhibitors can cause a persistent, dry cough in some individuals, which is thought to be due to the accumulation of bradykinin, a substance that is usually broken down by ACE.
- Angioedema: Although rare, ACE inhibitors can cause angioedema, which is characterized by swelling of the face, lips, tongue, throat, or extremities. This side effect is more common in individuals of black African Caribbean origin.
- Hyperkalemia: ACE inhibitors can lead to an increased level of potassium in the blood, which can be problematic, especially in patients with existing kidney problems.
- Blood dyscrasias: Rarely, ACE inhibitors may cause blood disorders, such as a decrease in white blood cells or platelets.
Therapeutic Use:
ACE inhibitors have several therapeutic uses, including:
- First-line step-1 therapy for younger patients (<55 years) with hypertension, as well as patients with type 1 or type 2 diabetes.
- Drug of choice for treating hypertension in patients who also have congestive heart failure (CCF) or have experienced a myocardial infarction (heart attack).
It is important to note that the use of ACE inhibitors should be individualized and prescribed by a healthcare professional based on the patient’s specific medical condition, response to treatment, and any potential contraindications.
In summary, ACE inhibitors block the action of ACE, which prevents the conversion of angiotensin I to angiotensin II. They are contraindicated in certain conditions such as hypersensitivity, renal artery stenosis, and pregnancy.
Common side effects include hypotension, dry cough, and rarely, angioedema and hyperkalemia. ACE inhibitors are therapeutically used as first-line therapy for hypertension in younger patients and in patients with diabetes, as well as in those with heart failure or post-myocardial infarction. It is important to consult with a healthcare professional for appropriate use and monitoring.
Angiotensin-II receptor antagonists/Blockers ARBs
Candesartan
Eprosartan
Irbesartan
Lostran
Olmesartan
Telmisartan
Valsartan
Mechanism of action:
Block the action of Angiotensin II at the AT21 receptor and thus have similar effect to ACEIs
Side effects:
Hypotension (especially first dose in patients on diuretics)
Renal impairment
Angioedema (rare)
Hyperkalaemia
Blood dyscrasias (anaemia)
Therapeutic use:
Low cost agents first line step 1 therapy for younger patients <55yrs
Useful alternative when ACEIs not tolerated due to cough ( do not block breakdown of bradykinin and therefore don’t cause cough)
Consider ARB instead of ACEIs in black African or African Caribbean population (due to greater risk of angioedema with ACEIs)
Dose:
Losartan 50mg daily increase if required over several weeks to 100mg daily.
Avoid combined use of ACEIs and ARBs due to increased risk of Hyperkalaemia, hypotension and impaired renal function especially in patients with diabetic nephropathy
Renin inhibitors
Aliskiren
Mechanism of action:
Inhibits renin directly and therefore prevents the conversion of angiotensin to angiotensin I
Contraindications:
Hypersensitivity and angioedema
Renal artery stenosis
Severe renal impairment (GFR <30ml/min/1.73m2)
Pregnancy
Combination with ARB or ACEIs is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60ml/min/1.73m2) and is not recommended in other patients.
Side effects
Hypotension (especially first dose in patients on diuretics)
Renal impairment
Angioedema (rare but important)
Hyperkalaemia
Blood dyscrasias
Therapeutic use:
Expensive
Evidence is limited (not recommended in NICE) and is reserved for resistant hypertension
Dose:
150mg OD, increased if necessary to 300mg Once daily.
Alpha blockers
Doxazosin
Indoramin
Prazosin
Terazosin
Mechanism of action:
Selectively block alpha-1 receptors responsible for noradrenaline (norepinephrine) mediated vasoconstriction which decreases peripheral resistance
Doxazosin:
Side effects:
Postural hypotension (especially first dose), dizziness, vertigo, headache, fatigue, asthenia, oedema, sleep disturbance, nausea, rhinitis.
Therapeutic use:
Appropriate add on therapy step 4 for patients uncontrolled by other agents not for monotherpay (ALLHAT trial demonstrated increased heart failure and stroke compared to thiazides)
Appropriate first line for patients with prostatism
Useful for hypertension associated with CKD
Dose:
1mg daily increased every 1-2 weeks according to response up to 16mg daily
Beta blockers
Propranolol
Acebutolol
Atenolol
Bisoprolol
Carvedilol
Celiprolol
Labetolol
Metoprolol
Nadolol
Nebivolol
Oxprenolol
Pindolol
Timolol
Mechanism of action:
Block beta-1 adrenoreceptors in the heart and beta-2 adrenoreceptors in the peripheral vasculature, bronchi, pancreas and liver.
Exact mechanism of action in HT unknown, although known to decrease CO.
Side effects:
Bradycardia
Heart failure
Hypotension
Arrhythmias
Bronchospasm
Peripheral vasoconstriction
Gastrointestinal disturbances
Fatigue
Sleep disturbances
Sexual dysfunction
Exacerbation of psoriasis
Contraindications:
Asthma
Uncontrolled heart failure
Bradycardia
Heart block
Severe peripheral vascular disease
Caution:
Diabetes-May cause deterioration in glucose tolerance and mask the symptoms of hypoglycaemia
If no alternatives in asthma, use cardioselective beta blockers
Therapeutics use:
Appropriate add-on therapy step 4 for patients uncontrolled by other agents
Drugs of choice to treat HT in patients who also has CCF or is post MI
Choice of B-blocker will depend on their relative characteristics:
Cardio selectivity:
Eg Atenolol, bisorprolol, metoprolol
Tendency to block B1receptors in heart rather than B2 receptors in lungs but not cardiospecific and still have potential to block B2 receptors in lungs therefore caution required.
Can be used with caution in asthmatics if no other option available
Also less likely to be a problem in diabetics
Initrinsic sympathomimetic activity (ISA)
Eg Oxprenolol, pindolol, acebutolol, celiprolol.
Capacity to stimulate as well as block adrenergic receptors.
Less bradycardia & cold extremities than other B blockers.
Lipid/water solubility:
Eg water soluble: atenolol, celiprolol
Lipid soluble: propanol
Water soluble less likely to cross blood brain barrier and therefore cause less sleep disturbances and nightmares
Water soluble excreted by the kidneys and may accumulate in renal impairment therefore dose reduction maybe necessary.
Dose:
Bisoprolol 5-10mg daily max 20mg daily
Propranolol 80mg twice daily increased at weekly intervals if required to Maintaince of 160-320mg
Centrally acting agents
Methyldopa
Clonidine
Moxonidine
Mechanism of action:
Methyldopa and clonidine act at presynaptic a2 receptors to decrease sympathetic outflow which induces vasodilation
Moxonidine selectively blocks imidazole receptors and has less action on a2 receptors resulting in less central adveres effects.
Therapeutic use:
Due to adverse effects methyldopa and clonidine are reserved for resistant hypertension not in (NICE guidelines)
Methyldopa is the drug of choice in hypertension of pregnancy due to it is proven safety record
Moxonidine evidence is limited not in NICE guidelines and is reserved for resistant hypertension.
Methyldopa contraindications include depression
Side effects:
GI, dry mouth, mouth ulcers, inflammation of salivary glands, bradycardia, exacerbation of angina, postural hypotension, oedema, sedation, nightmares, depression, and other central effects caution with driving
Dose
250mg 2-3 times daily increased according to response up to a maximum of 3g daily
Clonidine
Caution include withdrawing therapy slowly to avoid hypertensive crisis
Side effects
Dry mouth, sedation, caution with driving, depression, fluid retention, bradycardia, Raynaud phenomenon.
Dose:
50-100mcg 3 times daily increased according to response up to maximum 1.2mg daily
Moxonidine
Caution
Include withdrawing therapy slowly
Contraindications include cardiac arrhythmias
Side effects:
Dry mouth, headache, fatigue, nausea, sleep disturbances,
Dose
200mcg daily increased after 3 weeks according to response up to a maximum of 600mcg in 2 divided doses.
Vasodilators
Hydralazine
Monoxidil
Mechanism of action: Directly relax smooth muscle—> vasodilation
Therapeutic use:
Reserved for add on therapy in resistant hypertension due to severe side/effects
Hydralazine
Side effects
Tachycardia, palpitations, flushing, hypotension, fluid retention, GI and others.
Dose 25mg twice daily increased according to response of 50mg BD
Minoxidil
Side effects
Sodium and water retention, weight gain, peripheral oedema, use in combination with diuretic, Tachycardia, use in combination with B blockers, hirsuitism
5mg daily in 1-2 doses increased according to response up to a maximum 50mg daily in divided doses.
Treatment of hypertension in pregnancy
•When using medicines to treat chronic hypertension in pregnancy ailments for target blood pressure of 135/85mmHg.
•Consider Labetalol to treat chronic hypertension in pregnant women. Consider Nifedipine for women while labetoalol is not suitable or Methyldopa if both labetalol and nifedipine are not suitable. Base the treatment on S/E, risks including fetal effects and woman’s preferences.
•Offer pregnant women with chronic hypertension aspirin 75mg to 150mg OD from 12weeks. Community pharmacy can’t legally sell aspirin as pharmacy med for prevention of pre-eclampsia in pregnancy in England. Aspirin for this indication must be prescribed.
Treatment post natal period and during breastfeeding ACE inhibitors first line except in women of African or Caribbean origin in whom calcium channel blockers would be used first line. Second line adding thiazide and thiazide like diuretics is not recommended in breastfeeding therefore beta blockers should be used instead.
According to the National Institute for Health and Care Excellence (NICE) guidelines, the treatment of hypertension in pregnancy depends on the severity of the condition and the presence of complications. Here is an overview of the treatment recommendations for hypertension in pregnancy according to NICE guidelines:
- Lifestyle modifications: For women with mild hypertension (blood pressure less than 150/100 mmHg) and no evidence of target organ damage, lifestyle modifications are recommended. These include maintaining a healthy weight, regular exercise, reducing sodium intake, and avoiding tobacco and excessive alcohol consumption.
- Antihypertensive medication: Antihypertensive medication may be considered for women with moderate to severe hypertension (blood pressure 150/100 mmHg or higher) or those with target organ damage. The choice of medication depends on factors such as the gestational age, presence of complications, and individual patient characteristics. The preferred antihypertensive agents during pregnancy include labetalol, methyldopa, or nifedipine.
- Monitoring and follow-up: Women with hypertension in pregnancy should be closely monitored to assess blood pressure control and detect any complications. Regular blood pressure measurements and urine tests for proteinuria are recommended. The frequency of monitoring depends on the severity of hypertension and the presence of complications.
- Management of complications: If complications such as preeclampsia (high blood pressure with proteinuria) or eclampsia (seizures) develop, additional interventions may be required. This may include hospital admission, close monitoring of blood pressure and fetal well-being, and potential delivery of the baby.
It is important to note that the management of hypertension in pregnancy should be individualized based on the specific circumstances of each patient. Healthcare professionals should consider factors such as the woman’s overall health, gestational age, presence of complications, and potential risks and benefits of treatment options.
Please consult with a healthcare professional or refer to the NICE guidelines for detailed and up-to-date recommendations on the treatment of hypertension in pregnancy.
Hypertension management in diabetes type one
Page 19,22,34,35,36 NICE guidance
Blood glucose target for adults with type diabetes:
Fasting plasma glucose level of 5-7 mmol/litre on waking
Plasma glucose level of 4-7mmol/litre before meals at other times of day
Control of cardiovascular risk
Aspirin don’t offer aspirin for the primary prevention of cardiovascular disease in adults with type 1 diabetes
Identifying cardiovascular risk:
eGFR
Smoking
Blood glucose control
Blood pressure
Full lipid profile including LDL HDL, triglycerides and cholesterol.
Age
Family history of CVD
Abdominal adiposity
Blood pressure targets:
For ACR 70mg/mmol aim for clinical systolic blood pressure less than 140mmHg target 120-139mmHg and clinic diastolic blood pressure less than 90mmHg
> ACR 70mg/mmol aim for less than 130 or between 120-129 mmHg and diastolic less than 80mmHg
In adults aged 80 or more aim for 140-149/90mmHg
Start with a trial of renin angiotensin system blocking drug as first like for hypertension in adults with type-1 diabetes
Life style changes advise
Selective beta blockers for adults on insulin
Low dose thiazides maybe combined with beta blockers
Calcium channel antagonist only use long acting preparations
According to the National Institute for Health and Care Excellence (NICE) guidelines, the treatment of hypertension in patients with type 1 diabetes involves a combination of lifestyle modifications and medication. Here is an overview of the treatment recommendations for hypertension in type 1 diabetes according to NICE guidelines:
- Lifestyle modifications: Lifestyle changes play a crucial role in the management of hypertension in patients with type 1 diabetes. These include maintaining a healthy weight, following a balanced diet low in sodium and saturated fats, engaging in regular physical activity, limiting alcohol consumption, and avoiding tobacco use.
- Blood pressure targets: NICE recommends a target blood pressure of less than 140/80 mmHg for most adults with type 1 diabetes. However, individualized targets may be set based on the person’s age, presence of complications, and overall health.
- Antihypertensive medication: If lifestyle modifications alone are not sufficient to achieve the target blood pressure, antihypertensive medication may be prescribed. The choice of medication depends on factors such as the person’s age, presence of kidney disease, and any other specific health considerations. Commonly used antihypertensive medications include angiotensin-converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs), calcium channel blockers, and thiazide diuretics.
- Monitoring and follow-up: Regular monitoring of blood pressure is essential to assess the effectiveness of treatment and make any necessary adjustments. NICE recommends routine blood pressure checks at least once a year for people with type 1 diabetes. More frequent monitoring may be necessary for those with higher blood pressure or additional risk factors.
- Management of co-existing conditions: It is important to consider the management of other conditions that may coexist with hypertension and type 1 diabetes, such as dyslipidemia (abnormal blood lipid levels) and kidney disease. Treatment of these conditions may involve additional lifestyle modifications and medication, as appropriate.
It is important to note that the treatment of hypertension in type 1 diabetes should be individualized based on the specific needs and circumstances of each patient. Healthcare professionals should consider factors such as the person’s overall health, presence of complications, and potential risks and benefits of treatment options.
Please consult with a healthcare professional or refer to the NICE guidelines for detailed and up-to-date recommendations on the treatment of hypertension in type 1 diabetes.
Hypertension NICE guidance
Step-1
Offer an ACE inhibitor or an ARB to patients who have type 2 diabetes and are of any age or family origin or are aged under 55 but not of Black African Caribbean origin.
•If an ACE inhibitor is not tolerated due to cough or a/e offer ARB to treat hypertension.
Don’t combine an ACE inhibitor with an ARB to treat hypertension.
Offer a calcium channel blocker CCB to adults starting step-1 antihypertensive treatment who:
Are aged 55 or over and do not have type 2 diabetes or are of black African or African Caribbean family origin and do not have type 2 diabetes of any age.
•If a CCB is not tolerated due to oedema or other reasons offer a thiazide like diuretic to treat hypertension.
•If there is evidence of heart failure offer a thiazide like diuretic and follow NICE guidelines on chronic heart failure.
If starting it changing diuretic treatment for hypertension, offer a thiazide like diuretic such as indapamide in preference to a conventional thiazide diuretic such as bendroflumethiazide or hydrochlorothiazide.
Step 2 treatment:
Check adherence and support adherence in line with NICE guidelines.
If hypertension is not controlled in adults taking step-1 of the following drugs in addition to step-1 treatment:
CCB
Thiazide like diuretic
If hypertension is not controlled in adults taking step treatment of a CCB offer a choice of 1 of the following drugs in addition to step 1
ACE inhibitor or an ARB or a thiazide like diuretic.
If hypertension is not controlled in adults of black African or African Caribbean family origin who don’t have type 2 diabetes taking step-1 treatment consider an ARB in preference to an ACE inhibitor in addition to step-1 treatment.
Step-3 treatment:
Review the medications to ensure they are being taken at the optimal tolerated doses and discuss adherence.
If hypertension is not controlled in adults taking step-2 treatment offer a combination of:
An ACE inhibitor or ARB for black people of African origin.
CCB
And
Thiazide like diuretic
Step-4 treatement:
If hypertension is not controlled in adults taking the optimal tolerated doses of an ACE inhibitor or an ARB plus a CCB and a thiazide like diuretic, regard them as resistant hypertension.
Before considering further treatment for patients with resistant hypertension.
Confirm elevated clinic blood pressure measurements using ambulatory or home blood pressure recording.
Assess for postural hypotension.
Discuss adherence
For people with confirmed resistant hypertension considering a fourth antihypertensive drug as step-4 treatment.
Consider further diuretic therapy with low dose spironolactone for adults with resistant hypertension starting step-4 who have a blood potassium of 4.5mmol/L or less. Particular caution in people with a reduced estimated glomerular filtration rate because they have an increased risk of hyperkalaemia.
Monitor sodium, potassium and renal function within one month of starting treatment and repeat as needed.
Consider an alpha blocker or beta blocker for adults with resistant hypertension starting step-4 treatment who have a blood potassium level of more than 4.5mmol/l.
If blood pressure remains uncontrolled in people with resistant hypertension taking the optimal tolerated doses of 4 drugs seek specialist advice.
AI:
As of my knowledge, the most recent NICE (National Institute for Health and Care Excellence) guidance on the treatment of hypertension was published in 2019. However, I can provide you with an overview of the general treatment approach recommended by NICE for hypertension management. Please note that it is always best to consult with a healthcare professional for personalized advice and to ensure you have the most up-to-date information.
According to NICE guidance, the treatment of hypertension (high blood pressure) depends on the individual’s blood pressure level and their risk of cardiovascular disease. Here are some key recommendations:
- Lifestyle Modifications: For individuals with hypertension, lifestyle changes are usually the first step in management. These may include:
- Regular exercise: Engaging in at least 150 minutes of moderate-intensity aerobic activity, such as brisk walking, per week.
- Healthy diet: Following a balanced diet that is low in salt, saturated fats, and processed foods, and rich in fruits, vegetables, and whole grains.
- Weight management: Achieving and maintaining a healthy body weight.
- Limiting alcohol intake: For men, a maximum of 14 units per week, and for women, a maximum of 14 units per week.
- Smoking cessation: Encouraging individuals to quit smoking if they are smokers.
- Medication: If lifestyle modifications alone are insufficient to control blood pressure, medication may be prescribed. The choice of medication will depend on various factors, including age, ethnicity, and any other underlying health conditions. NICE recommends the following medications as first-line treatment options:
- ACE inhibitors (Angiotensin-Converting Enzyme inhibitors)
- ARBs (Angiotensin Receptor Blockers)
- Calcium channel blockers
- Thiazide-like diuretics
- Combination Therapy: If blood pressure is not adequately controlled with a single medication, NICE recommends combining different classes of antihypertensive drugs to achieve the target blood pressure.
- Regular Monitoring: Individuals with hypertension should have their blood pressure regularly monitored to assess the effectiveness of treatment and make adjustments if necessary.
It is important to note that the specific treatment plan for hypertension should be tailored to each individual based on their unique circumstances and in consultation with a healthcare professional.
What are risk factors for developing hypertension?
Ethinicity (individuals of Black Afro-Caribbean origin are at increased risk of hypertension.
Obesity BMI of 32kg/m2 >30kg/m2
Smoking
Stress
Family history of hypertension or CVD
History of type 2 diabetes mellitus
Combined oral contraceptives
OTC medicine use such as NSAIDs eg Ibuprofen may further increase risk of developing hypertension due to increased sodium/water reabsorption and vasoconstriction.
How would you confirm diagnosis of hypertension?
In order to confirm the diagnosis, patient should undergo ambulatory BP monitoring ABPM, or if not possible, home BP monitoring HBPM.
When using ABPM, ensure that at least two measurements per hour are taken during her waking hours and use the average value of at least 14 measurements to confirm the diagnosis. If using HBPM, BP should be recorded twice daily ideally morning and evening for at least 5 days, preferably 7 days. ABPM daytime average or HBPM average of >135/85mmHg is a diagnostic of stage 1 hypertension whereas >150/95mmHg is a diagnostic of stage 2 hypertension.
•When measuring BP in clinic or when imitating ABPM/HBPM, ensure that a correct technique is used and explained to patient.
What other investigations are carried out pending diagnosis of hypertension?
Investigations of other target organ damage:
This includes testing for protein in the urine (I.e albumin:creatinine ratio) and may help detect an underlying chronic kidney disease, possibly secondary to diabetes if patient is diabetic (type-2).
Blood sample to measure glucates haemoglobin (HbA1C) electrolytes, creatinine and eGFR, total cholesterol and HDL.
Examination of fundí to identify any undiagnosed hypertensive retinopathy.
12-lead electrocardiogram may help rule out some of the co-existence of cardiovascular conditions, such as atrial fibrillation or ischaemic heart disease.
Formal assessment of cardiovascular risk
Qrisk
What are the clinical consequences of uncontrolled hypertension?
The inadequate control of BP may lead to an increased risk of:
Myocardial infarction
Cerebral vascular accident ie stroke
Heart failure
Renal kidney disease
Peripheral vascular disease
Vascular dementia
Ocular complications (retinopathy)
The presence of type-2 diabetes mellitus and lifestyle factors such as smoking increase these risks further.
What is the target BP and is use of indapamide 2.5mg OD appropriate?
What’s 1st line treatment if patient were to be 24wks pregnant?
Indapamide is a thiazide like diuretic and should not be used as first line option for the management of hypertension unless the patient couldn’t tolerate ACEi/ARB/CCB or these options were contraindicated. As some of it side effects, indapamide may exacerbate hyperglycaemia, potentially worsening symptoms or contour of diabetes. It can also cause electrolyte disturbances such as hypercalcaemia or hyponatraemia.
Offer advice on how to improve lifestyle and smoking cessation but also weight reduction, exercise and stress management which would complement any pharmacological interventions.
As far as the pharmacological management of hypertension is concerned, the presence of diabetes mellitus and ethnicity of black African points towards initiation of ARB eg Candesartan 8mg OD as she is at greater risk of ACE inhibitor induced angioedema compared to other ethnicities in preference to ACE inhibitors.
ACE inhibitors would be an alternative for Mrs JT if the ARB is not tolerated although that is unlikely.
The target clinic BP should be set at 140/90mmHg
Considering patient African origin her BP may particularly be responsive to a CCB such as nifedipine which is likely the most appropriate option. Note that nifedipine is unlicensed for use in pregnancy and an alternative would be labetalol 100mg BD and titrated to response may be considered instead. As beta blocker, labetalol should however be used with caution in diabetes (may affect control of blood glucose or mask the symptoms of hypoglycaemia)
Cardiac physiology
Cardiac anatomy and mechanical cycle
Describe the anatomy and related function of the heart?
Explain the mechanical cycle of the heart?
Describe the anatomy/physiology and related function of the heart?
2 mechanical bumps right and left side
Right side deals with deoxygenated blood from the body bumping blood back into lungs and left side oxygenated blood from lungs then distributing it back to the rest of the body
2 atria
2 ventricles
4 chambers
2 top chambers left and right atria where blood is received from veins
Right side; blood is received from superior and inferior vena cava.
Left side; blood is received from the pulmonary vein.
Right ventricle; fills with deoxygenated blood and pumps it to the lungs
Left ventricle; fills oxygenated blood and pumps it to the body via the aorta hence why the left side has thicker wall generate more forces than the right side.
Left and right are separated by a septum.
Atria receives blood from veins Ventricles push blood into the arteries
The right side pushes blood into pulmonary artery and the left side pushes blood into the aorta to go to the rest of the body.
The top and bottom chamber are separated by valves and they are a series of one way valves
The heart has four one way valves, all work by a passive process so weight of blood pushes on valves this causes it to open.
The two atrioventricular valves:
Bicuspid (mitral) valve left side
Tricuspid valve right side
All the valves are supported by a chordae tendieae and they are activated by papillary muscles and they can contract with ventricles or prevent back flow so seal the valve shut separating atria form ventricles.
Arteries also have valves; pulmonary and aortic valves
Arteries only not veins
These valves contain three cusps
Semi lunar half moon cusps
Evertion prevented by upturned nature and positioning of cusps
Close under back pressure
No valves between atria and veins why
AI:
The heart is a vital organ in the human body that plays a crucial role in circulating blood throughout the body. It is a muscular organ located in the chest, slightly tilted to the left. The anatomy of the heart consists of four chambers: two upper chambers called atria and two lower chambers called ventricles. The heart is surrounded by a protective sac called the pericardium.
The heart functions as a pump to circulate oxygenated blood to the body’s tissues and organs while simultaneously receiving deoxygenated blood from them. The right side of the heart receives deoxygenated blood from the body and pumps it to the lungs for oxygenation. The left side of the heart receives oxygenated blood from the lungs and pumps it to the rest of the body.
The heart’s functioning is regulated by a specialized electrical system that controls its rhythm. This system includes the sinoatrial (SA) node, atrioventricular (AV) node, and bundle of His. The SA node initiates the electrical signals that cause the heart to contract, while the AV node delays the signal to allow for proper coordination of atrial and ventricular contractions.
The heart is also supplied with its own network of blood vessels called coronary arteries, which provide oxygen and nutrients to the heart muscle. This ensures the heart’s continuous functioning, as interruptions in the blood supply can lead to heart conditions like coronary artery disease or heart attacks.
Overall, the heart’s anatomy, physiology, and related functions work together to maintain the circulation of blood throughout the body, supplying oxygen and nutrients to the organs and tissues and removing waste products.
Whats the heart doing in diastole?
Diástole heart is relaxing and filling.
The AV valves are closed and the aortic pulmonary valves are closed and this is when the heart fills with blood from the veins. The ventricles are relatively empty and atria start to fill with blood as the diastole proceeds, the weight of the blood starts to eventually open the AV valves but the aortic and pulmonary valves will remain closed so blood will pass from Atria into the ventricles and ventricles start to fill with blood.
End stage of diastole the AV valves are open and this is when the atria begins to contract to push remaining blood into the ventricles but the aortic and pulmonary valves remain closed. This is where the blood is being transferred to the ventricles ready for pumping into the arteries.
What is systole?
This is an active phase where contraction and emptying occurs.
Start of systole the AV valves will close this prevents back flow of blood blood from ventricles into atria but the aortic and pulmonary valves remain closed. At this point ventricles begin to contract so the blood now remains inside the ventricles and start to feel pressure, no change in volume cause blood can’t go back into atria cause AV valves are closed and can’t be pushed into arteries cause the aortic and pulmonary valves are closed. The heart begins to contract so the pulmonary and aortic valves are open and at this point the blood is pushed into aortic and pulmonary arteries
Cardiac cycle mechanical events
Systole and Diastole
Systole: contraction and emptying
Isovolumetric ventricular contraction (valves closed)
Ventricular ejection (valves open)
*End systolic volume- amount of blood in ventricle at end of systole.
Diastole: relaxation and filling
Isovolumetric ventricular relaxation (valves closed)
Ventricular filling (80% before atrial contraction)
End diastolic volume- amount of blood at end of diastole.
Stroke volume= end diastolic volume-end systolic volume
Stroke volume amount of blood ejected by heart in a single beat
For the heart to work efficiently, all the cardiomyocytes have to be connected. There are two important types of connections between cells; desmosome and this provides mechanical support so cells are attached and can’t pull away from each other and gap junctions provide transmission of action potential.
This mechanical system needs to be protected via lubricants otherwise heart will rub against other surrounding tissue. Therefore, the heart so surrounded by a pericardial sac, this is a double walled sac, tough covering. Has two functions anchors the heart and it has a secretory lining, pericardial fluid (lubrication).
If this is inflamed or infected Pericarditis- painful rubbing due to viral or bacterial infection fluid become inflamed it is very painful.
Cardiac electrical activity and ECG
Describe anatomy and related function of heart
Explain how the conduction system coordinates activity in the heart.
Explain the ionic movements that underlay electrical activity in the heart.
Describe the cardiac cycle including the ECG
What are the components of electrical activity of the heart?
The heart is a simultaneous dual pump avg 70 bpm
Each beat is triggered by depolarisation of the membrane via action potential.
Regions of autorhythmicity:
•SA node top right atria pace maker region where most of the action potential is generated. Intermodal pathway; 30millisecond for action potential to pass across right atria into the AV node only point of conduction between atria and ventricles. All electrical activity pass from atria to the ventricles must pass into the AV node this takes 100milli-seconds.
Once across into the ventricles the action potential follows the bundle of his which stretches down the septum and round into the walls of right and left ventricles and Branches out into purkinje vibres that continue to pass the action potential around this takes 30ms. The action potentials then get passed through ventricles walls via the cardiomyocytes.
•AV node
•Bundle of his
•Purkinje fibres
Electrical activity SAN
Sanoatrial node SAN are autorhythmic cells 1% And they initiate and conduct action potentials or electrical activity in the heart.
Pace maker cells in the heart
Slowly drift to threshold because they only depolarise or re-polarise no resting potential. One membrane fully polarised there is a slow depolarisation step.
What is causing this slow drift? ion channels in pace maker cells start to allow this slow drift to happen and start to allow sodium ions into the cells causing increase in the charge of membrane potential and start slow depolarisation. As they approach threshold the transient Ca ion channels open to let Ca in this starts to build the depolarisation.
when threshold is reached these transient Ca ion channels close and the long lasting Ca ion channels open to let lots of Ca ions in and there is a rapid depolarisation event.
At the peak these long lasting channels close and potassium channels open letting potassium out quick repolarisation and there is no resting potentials and this process repeats
No resting potentials- the pace maker potentials is a relatively slow depolarisation caused by slow drift towards threshold and rapid depolarisation and depolarisation events.
What changes in membrane permeability can underline this depolarisation?
Na+
Increased influx of Na+ ions due to activation of Voltage gated cation channels called funny channels close with depolarisation.
There is also decreased efflux of K+ this is because delayed rectifier of K+ channels are closed.
There is a voltage calcium channel open as well towards end of slow drift of thresholdetting Ca in as well but these are closed by time threshold is reached
At threshold the long lasting voltage gated calcium channel ions open and much larger influx of Ca and much rapid depolarisation. At peaks these are closed and the delayed rectifier K+ channels open letting potassium out so a rapid repolarisation of membrane occurs. Process starts again
What is normal pacemaker cell activity?
Normal rate of action potential discharge in auto-rhythmic tissues of the heart.
Tissue
SA node (normal pacemaker) action potential per minute 70-80
AV node 40-69 action potential per mins
Bundle of His and Purkinje fibres 20-40 action potentials per minute.
SAN define how regular your heart is beating.
Pace maker cells
Cardiac action potentials in contractile cells
cardiomyocytes can also carry action potentials, they can’t generate their action potentials but they can pass action potentials from the prukinjie fibres across the cardiomyocytes into the next cardiomyocytes; has a different action potential to the pace maker cells this is because it has a resting potential or phase.
1- Influx of Na+ ions that causes a rapid depolarisation, this is partly rectified by opening of K+ channels to pump K+ out. There is a plateau phase of action potential where Ca2+ starts to slowly enter these cells. At the end of Plateau phase there is a rapid repolarisation caused by the K+ being pumped out again. This eventually reach the resting potentials till next action potential is received to fire again.
Ventricular action potentials
•After membrane depolarisation:
Voltage gated calcium channels open
L type (long lasting)
Decreased K+ permeability
•Repolarisation:
Ca+ channels inactivate
K+ channels (delayed rectifiers) open to cause repolarisation
Similar channels but very different action potentials
Excitation-contraction coupling
How do cardiomyocytes couple the electrical activity to the functional contraction of the cell once it receives the action potentials?
In plateau phase this lets Calcium into the cardiomyocytes cells, calcium is essential for contraction of cardiomyocytes cells. The action potentials will increase cytosolic calcium and this Ca is coming from extracellular space crossing into the cardiomyocyte via long lasting calcium channels and then this Ca will bind to the Ryanodine receptors on the external surface of the sarcoplasmic reticulum. This leads to the opening of Ca2+ channels intrinsic to these receptors and cause more Ca to leave the endoplasmic reticulum and increases intercellular Ca further. This Ca activities troponin and cross bridge formation.
The Ca sensitive receptors on SR, there are also two types of channels that remove Ca from they cytoplasm to switch off contraction and these are the Ca2+ ATPass pumps on the sacriolasmic reticulum and the
Na+—Ca2+ exchanger removes Ca2+ from the cytosol back to the extracellular space
What are the effects of altered extra-cellular K+ and altered Ca2+ homeostasis?
Abnormal levels of K+ resting potentials:
Increase or decrease results in decreased cardiac excitability and contractility.
Rise in extracellular K+ reduces resting potentials (depolarisation)
Inactivates Na+ channels
Arrythmias and fatalities
Decreased extracellular K+ increases resting potentials (hyperpolarisation)
Bradycardia; cardiac rhythm abnormalities.
Ca2+:
Changes in extracellular Ca2* affect membrane permeability which in turn causes cardiac rhythm abnormalities.
Ca2+ blockers reduce force of contraction inotropy
Digoxin increases cytosolic Ca2+ contractility.
How does the action potential and contractile response overlap?
When Action potential Plateau phase occurs, the contractile response starts to build up due to influx of Ca2+ this would peak and as the membrane starts to repolarise and Ca2+ gets put back into scaroplasmic reticulum or pump out of cell so we’ll lose the contractile response.
There is a refractory period this prevents the heart from starting from staring a second cycle or contraction before first cycle is complete so one beat at the time, cardiomyocytes can’t start an another contraction.
ECG & diagnosis
ECG records the activity of the heart. ECG works by putting sensors on arms ankle and around the heart and it detect the activity of the heart.
ECG generates a trace of the heart activity:
P QRS T
P-wave depolarisation of atria in response to SA node triggering
PR interval: delay of AV node to allow filling of ventricles
QRS complex: depolarisation of ventricles triggers main pumping contractions.
ST segement:
Beginning of ventricle repolarisation should be flat
T wave: ventricular repolarisation
This shows global activity of the heart.
ECG can diagnose:
•Abnormalities in rate
•Abnormalities in rhythm:
Atrial flutter
Atrial fibrillation
Ventricular fibrillation
Heart block
•Cardiomyopathies:
Ischemia
Infract
Cardiovascular risk assessment
Importance of CV assessment
Tools to estimate CV risk:
Framingham study
ASSIGN
QRISK
NICE recommendations
Communication of CV risk to patients
State national guidelines for CV?
Lipid modification- cardiovascular risk assessment abd the modification of blood lipids for the primary and secondary prevention of CVD NICE 2014 updated 2016
JBS joint British societies, consensus recommendations for the prevention of cardiovascular disease.
Both guidelines state that there must be a multifactorial approach to assess the risk CVD risk
Why is CVD risk assessment is important?
CVD is leading cause of premature death and morbidity in uk.
High NHS costs (9-billion for heart and circulatory disease)
Improvements in mortality since NSF for CHD in 2000
Since 2008 NICE guidance systematic strategy to ID all 40-47yrs likely to be at high risk.
How is CVD risk assessed?
Different tools for estimation of CVD risk
1- Framingham equations consists of CV risk assessment charts
Based on equations developed from the Framingham heart study in 1948
Estimation of CVD risk based on:
Age
Gender
BP
Smoking status
Cholesterol
Study aims to identify risk factors for the development of CVD
Baseline+ follow-up every 2 years
1971 second generation recruits
2002 third generation recruits
Limitations: dose not take into account risk factors like ethnicity, family history of CVD, BMI, Socioeconomic status.
Framingham based equations for risk reflect risks of CVD in 1960-1989 in a North America cohort.
Tend or overestimate risk in current uk population by 50% but underestimate in other ethnic origins and diabetic populations.
ASSIGN took risk
Developed in 2006, includes social deprivations and family history.
Score for risk factor 1-99
High risk is a score more than 20
Approved for use by SIGN and Scottish gov health directories.
Compute based online system
QRISK
Recommended by NICE
QRISK updated annually
Includes ethnicity, treated HT, social deprivations, BMI, family history of premature CVD, other conditions, (AF, DM, CKD, RA)
Undergone independent external validation
Computer based online system.
QRISK-3 includes CKD stage 3 as well as 4 or 5
Migraine
Corticosteroids
SLE
Atypical antipsychotic
Severe mental illness
Erectile dysfunction
Variability in systolic bp readings
NICE lipid modification guidance
Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of CVD.
1- identifying and assessing CVD risk
ID of people for full formal risk assessment:
Systemic strategy
All >40 years
Full formal risk assessment is recommended if: 10 year risk CVD >10%
Full formal risk assessment
Remember: tools only provide an approximation of CVD risk so interpretation of CVD scores should always reflect informed clinical judgement.
Use QRISK to assess CV risk for primary prevention up to age 84 yrs.
Use QRISK to assess CV risks in type 2 DM
Don’t use QRISK for:
Type-1 diabetes mellitus
Pre-existing CVD
Risk of familial hypercholesterolaemia/other inherited lipid abnormalities
> 85yrs (especially if smoke/HT)
All considered high risk and need to be managed.
Remember underestimation of risk may occur:
If underlying medical conditions or treatment increased CV risk eg HIV
In patients already treated with antihypertensive or lipid modification therapy, or recently stopped smoking.
Smoking status
Patients who have stopped smoking in previous 5 years should be considered as smokers for CV risk.
Risk from smoking more than 5 years ago depends on life time exposure and risk will lie somewhere between non smoker and smoker thus use clinical judgment.
Pack years: a pack year is smoking 20 cigarettes a day for one year.
Number of pack years= packs smoked per day x years as a smoker
Or to calculate the number of pack years if it’s not given:
number of cigarettes smoked per day x number of years smoked/20 (1 pack has 20 cigarettes)
Patient who has smoked 15 cigarettes a day for 40 years has a 15x40/20= 30 pack years smoking history
10 cigarettes a day for 6 years has 10x6/20= 3 year smoking history.
Communication about risk and assessment:
NICE recommends all aspects of CVD disease and risk should be explained to patients so they can make an informed decision about therapy and lifestyle changes.
Patients vary in what they consider to be an acceptable risk.
Easy for healthcare professionals
Not necessarily so easy for patients to decide
Explain absolute risk, likely benefits and likely harms.
Provide information without framing:
Without any treatment there is a 1in5 chance of having a heart attack or storke in the next years. However I can reduce this risk by 30% if I prescribe a statin.
Always present absolute risk and not relative risk if both disease and treatments.
30% relative risk reduction
5% absolute risk reduction
Aspirin as anti-platelet medication
Thromboxane TXA2 and Prostacyclin PGI2 are formed the degradation of cell membrane phospholipids via the action of phospholipase A2 which catalyse phospholipids into Arachidonic acid, this is further metabolised via cyclooxygenase COX into prostaglandin-G2 PGG2 (aspirin inhibits this specific step). Arachidonic acid is further metabolised into leukotrienese but this is not affected by aspirin.
PGG2 is unstable and is further metabolised into prostaglandin H2. The pathway splits here to allow for the synthesis of thromboxanes A2, prostacyclin PGI2 and PGD2, PGE2, PGF2alpha.
Thromboxane is platelet aggregations inducer.
Prostacyclin is a Platelet aggregation inhibitor.
Aspirin inhibition of COX results in the inhibition of all three pathways.
What is COX? Aspirin effects
Prostaglandin synthase
Membrane embedded protein
Hydrophobic channel into active site
Allows entry of hydrophobic Arachidonic acid directly from its synthesis site in membrane.
Active site is a heme moiety.
There are two major isoforms of COX and aspirin inhibits COX-1 isoform.
COX-1 is a homodimer consisting of along narrow hydrophobic channel buried in the lipid bilaterally, with a hairpin bend at the end, leads to the active site.
Arachidonic acid binds close to this site and a number of transformations take place simultaneously, products also released from same channel.
Aspirin does not compete for the active site or for the binding site. Instead it undergoes a reaction with specific amino acid residue. Aspirin reacts with serine 529. Serine 529 where aspirin binds is not the active site.
Step to focus on is transformation of Arachidonic acid into prostaglandin G2 PGG2 via the action of COX. Aspirin inhibits this step!
COX facilitates two steps to the mechanism as it acts as an Endoperoxide synthase, which allows introduction of oxygen and cyclisation, then secondly it acts as an oxidase enzymes to convert peroxide into an alcohol.
Mechanism of Arachidonic acid transformation into PGG2?
COX facilitates two steps to the mechanism as it acts as an Endoperoxide synthase, which allows introduction of oxygen and cyclisation, then secondly it acts as an oxidase enzymes to convert peroxide into an alcohol.
1-COX facilitates removal of the hydrogen, from the Arachidonic acid, because this enzyme is catalysed, this removal is steroselective and it is therefore very precise.
The removal of the hydrogen results in the formation of a radical and that radical can be arranged through resonance to have the radical in the optimal position for introduction of oxygen. Once radical has rearranged it reacts with a molecule of oxygen forming a bind between Arachidonic acid and oxygen.
The resulting peroxide now contains a radical and this reacts again with the Arachidonic acid through addition to double bond. At this point, a cyclisation reaction occurs between the 2 chains to form a five membered ring. Further arrangement, relocates the radical and introduction of a second molecule of oxygen.
COX undertakes its second action of introduction of a peroxide and its conversion to an alcohol to give prostaglandin G2. PGG2 is very unstable and is readily transformed into PH2.
a peroxide and it is conversion
At the active site heme, simultaneous insertions of two oxygens and cyclisation occurs.
Mechanism of aspirin inhibition of COX?
Aspirin undergoes a reaction with serine 529. This is a unique mechanism of action. All of the salicylates and other anti-inflammatory drugs, like ibuprofen, are competitive inhibitors.
Aspirin reaction with serine 529 is anchored through the involvement of 2 nearby tyrosine residues; tyrosine 385 and tyrosine 348.
Tyrosine 385 forms a hydrogen bond with acetyl portion of aspirin and that positions it in the correct place for the reaction. That hydrogen bond is strengthened through a second hydrogen bond between tyrosine 385 and tyrosine 348.
This docking allows the serine hydroxyl group to undergo a transesterification reaction.
The nucleophilicity of the hydroxy group of serine is improved by the carboxylate anion of aspirin extracting the proton and the oxygen is then able to attack the electron poor base of the carbonyl resulting in formation firstly of the tetrahedral intermediate and subsequently breaking if the bind between the acetyl group and rest of the aspirin.
This leaves the serine residue acetylated. This acetylated residue blocks the access of Arachidonic acid into the active site. It is an irreversible reaction and can only be overcome by synthesis if a new COX enzyme by the cell.
Why is aspirin an effective anti-platelet drug?
It irreversibly inhibits COX-1
Thromoxane A2 an inducer of platelets aggregation will not be synthesised.
Platelets are unable to synthesis COX-1 so synthesis of theomboxanes is halted for the lifetime of the platelet
Prostacyclin an inhibitor of aggregation will also not be synthesised but prostacyclin synthesis is more common in endothelial cells which can regenerate COX enzymes.
This means even with very low dose aspirin can work to inhibit platelets aggregation
Alternatives to aspirin
ADP receptor anataginists
Two classes of ADP receptor antagonist
Thienopyridines:
Eg Clopidogrel, Prasugrel
Antagonise the P2Y12 subtype of the ADP receptor
Not active in vivo undergoes metabolism
Once activistas the think forms a disulphide bind with the receptor
Irreversible antagonist.
Draw mechanism of active metabolite of clopidogrel active group thiol SH
Draw SAR of clopidogrel and prasugrel
Other P2Y12 antagonists
Gangrelor (intravenous use only prior to surgery doesn’t require metabolism)
Ticagrelor used in combination with aspirin (alloetwric inhibitor does not directly compete for binding with ADP
Structurally different
Drugs have also been developed for other receptors and enzyme involved in the process of aggregation including Selexipag which is a prostacyclin receptor agonist so inhibits aggregation by enhancing the activity if prostacyclin.
Cilostazol; phosphodiesterase inhibitor and eptifibatide, which is an antagonist of glycoprotein 2A/3b receptors. Eptifibatide is natural product found in snake venom and competes with binding with fibrinogen as it contains the same arginine, glycine, glutamic acid better known as RGD motif.
Summary:
Aspirin is a highly effective drug for reducing platelet aggregation due to its unique chemical reaction with COX enzyme and halts prostaglandin synthesis.
Drugs used in CVD
Treatment for high cholesterol and lipid levels.
There are 5 types of treatment:
Fibrates (ciprofibrate)
Bile acid and sequestrants (colestyramine)
Statins (mevastatin)
Ezetimibe (ezetimibe)
Plant sterols and stanols (sitosterols)
Fibrates
Affect both lipid and cholesterol levels.
Prodrug active drug is the acid
SAR of Fibrates
Para chloro or chloro containing groups increases half life.
Ring area can be extended
Spacer
Methyl groups essential
Acid group is essential for activity.
Overall it is an isobutyric acid group. It is then possible for there to be a spacer group between that unit and the rest of the molecule. The ring area can be extended and in particular substitution with a chloro group at the para position or a group that includes the chloro unit is useful for increasing the half life based on the enhanced lipiophilicity.
This SAR can be seen in marketed Fibrates.
Gemfibrozil has the spacer included
Fenofibrate an extended ring structure and the acid masked as a pro-drug. Bezafibrate and Ciprofibrate have the enhanced lipophilicity because of inclusion of halogen moieties.
Clofibrate
Gemfibrozil
Fenofibrate
Bezafibrate
Ciprofibrate
Bile acid sequestrants
Anion exchange resins
Polymers consisting of cationic backbone
Neutral by presence of conjugated anions
In presence of another anion, exchanged if anion has higher affinity for binding.
Large 1millionMW not absorbed not metabolised.
Bile acid sequestrants: are a type of chemical drug that don’t have a specific biological target. Bile acid sequestrants are anion exchange resins. They are polymers with a cationic backbone but overall neutral due to the presence of weakly bound anions.
Colestyramine and Colestipol are chloride anions when these polymer are in the presence of an anion that can be bound more tightly. The two anions exchange.
The polymers are very large which means they can’t be absorbed and they are not metabolised as they don’t contain readily degradable bonds. Thus excreted as whole polymer.
These are 2 major bile acids in humans; glycocholic acid and Taurochilic acid and they are synthetically produced in the body from cholesterol. If patient takes sequestrants, the anion exchange and the polymer is excreted with the bile acid attached to it. This means increases secretion of the bile acids. So more are produced from cholesterol, and that means overall cholesterol levels are lower/reduced.
Statins
Screening of over 8000microbial extracts
Two natural products identified
From fungi
Statins major treatment for high cholesterol.
Lovastatin no longer used but is twice as potent and was a prodrug
Mevastatin
Statins mechanism of action
•Synthesis of mevalonate form acetyl CoA synthetic pathway towards cholesterol.
•Statins interfere with the process of steroid biosynthesis
•Early stage of steroid synthesis begins with the synthesis of mevalonate form acetyl CoA.
This involves 2 molecules of acetyl CoA reacting together through a Claisne reaction to give acetoacetyl CoA.
A third acetyl group is then introduced through an aldol reaction to give hydroxy-3-methyl CoA or HMG CoA. This is the substrate for an enzyme, HMG CoA reducatse, that produce mevalonate.
That enzyme reaction is the rate determining step of cholesterol biosynthesis. Which means if we alter step we alter not only synthesis of cholesterol but because cholesterol is a precursor to adrenocorticoids and the sex hormones. Mevalonate is also the precursor for any terpenes that are synthesised in the body.
The reaction of HMG CoA resultase is a two step reaction. In the first step, the ester is reduced, resulting in the carbonyl being converted to a hydroxyl.
Second step there is an oxidation and the CoA unit is removed, leading to mevalonate.
Both substrate and product are drawn in two orientations because orientation is important for understanding the mechanism of action of statins.
Slide 10:
Statins inhibit HMG CoA reductase and they do this because they naturally mimic the intermediate, the product of that first reduction mevaldic acid hemithioacetal. To do this mimicking they have to be metabolised. The lactan ring in the natural product is opened: hence why we call it a pro drug.
Both have same functional groups and stereochemistry. The statin binds 10,000 times better than the substrate, because it mimics the intermediate and because the more hydrophobic section of the drug molecule can bind into a secondary binding site which is normally occupied by CoA part of the substrate m. The statins are highly selective inhibitors working specifically on this enzyme and they can categorise as non covalent reversible inhibitor.
Statins modifications
1- semi synthetic derivatives
2-simvastatin 2-3x more potent than lovastatin
3-pravastatin not a pro-drug, already has lactam ring opened, comes form mevastatin and is synthesised by microbial hydroxylation reaction. Better a/e profile and it is pharmacokinetic ms are altered. It is less lipophilic. Simvastatin more potent and is. A prodrug longer half life due to its steric interference of the additional methyl groups on ester side chain.
2nd generation:
Synthetic and not prodrugs. This generation involves alterations of the decal in ring structure. The part of molecule that binds the CoA binding site. It is replaced by a highly hydrophobic ring structure.
Fluvastatin, atorvastatin, rosuvastatin. Designed to have reduced lipophilicity to involve better targeting to the liver where it can have more action.
Statin SAR
Intermediate mimic
Can be ring closed
Can contain a double bond
Can’t change distance OH to ring
CoA binding site (natural products)
Decalin ring
Variation of ester
Variation at position Y
CoA binding site (synthetic products)
Nitrogen containing ring (5or6 membered)
Same ortho substituents
Statins binding interactions
Simvastatin
Atorvastatin
Slide 13
If we look at the structure activity relationship for the statins. The molecules all contain an intermediate mimic which can be closed as the lactone or be the free acid. That unit can also include a double bond as in rosuvastatin, but can’t be altered in length. Then for binding to the CoA binding site. In the first generation of natural products, a decalin ring is required. But modification of that structure is possible both at position Y and in the nature of the ester that’s attached to the decalin ring. In the second generation of synthetic products, a more variable structure activity relationship is possible. What’s required is an aromatic ring containing nitrogen. Although that ring can be 5 or 6 membered and the position of the nitrogen can be changed within it. However, consistently that ring structure then needs to be ortho substituted with all of the successful molecules having exactly the same substituents.
Ezetimibe
Inhibits absorption of cholesterol at intestinal wall related to inhibition of Norman-Pick C1-like 1 NPC1L1protein.
Lead compound SCH 48461
Designed as an Acyl-coenzyme A:cholesterol acyltransferase ACAT inhibitor.
ACAT involved in cholesterol uptake in the intestines through catalysing formation of cholesterol esters.
ACAT inhibitor is also involved in cholesterol uptake because it changes cholesterol into cholesterol esters.
Azetidinone skeleton good for activity
48461 was extensively metabolised. That occurred in the body through three different processes; de methylation hydroxylation and ring opening of the azetidinone ring.
•Demethylation can occur on both of the methyl ethers and hydroxylation could occur on both the ring structure shown and on the aliphatic chain.
Structure was further modified to enhance metabolism so hydroxyl groups were introduced where hydroxyl was useful in the aliphatic chain and demethylation product on one of the rings. Fluorine groups were introduced to both those ring structures, stopping in one case de methylation and in another hydroxylation. Ezetimibe is 50 times more active than lead molecule 48461.
Ezetimibe SAR draw the Structure?
Azetidinone essential for activity
Mono substituted more active than Di
Arylalkyl group length of chain matters, Stereochemistry doesn’t.
Substitution by aromatic group essential on the nitrogen drinks thagveit be an alkoxy aryl
S stereochemistry required
Oxygen group required.
An SAR was designed based on 150 different products and gave rise to the most important features.
Firstly, we need the azetidinone ring. Without it, no activity. And we also need this ring to be attached with a fixed stereochemistry. It’s the S configuration that’s required, and that ring substituent also needs to contain an oxygen. The nitrogen must also be substituted by a ring. But that ring doesn’t have to have an oxygen substituent present. The aryl alkyl group. the stereochemistry doesn’t matter, but the length of the chain does matter for activity. And finally, at that same position, you can introduce 1 or 2 substituents, but it’s better to introduce just that single substituent.
Plant sterols and stanols
Slide 20
So that brings us to the end of the prescription based mediations that are used for the treatment of high cholesterol. But before we finish, if we have a look at the plant sterols and stanols, the molecules which are used in products like Benacol and Flora Proactiv. These molecules do naturally occur in our diets, but levels can be increased by incorporating more within food and encouraging people to use them as substitutes for other dairy products. They’re incorporated into these foods as their esters and they lower blood cholesterol by inhibiting the absorption from the gut. And they themselves are not absorbed.
Interestingly, although I’ve said they’re natural Benacol was invented in Finland, where the steroid is actually obtained as a product or by-product of the wood pulping industry.
Slide 21
How do they work? Well, when cholesterol is absorbed from the gut, it’s absorbed in the form of mixed micelles, formed between bile salts and cholesterol. The plant sterols and stanols compete for the formation of the mixed micelles. And because they compete with the cholesterol more cholesterol is excreted. The mixed micelles containing the bile acids are less able to be absorbed.
Slide 22
So that’s the med chem of drugs used in treatment of high cholesterol. This graph shows the projected impact of ezetimibe moving the treatment of high cholesterol away from statins into either ezetimibe, on its own or actually quite commonly in combination therapy with statins.
Lipid transport and function
•Cholesterol Cholesterol is a 27 carbon compound with a unique structure with a hydrocarbon tail, a central sterol nucleus made of four hydrocarbon rings, and a hydroxyl group. The center sterol nucleus or ring is a feature of all steroid hormones.
•Triglyceride 3 fatty acid chains and glycerols Definition. A triglyceride (TG) molecule consists of a glycerol backbone esterified with three fatty acids. Triglycerides are the main constituent of vegetable and animal fats in the diet, and are the main constituent of the body’s fat stores.
•Fatty acids: a carboxylic acid consisting of a hydrocarbon chain and a terminal carboxyl group, especially any of those occurring as esters in fats and oils.
Saturated single bond
Unsaturated double bond:
mono-unsaturated and poly-unsaturated
Why is lipid needed in the body?
Essential fatty acids for hormones and cell membranes
Gene expression
Hormones prostaglandins
Energy and store 1g=37kj
Phospholipids
Structural eg brain
Protects organs
Insulation
Vitamins antioxidants
How is fat absorbed from diet?
Lipids are only broken down in the duodenum and small intestines.
Dietary fat: triglycerides
In the duodenum, lipids combine with bile salts to form fat droplets.
Lipase from pancreas digests triglycerides to monoglycerides and fatty acids.
Monoglycerides and fatty acids diffuse into epithelial cells where the recombine with proteins to form
lipo-proteins called chylomicrons these enter lymphatic capillary and go to liver and other tissues where they are required.
Fat is broken down in the duodenum and it is emulsified via bile salts that is released by gall bladder then pancreatic lipase can hydrolyse the fat micelle droplets into monoglycerides and free fatty acids. They get absorbed into epithelial cell and reaggregate to form triglycerides that aggregate and coated with lipoprotein to form chylomicrons that transport lipids around the body. These passively diffuse through lipid bilayer of the luminal membranes.
What is a lipoprotein?
•Lipids and cholesterol transported in the blood as complexes of lipids and proteins called lipoprotein.
•Hydrophobic core of lipid consists of (triglycerides and cholesteryl esters)
•Hydrophilic coat of polar phospholipids, free cholesterol and apoprotein.
Apoproteins act as ligands for specific receptors that are present on different cells throughout our body help facilitate those lipoproteins to be taken up into target cells.
Components of lipoprotein determine it is target cell or what role. We differentiate lipoproteins in size and density.
Lipoprotein with larger amount of protein are generally more dense because proteins are heavier than lipids and those consisting of more lipids have lower density.
Lipoprotein classes
•Differ in relative proportion of core lipids and types of apoproteins.
•Apoproteins bind to specific receptors on liver and other tissues.
•lipoproteins 5 classes differ in size and density each with different functions.
•Chylomicrons mainly triglycerides
•Very low density lipoproteins VLDL
•Low density lipoproteins LDL
•Intermediate density lipoproteins IDL
•High density lipoproteins HDL good cholesterol
Pathways for exogenous lipids
•Cholesterol and TG from the diet are absorbed in the ileum, transports in the chylomicrons to the lymph, blood then capillaries to the muscles and adipose tissue.
•TG is hydrolysed by lipoprotein lipase—> glycerol and free fatty acids released, which are taken up into tissues.
•Remaining chylomicrons remnants with cholesteryl esters travel to the liver bind to receptors and are endocytosed.
•Cholesterol is then stored, oxidised to bile acids or enters the endogenous pathway.
Pathways for endogenous lipids
Cholesterol (from diet and newly synthesised in the liver) and newly synthesised TG travel as VLDL to muscles and adipose tissue.
TG is hydrolysed in tissues by lipoprotein lipase to glycerol and FFA liberated.
Lipoprotein particles become smaller but retain cholesteryl esters and become LDL, which binds to LDL receptors on cells LDL receptors recognise apoB100 on LDL particles.
Cholesterol deposited in tissues for cell memebranes and other functions
Cholesterol can return to plasma and liver for tissue via HDL reverse cholesterol transport.
Cholesterol esterified with LCFA in HDL and transferred to VLDL or LDL in plasma by cholesteryl ester transfer protein CETP.
Lipid endogenous and exogenous pathway pharmacology and how they interlink?
The lipid endogenous pathway and exogenous pathway are two interconnected processes involved in the metabolism and transport of lipids in the body.
The endogenous pathway refers to the synthesis of lipids within the body. It involves the liver, which produces lipoproteins such as very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL). VLDL is synthesized in the liver and carries triglycerides, cholesterol, and other lipids to peripheral tissues. As VLDL circulates in the bloodstream, triglycerides are gradually removed, converting VLDL into LDL. LDL is responsible for delivering cholesterol to peripheral tissues for various cellular functions.
On the other hand, the exogenous pathway involves the absorption of dietary lipids from the intestine. When we consume food rich in fats, they are broken down into fatty acids and monoglycerides in the small intestine. These products are then absorbed by the intestinal cells and reassembled into triglycerides. The triglycerides are packaged into chylomicrons, which are large lipoproteins. Chylomicrons transport dietary lipids from the intestine to various tissues, including adipose tissue and muscle.
The interlink between the two pathways occurs through the exchange of lipids between VLDL and chylomicrons. After dietary lipids are transported to peripheral tissues by chylomicrons, the remnants of chylomicrons are taken up by the liver. The liver then processes these remnants, synthesizing VLDL and incorporating them into the endogenous pathway. This interplay between endogenous and exogenous pathways ensures the proper metabolism and distribution of lipids in the body.
Overall, the endogenous and exogenous pathways work together to regulate lipid metabolism, ensuring a balance between the production, transport, and utilization of lipids in the body.
Functions of apolipoproteins?
ApoB48:
In chylomicrons, essential for intestinal absorption of dietary lipids
ApoE:
In chylomicrons mediates uptake of chylomicrons remnants into liver by LDL receptor.
ApoB100:
In VLDL, IDL, LDL- main physiological ligand for LDL receptor and synthesised in liver.
ApOA1:
In HDL promotes cholesterol efflux from tissues to liver for excretion.
LDL receptor pathway?
LDL lipoprotein enter liver cells bind to it is receptors on the liver hepatocytes which causes receptor mediated endocytosis and when this happens the LDL receptor basically taken up into coated vesicles in these vesicles there is a drop in PH levels from pH7 to 5 which causes the LDL to dissociate from the LDL receptor
—>LDL lipoproteins and LDL receptor separation.
Vesicle pinches apart into smaller vesicles one that contains free LDL lipoproteins and the other contains receptors which no longer have the LDL bound to it. The vesicle that has the LDL in fuses with the lysosomes, do endosome fusing with lysosomes the enzymes in the lysosomes can cause the release of cholesterol into the cytosol where it can be used in cell membrane formation in the synthesis of steroid hormones and bile acids and to make further lipoproteins and further regulatory action.
Vesicle that contains empty receptors and basically recycle these back into cell surface. Recycling vesicle fuses with cell membrane turns it inside out via exocytosis. LDL receptors return to the cell surface so they can be used again so we can have another LDL.
Reverse cholesterol transport
Net movement of cholesterol from peripheral tissues back to liver.
When body has excess cholesterol it gets removed from the cells and returns to liver where it can be excreted.
Make HDL in liver and small intestine
Pre-beta HDL they take up cholesterol from tissues when they circulate around, the LCAT enzyme esterifies cholesterol and HDL molecules and causes the HDL particles to become more spherical and it changes it shape HDL3 these get transferred via the enzyme CETP so HDL returns back into liver and gets taken into hepatocytes so the cholesterol it isn’t carrying can be excreted.
Lipid transfer proteins in lipid transport
ACAT-acyl CoA: cholesterol acyltransferase
Catalyse intracellular synthesis of cholesteryl ester in macrophages, adrenal cortex, gut, liver.
Tamoxifen is a potent ACAT inhibitor.
LCAT- lecithin cholesterol acyltransferase
PLTP phospholipids transfer protein
Transfer of cholesterol and TG between different classes of lipoprotein particles in plasma
Dyslipidaemia
Disorder of lipid metabolism including lipoprotein overproduction and deficiency.
Due to genetic variations and inherited diseases
Genetics
May be manifested by:
Increased total cholesterol TC eg atherosclerosis
Increased low density lipoproteins eg increase cholesterol that could be deposited in arteries
Increased triglycerides
Decreased high density lipoprotein
Could be due to genetics, inherited conditions, malfunction.
Major risk factors for coronary heart disease, with the risk directly related to cholesterol levels.
Stages of atherosclerosis
Injury in endothelial cells can be cause by high blood pressure, high cholesterol levels can also damage the blood vessels so does smoking and diabetes. Endothelial cells line up the blood vessel so damage or endothelial cells can cause adhesion molecules to come to surface of endothelial cells and monocytes also start to bind to endothelial cells and get into lower layer of blood vessel. Oxidised LDL so cholesterol can be deposited which becomes oxidised and combines with macrophages to form a foam cell.
As foam cells starts to form the start to stick to blood vessels underneath the endothelial cell layer this results in plaque formation. Plaque formation leads to
Smooth muscles migration, adherence and aggregation of platelets, adherence entry of leukocytes and smooth muscle migration and T cell activation and as this plaque starts to enlarge and expand a necrotic core forms where blood doesn’t reach these cells anymore so no supply of oxygen or nutrients and fibrous cap formation on top of endothelial cells. perpetuation of inflammatory response and necrotic core leads to thinning of fibrous cap and plaque ruptures. Haemorrhage from plaque micro-vessels which can lead to heart attack or stroke.
Lipid transport
•LDL (“bad cholesterol”)
• 60-70% of TC
• Oxidised- deposited in blood vessels, leads to atherosclerosis
•HDL (“good cholesterol”)
• 20-30% of TC
• Transports excess cholesterol from peripheral tissues to the liver
• Antioxidant- decreased adverse effects of LDL
• VLDL
• Mostly cholesterol and little protein
• TG
• Fatty acids and glycerol
• Absorbed from intestine
• Circulates in blood, stored in adipose tissue (obesity in liver etc)
• Associated with risk of CHD
Targets by NICE
Targets
•Until 2014, NICE recommended:
• TC <4.0 mmol/L
• LDL <2.0 mmol/L
• HDL > 1.0 mmol/L
• TG <2.3 mmol/L
•Now:
• No specific targets by NICE
• (<5 mmol/L TC and <3 mmol/L LDL considered OK by experts, unless family history or existing heart disease.
• Aim for >40% decrease in non-HDL cholesterol
Epidemiology
Epidemiology
•UK population has one of the highest rates of dyslipidemia in the world
• 60% adults in England have TC>5 mmol/L
• Average TC in middle aged men and women between 5 and 6 mmol/L
• Increases as you get older
• Western diet leads to high TC/LDL
•South Asian populations- higher% of population with HDL <1.0 mmol/L e.g 20% Pakistani men have low HDL
Aetiology
Primary dyslipidaemia (60%)
• Combination of diet and genetics
• Genetics - 5 inherited conditions
• Diet and Lifestyle -
• High saturated fat
• Physically inactive
• Overweight or obese
• Smoking
• Large waist circumference
Secondary dyslipidaemia (40%)
• Underlying cause
• Disease or certain drugs eg diabetes, liver disease, thiazides, GC
• Natural rise as age and after menopause
Primary dyslipidaemia
Inherited conditions that increase blood lipids.
Familial hypercholesterolaemia (FH)
Inherited higher level from birth
Average- 1 person/day has FH has a heart attack.
Mutations in LDLR or APOB or PCSK9
Honozygous rare 1/250,000 > 20mmol/L
Heterozygous 1/250 populations, CHD 20 years before general population of untreated-8mmol/L.
Familial combined hyperlipidaemia
Inherited 1in100 of uk population
High cholesterol and triglycerides- raised by age 20-30
Raises VLDL and more compact and dense LDL normal.
Fasting TG> 1.5mmol/L
Type 3 hyperlipidaemia
Inherited 1/5000–1/10,000
High cholesterol and triglycerides
Mutations in ApoE
Primary dyslipidaemia
• Polygenic hypercholesterolaemia
• More than 1 gene with changes
• >12 genes linked to high cholesterol
• Primary hypertriglyceridaemia
• Lipoprotein lipase deficiency
• Affects 1 in a million
• Very high triglyceride
• Lysosomal acid lipase deficiency
• Breaks down fat in lysosomes normally but instead fat builds up in cells
• Rare condition- affects <1 in a million in UK
What are the key signs/symptoms of hyperlipidaemia?
Corneal arcus
Tendon xanthomas
Xanthelesma
Secondary dyslipidaemia
*Underlying disorders:
Diabetes mellitus
Hypothyroidism
Chronic renal failure
Alcoholism
Liver disease
*Certain drugs:
Thiazide diuretics
Loop diuretics
Beta Blockers
Oral contraceptives
Ciclosporin
Glucocorticoids
Isotretinoin
Tamoxifen
Protease inhibitors of HIV
Lipoprotein a risk factor
LDL species strongly associated with atherosclerosis.
Localised in atherosclerotic lesions.
Apo(a) structurally similar to palsminogen.
Lpa inhibits binding of plasminogen to receptors on endothelial cells- leads to less plasminogen generation and promotion of thrombosis
(Plasminogen is the precursor of plasmin, which lyses fibrin clots to fibrin degradation products (FDP) and D-dimer; the conversion to active protease is mediated by tissue-type (tPA) and urokinase-type (uPA) plasminogen activators. Generated plasmin is quickly inactivated by its main inhibitor alpha2-antiplasmin.)
Non pharmacological treatment of dyslipidaemias
Non-pharmacological treatment of dyslipidaemias:
- Dietary modification
• Low saturated fat, low trans fat, high mono or polyunsaturated fat - to decrease LDL and increase HDL
• Oily fish twice weekly
• Plant sterols and stanols to decrease cholesterol absorption from gut
• High fibre - soluble fibre (from fruit and veg) may decrease cholesterol absorption from gut.
• Weight loss - BMI <25
• Smoking
• Physical activity - 30 min x 5 times per week
• Reduce alcohol
Lipid lowering drugs
Statins inhibit an enzyme involved in the synthesis of cholesterol in the liver . Statins inhibit the
(3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors)
HMG-CoA reductase enzyme which is the Rate limiting enzyme in the synthesis of cholesterol in the liver.
Drugs not routinely recommended:
Fibrates
Inhibitors of cholesterol absorption
Nicotinic acid
Alirocumab and evolocumab (biologics anti-monoclonal antibodies)
Inclisiran (interferon molecule)
Lomitapide
Omega 3 fatty acids no longer recommended at all
Combination with diet therapy and correction of other modifiable risk factors.
What are Statins?
Atorvastatin
Rosuvastatin
Simvastatin
Pravastatin
Statins are HMG-CoA reductase inhibitors which is a rate limiting enzyme involved in cholesterol synthesis as it catalyses conversion of HMG-CoA to mevalonic acid.
Inhibit HMG CoA reductase
Competitive and reversible non covalent inhibitor
Decrease in cholesterol synthesis
Increase in LDL receptors
Increased cholesterol uptake
Reduction of blood LDLs
More effective at reducing cholesterol that other drugs
Not great for moderate to high TG
Reduce CV events and mortality irrespective of initial cholesterol concentration.
How is Cholesterol synthesised in the body?
Acetyl-CoA enzyme which metabolised into acetoaceytl-CoA and this is then converted into HMG-CoA which’s the substrate for the enzyme which the statins target.
HMG-CoA is usually converted to L-Mevalonate by the HMG-CoA reductase enzyme.
Once converted to L-Mevalonate through a series of biosynthetic alterations which result in cholesterol production, prenylated proteins eg G proteins and Ras.
***Cholesterol is synthesized in the body through a pathway known as the mevalonate pathway. This pathway involves a series of enzymatic reactions that occur mainly in the liver and other tissues. Here are the key steps involved in cholesterol synthesis:
- Acetyl-CoA Formation: Acetyl-CoA, which is derived from the breakdown of carbohydrates, fats, and proteins, is the starting point of cholesterol synthesis.
- Formation of HMG-CoA: Acetyl-CoA is converted into 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) by the enzyme HMG-CoA synthase.
- Mevalonate Formation: HMG-CoA is then converted into mevalonate by the enzyme HMG-CoA reductase. This step is considered the rate-limiting step of cholesterol synthesis.
- Conversion of Mevalonate: Mevalonate undergoes a series of enzymatic reactions to form isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are important building blocks for cholesterol synthesis.
- Cholesterol Synthesis: IPP and DMAPP are condensed to form geranyl pyrophosphate (GPP), which is then converted to farnesyl pyrophosphate (FPP). FPP is further converted into squalene, which is the precursor for cholesterol synthesis. Squalene is then converted into lanosterol and finally into cholesterol.
The end product of cholesterol synthesis is cholesterol itself, which is a vital component of cell membranes and is involved in various physiological processes. Cholesterol is necessary for the production of hormones such as cortisol, estrogen, and testosterone. It is also important for the synthesis of vitamin D and bile acids, which aid in digestion.
While cholesterol is essential for the body, it is important to maintain a balance. Excess cholesterol can accumulate in the arteries and lead to the development of atherosclerosis, a condition characterized by the buildup of plaque and narrowing of the arteries. This can increase the risk of heart disease and stroke. Therefore, it is crucial to maintain a healthy cholesterol level through a balanced diet and lifestyle choices.
Statins mechanism of action
Use of statins decrease cholesterol synthesis and unregulates LDL receptors synthesis, leading to LDL-C clearance from plasma to liver, ie. Reduces plasma LDL-C. Reduces plasma TG and increases HDL-C.
Statins are fast acting: Simvastatin and Pravastatin:
Specific, reversible, competitive HMG-CoA reductase inhibitors (Ki 1nM) inhibitory constant.
Extensively metabolised via CYP450 and glucuronidation.
Simvastatin-inactive prodrug metabolised in liver to active form.
Long lasting: Atorvastatin, Rosuvastatin.
Statins mechanism of action:
Statins target HMG-CoA reductase enzyme this reduces cholesterol synthesis in the liver.
Decrease in cholesterol synthesis this results in decrease of intracellular cholesterol. This causes the body to increase LDL receptor (B-E receptor) synthesis on the cell surface so liver takes up more cholesterol so this leads to more VLDL binding to the LDL receptors recognising the ApoB100 proteins on the VLDL surface, this leads to reduction in serum LDL concentration. Small TG effect slightly reduced.
Statins are a class of medications commonly prescribed to lower cholesterol levels in the body. They work by inhibiting an enzyme called HMG-CoA reductase, which plays a key role in the synthesis of cholesterol. Here’s a breakdown of the mechanism of action and pharmacology of statins:
- Inhibition of HMG-CoA Reductase: Statins primarily exert their effects by blocking the activity of HMG-CoA reductase, the enzyme responsible for converting HMG-CoA to mevalonate in the cholesterol synthesis pathway. By inhibiting this enzyme, statins reduce the production of cholesterol in the liver.
- Decreased Cholesterol Synthesis: With reduced levels of HMG-CoA reductase activity, the liver cells respond by increasing the number of LDL receptors on their surface. These receptors help in the uptake and clearance of LDL cholesterol from the bloodstream, leading to a decrease in circulating LDL cholesterol levels.
- Lowering LDL Cholesterol: By reducing LDL cholesterol levels, statins help prevent the buildup of cholesterol in the arterial walls, reducing the risk of atherosclerosis and related cardiovascular diseases.
- Modulation of Inflammatory Processes: Statins have been found to have anti-inflammatory effects independent of their cholesterol-lowering properties. They can reduce the production of inflammatory markers and cytokines, which play a role in the development and progression of atherosclerosis.
- Increase in HDL Cholesterol: Statins may also increase the levels of high-density lipoprotein (HDL) cholesterol, often referred to as “good” cholesterol. HDL cholesterol helps remove excess cholesterol from the arteries and transports it back to the liver for excretion.
- Pharmacokinetics: Statins are typically administered orally and are absorbed in the digestive tract. They are extensively metabolized in the liver by various enzymes, including cytochrome P450 enzymes, before being eliminated from the body through bile and feces. The dosage and frequency of statin administration depend on the specific medication prescribed.
It is important to note that statins are generally well-tolerated, but they may have potential side effects such as muscle pain, liver enzyme abnormalities, and, rarely, muscle damage. It is crucial to discuss any concerns or potential interactions with other medications with a healthcare professional before starting statin therapy. Regular monitoring of liver function and muscle symptoms is typically recommended during statin treatment.
Statins protective effects in the vasculature
Statins protective effects:
Plaque stability reduce risk of plaque rupture and decrease risk of MI or stroke.
Decreases cell infiltrate and MMP
Increase collagen, VSMC, TIMP
Increase Neovascularisation of ischemic tissues (increase blood flow to plaque area so reduce necrotic core)
Anti-thrombotic:
Decrease TF, PAI-1, platelet aggregation
Increase fibrinolytic activity, tPA, eNOS.
Anti-oxidant:
Decrease NADPH oxidase. Superoxide, oxidation of LDL
Increase radical scavengers.
Anti-inflammatory:
Decrease NF-KapaB, IL-1, TNF, MMP, CRP.
Leukocytes-endothelial interactions
Adhesion molecules
Macrophages/T-cell activation
Complement injury
Smooth muscle cell proliferation
Monocytes chemotaxis
What genetic factors influence response to statins?
•CYP 3A4, 3A5, 2C8, 2C9, 2D6 metabolise statins
•ABCs-A1, G1, G5, G8, B1, C2, MCT4, OATP2
•Lipoproteins lipase
•ApoA1, A2, C3, A4, A5, B, E
•Cholesteryl ester transfer protein
•Lecithin cholesterol acyltransferase
•PPAR alpha
•SREBP 1&2
IL-1beta, IL6 polymorphisms influence response to Pravastatin.
You’ve mentioned several genetic factors that can influence the response to statins. Here’s a breakdown of how these genetic factors may impact the effectiveness and metabolism of statins:
- Cytochrome P450 Enzymes: Genetic variations in CYP3A4, CYP3A5, CYP2C8, CYP2C9, and CYP2D6 can affect the metabolism of statins. These enzymes are involved in the breakdown of statins in the liver. Genetic variations in these enzymes can result in differences in how quickly or slowly statins are metabolized, which can impact their effectiveness and potential side effects.
- ATP-Binding Cassette (ABC) Transporters: ABC transporters, such as ABCA1, ABCG1, ABCG5, ABCG8, ABCB1, and ABCC2, play a role in the transport of statins and cholesterol in the body. Genetic variations in these transporters can affect the uptake, distribution, and elimination of statins, potentially influencing their efficacy and safety.
- Lipoproteins and Apolipoproteins: Genetic variations in lipoproteins, such as lipoprotein lipase, and apolipoproteins, including ApoA1, ApoA2, ApoC3, ApoA4, ApoA5, ApoB, and ApoE, can impact lipid metabolism and the response to statin therapy. These variations can influence the levels of LDL cholesterol, HDL cholesterol, and triglycerides, which are key targets of statin treatment.
- Cholesteryl Ester Transfer Protein (CETP): CETP is involved in the transfer of cholesteryl esters between lipoproteins. Genetic variations in CETP can affect the levels of HDL cholesterol and the response to statins.
- Lecithin Cholesterol Acyltransferase (LCAT): LCAT is an enzyme involved in the conversion of free cholesterol to cholesteryl esters, which are then incorporated into lipoproteins. Genetic variations in LCAT can impact cholesterol metabolism and potentially influence the response to statin therapy.
- Peroxisome Proliferator-Activated Receptor Alpha (PPARα): PPARα is a nuclear receptor that regulates lipid metabolism and inflammation. Genetic variations in PPARα can affect the response to statins, particularly in terms of lipid-lowering effects.
- Sterol Regulatory Element-Binding Proteins (SREBPs): SREBPs are transcription factors that regulate the expression of genes involved in cholesterol synthesis and metabolism. Genetic variations in SREBPs can impact the response to statins by affecting cholesterol homeostasis.
- Interleukin Polymorphisms: Polymorphisms in genes encoding interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) have been associated with variations in the response to specific statins, such as pravastatin.
It’s important to note that while genetic factors can influence the response to statins, they are just one piece of the puzzle. Other factors such as lifestyle, diet, and overall health also play a significant role in the effectiveness of statin therapy. Consulting with a healthcare professional can provide personalized guidance regarding statin therapy based on individual genetic factors and overall health status.
Effectiveness of statins
Limited systemic bioavailability 50-80% first pass so high first pass metabolism 50-80% is metabolised in the liver. This is not a problem cause target organ is liver.
Some are prodrugs eg Simvastatin and lovastatin
Some work better if taken at night
Typical LDL reduction from 20-40% eg lovastatin to 40-60% atorvastatin
10-20% reduction in triglycerides
5-10% increase in HDL.
Nester CV outcomes and effects on inflammation and oxidative stress.
Widespread use primary and secondary prevention of CVD from RCT results-effective.
Benefits outweigh the harm in high risk patients increase risk of developing type 2 diabetes with more lipophilic statins.
Studies in COPD no benefit, pneumonia, cancer, spinal cord injury, mainly lack evidence,
Fibrates
Fibrates are derivatives of fibric acid- structurally related to thiazolidiones not widely used but used when statins are contraindicated or to reduce hypertrigylcerdemia.
Fibrates mechanism of action:
Agonists for PPARalpha-subfamily of nuclear receptors that modulate lipid and carbohydrates metabolism and induce differentiation of adupocytes.
Lipoproteins lipase results in breakdown of VLDL.
ApoA1 and ApoA5 results in increase in HDL production.
Increase hepatic LDL-C uptake, from
LDL with higher affinity to the LDL receptor.
Increase fatty acids uptake and conversion to acyl vi-A by the liver, therefore fatty acids aren’t even available for TG synthesis.
Decrease of VLDL from liver and hence TG levels reduced x
Anti-inflammatory effects:
Decrease APP synthesis-CRO and fibrinogen
Inhibits VSMC inflammation via NF-kB
Fibrates increases these proteins:
ApoAI
ApoAII
ABCA1
The above proteins increase HDL production that can reverse cholesterol transport and can increase HDL production that is involved in reverse cholesterol transport.
Fibrates decrease:
ApoCIII
TG
FFA
Fibrates increase Acyl-CoA synthase which increases amount of FFA that is converted to Acetyl CoA in the liver and cause there are lower free fatty acids FFA body can’t make as much triglycerides decrease in TG and decrease in VLDL production and increase clearance of VLDL and they decrease LDL particle too
Fibrates not recommended by NICE
Can be prescribed for hypertriglyceridemia-serum TG>10 mmol/L
Given when statins are contra-indicated or not tolerated.
Drugs that inhibit cholesterol absorption from gut
•Ezetimibe inhibits cholesterol absorption-used where statin contraindicated or in addition to statin
•Bile acid binding resins no longer recommended except in special circumstances as can aggravate hypertriglyceridemia
•plant sterols and stanols supplements and functional foods
Ezetimibe
Specifically blocks absorption of cholesterol without affecting absorption of fat soluble vitamins, TG or bile acids.
Higher potency than bile acid resins because it specifically inhibits or binds to proteins in GI epithelial cells that are responsible for cholesterol absorption, including:
NCPC1L1, aminopeptidase N and caveolin 1-Annexin A2 complex
Conjugated in intestine to Ezetimibe glucuronide (also pharmacologically active) and excreted in stools.
No important drug or food interactions reported
But only Lowers LDL-C by 17% as most of cholesterol is made in the liver.
Ezetimibe mechanism of action:
Inhibits cholesterol absorption in the intestine so decrease in chylomicrons production and remnant so therefore reducing VLDL and LDL that transports cholesterol around the serum.
Nicotinic acid derivatives
Nicotinic acid water soluble B vitamin
1.5-3g per day lowers both LDL and cholesterol and TG by inhibiting synthesis
Increases HDL cholesterol
Inhibits TG production and VLDL secretion
No longer recommended by NICE for primary/secondary prevention of CAD or CKD or diabetes of vasodilators effects.
Occasional use in combination with statin if not adequately controlled
Mechanism of action:
Mobilisation of FFA so that decrease amount of TG synthesis and decrease in VLDL secretion which leads to decrease in serum LDL
Targeting PCSK9
Proprotein convertase subtilisin/kexin type-9
PCSK-9
Binds to hepatic LDL receptors and promotes their lysosomal degradation.
Prevents recycling of the LDL receptors back onto the cell surface of hepatocytes limits LDL uptake into the liver.
PCSK-9 involved in preventing the amount of LDLR recycling through PCSK9 inhibition.
Monoclonal antibodies that inhibit PCSK9, results in increasing receptor number and LDL uptake
Treatment of primary hypercholesterolemia or mixed dyslipidaemia as adjunct to diet.
Combination with statin or with other lipid lowering drugs if statin not tolerated.
Approved by NICE in 2016
Action of PCSK9 inhibitors:
PCSK9 bind to LDL receptor and it promotes LDL receptor degradation via the lysosomes and therefore it can’t be recycled or retaken up on cell surface membrane and it can’t function as usual or take other LDL particles. However, anti-PCSK9 antibodies bind it PCSK9, preventing it from binding to the LDL receptors
PCSK9 inhibitors are a class of medications that work by targeting the PCSK9 protein in the body. Here’s a brief explanation of their mechanism of action:
- Role of PCSK9: PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) is a protein that plays a key role in regulating levels of low-density lipoprotein cholesterol (LDL-C) in the bloodstream. PCSK9 binds to LDL receptors on liver cells, leading to the degradation of these receptors and reducing their ability to remove LDL-C from the blood.
- Inhibition of PCSK9: PCSK9 inhibitors, such as evolocumab and alirocumab, work by blocking the action of PCSK9. These medications are typically administered as subcutaneous injections on a biweekly or monthly basis. By inhibiting PCSK9, these drugs prevent the degradation of LDL receptors and increase their availability on liver cells.
- Increased LDL Receptor Activity: With PCSK9 inhibitors, the increased availability of LDL receptors on liver cells allows for more efficient removal of LDL-C from the bloodstream. This leads to a significant reduction in LDL-C levels, which is the primary target for these medications. Lowering LDL-C is important because high LDL-C levels are associated with an increased risk of cardiovascular diseases, such as heart attacks and strokes.
- Additional Effects: In addition to lowering LDL-C, PCSK9 inhibitors may also have other positive effects on lipid metabolism. They can increase high-density lipoprotein cholesterol (HDL-C) levels and reduce triglyceride levels to some extent. These medications have also been shown to reduce the risk of cardiovascular events in patients with a history of cardiovascular disease.
It’s important to note that PCSK9 inhibitors are usually prescribed as an adjunct to diet and maximally tolerated statin therapy for patients with elevated LDL-C or familial hypercholesterolemia who have not achieved their target LDL-C levels with other treatments alone. The use of PCSK9 inhibitors should be done under the guidance of a healthcare professional who can assess the patient’s individual risk factors and determine the most appropriate treatment approach.
Inclisiran
Approved by NICE in 2021
Inclisiran is a small interfering RNA siRNA treatment that inhibits the translation of PCSK9 mRNA—> gene silencing
Can be designed for one specific gene in this case its PCSK9 gene so they cat to reduce gene transcription of that target .
1-GalNAC targets Inclisiran to the hepatocyte ASGPR.
2-Endosomal uptake, GalNAc cleavage, ASGPR revealed to cell membrane.
3-Inclisiran is slowly released from endosomes into the cell cytoplasm, resulting in a sustained therapeutic effect.
4-Inclisiran enters the RNA-induced silencing complex
5-Inclisiran sense, antisense strands separate.
6-Inclisiran antisense strands directs RISC to bind PCSK9 mRNA strands, triggering catalytic cleavage and reducing production of the PCSK9 protein.
7- Reduced PCSK9 results in increased LDL-C receptor recycling to the hepatocytes surface and increased clearance of circulating LDL-C.
Atherosclerosis
Understand development and progression of atherosclerosis.
The stages of atherosclerosis:
Artery wall made up of three layers:
•Inner most layer consists of endothelial cells and basement membranes.
•Middle layer made up of smooth muscle cells and elastic components
That allows the blood vessels and arteries to stretch and recoil in response to changes in blood flow and blood pressure
•Outer most layer consists of connective tissues
These 3 layers allow the blood vessel to form a tube and in the lumen in the middle hollow part of the tube is where the blood will flow. The endothelial cells detect blood flow. Blood consists of many different types of components and cells eg RBC.
Blood vessels, including arteries, play a crucial role in the circulatory system by transporting blood throughout the body. Here’s a brief overview of the physiology of blood vessels and arteries:
- Structure of Blood Vessels: Blood vessels are composed of three layers: the tunica intima, tunica media, and tunica externa. The tunica intima is the innermost layer, consisting of a single layer of endothelial cells that provide a smooth surface for blood flow. The tunica media is the middle layer, made up of smooth muscle cells and elastic fibers, which allow the vessel to contract and relax. The tunica externa is the outermost layer, consisting of connective tissue that provides support and protection to the vessel.
- Arterial Function: Arteries carry oxygenated blood away from the heart to various tissues and organs. They have thicker walls compared to other blood vessels to withstand the high pressure generated by the heart during systole (contraction). Arterial walls are highly elastic, allowing them to expand and recoil with each heartbeat, maintaining continuous blood flow and preventing pressure fluctuations.
- Vasodilation and Vasoconstriction: The smooth muscle cells in the arterial walls can contract (vasoconstriction) or relax (vasodilation) to regulate blood flow and blood pressure. Vasoconstriction narrows the arterial lumen, increasing resistance to blood flow and raising blood pressure. Vasodilation, on the other hand, widens the arterial lumen, reducing resistance and lowering blood pressure.
- Endothelial Function: The endothelial cells lining the blood vessels have several important functions. They regulate vascular tone by releasing vasoactive substances such as nitric oxide, which promotes vasodilation. Endothelial cells also help prevent blood clot formation by releasing substances that inhibit platelet aggregation and promote the formation of smooth, non-thrombotic surfaces.
- Capillaries and Exchange of Substances: Arteries branch into smaller vessels called arterioles, which further divide into capillaries. Capillaries are the smallest blood vessels, with thin walls consisting of a single layer of endothelial cells. Their primary function is to facilitate the exchange of oxygen, nutrients, and waste products between the blood and surrounding tissues. This exchange occurs through the process of diffusion.
Overall, the physiology of blood vessels, including arteries, is vital for maintaining proper blood flow, regulating blood pressure, and facilitating the exchange of substances between the blood and tissues. Dysfunction of blood vessels can lead to various cardiovascular conditions, such as hypertension, atherosclerosis, and peripheral artery disease, highlighting the importance of maintaining vascular health.
Stages of atherosclerosis
Aging causes these endothelial damage, this is due to many reasons eg LDL, smoking, free radicals. Overtime they start to leak and rupture so they let out blood into artery walls and they will leak out LDLs. Once LDL cross endothelial layer it gets into basement memebrane and start to accumulate, this become oxidised and this becomes a trigger for endothelial cells to start expressing markers that bind and attract immune cells to cross.
This leads to dysfunction and inflammation in the basement membrane, immune cells start to attack oxidised LDL and fragments of cells so macrophages switch to foam cells. This triggers smooth muscle cells to start migration and proliferation this results in a fibrous cap to block blood from entering the content of this plaque this forms a necrotic core. Ovetime this fibrous cap thins cell death proliferation will stop and this results in an unstable plaque that can rupture. This necrotic lipid core is now exposed to the blood and this triggers a cascade of event that will eventually block blood vessels due to clotting. If this happens in an artery it can starve the brain or the heart from oxygen.
Atherosclerosis is a chronic inflammatory disease that affects the arteries, leading to the formation of plaques and narrowing of the blood vessels. Here’s an overview of the pathophysiology of atherosclerosis:
- Endothelial Dysfunction: The development of atherosclerosis begins with the dysfunction of the endothelium, the inner lining of the blood vessels. Risk factors such as high blood pressure, smoking, high cholesterol levels, and diabetes can damage the endothelial cells, impairing their normal functions. This dysfunction leads to increased permeability, adhesion of white blood cells, and the release of inflammatory molecules.
- Formation of Fatty Streaks: In response to endothelial dysfunction, low-density lipoproteins (LDL) cholesterol particles penetrate the damaged endothelium and accumulate within the arterial wall. Macrophages engulf the modified LDL particles, forming foam cells. These foam cells, along with other immune cells, accumulate to form fatty streaks, which are the earliest visible signs of atherosclerosis.
- Formation of Fibrous Plaques: Over time, the fatty streaks undergo further changes. Smooth muscle cells migrate from the middle layer of the arterial wall to the intima, where they proliferate and produce extracellular matrix components. This results in the formation of fibrous plaques, which consist of a lipid core covered by a fibrous cap. The fibrous cap is composed of smooth muscle cells, collagen, and elastin.
- Complications and Plaque Rupture: As the plaques grow, they can narrow the arterial lumen, restricting blood flow. The fibrous cap of the plaque can become thin and vulnerable to rupture. If a plaque ruptures, it exposes its lipid core to the bloodstream, triggering the formation of blood clots (thrombosis). These blood clots can partially or completely block the artery, leading to severe ischemia or even complete occlusion of the vessel.
- Consequences: Atherosclerosis can affect any artery in the body, leading to various complications depending on the affected site. In coronary arteries, it can cause angina (chest pain) or myocardial infarction (heart attack). In the carotid arteries, it can lead to stroke. Peripheral arteries can be affected, causing peripheral artery disease with symptoms such as leg pain and impaired wound healing. Atherosclerosis can also affect renal arteries, leading to renal artery stenosis and hypertension.
The pathophysiology of atherosclerosis involves a complex interplay between inflammatory processes, lipoprotein metabolism, and the immune response. Understanding these mechanisms is crucial for developing strategies to prevent and treat atherosclerosis, focusing on risk factor modification, lifestyle changes, and medications to reduce inflammation and cholesterol levels.
Haemostatsis and thrombosis
When blood vessel is damaged, bleeding will occur and this activates a series of events that allows the blood vessel to stop leaking blood. This know as haemostasis, process of arresting blood loss from damaged blood vessels.
Wound—> vasoconstriction—> platelet activist ion and adhesion—> formation of haemostatic plug coagulation—> fibrinolysis
Atherosclerotic induced coagulation cascade is there no bleeding so this known as thrombosis and thrombosis is formation of clot in vasculature in the absence of bleeding there is no vasoconstriction, this is because platelet activation step is activated and everything downstream—> platelets activation and adhesion—> formation of haemostatic plug coagulation—fibrinolysis.
Thrombosis pathological formation of clot in vasculature in the absence of bleeding.
When a blood vessel is damaged, it triggers a series of events known as hemostasis, aimed at stopping blood loss. This involves vasoconstriction, platelet activation and adhesion, the formation of a hemostatic plug, coagulation, and fibrinolysis.
Thrombosis, on the other hand, is the pathological formation of a clot within blood vessels without bleeding. This occurs when the atherosclerotic-induced coagulation cascade is activated, leading to platelet activation and adhesion, followed by the formation of a hemostatic plug, coagulation, and fibrinolysis, despite the absence of bleeding.
Drugs for haemostasis and thrombosis
Thrombosis prevention-extensively used
Drugs affect Haemostatsis and thrombosis by affecting:
Platelet adhesion and activation
Blood coagulation (fibrin formation)
Fibrin removal (fibrinolysis)
Anti-platelets
Arterial thrombosismay be caused by a hardening of the arteries, called arteriosclerosis. This happens when fatty or calcium deposits cause artery walls to thicken. This can lead to a buildup of fatty material (called plaque) in the artery walls. This plaque can suddenly burst (rupture), followed by a blood clot.
Haemostasis represents a physiological response to prevent bleeding, the term thrombosis typically refers to the pathologic formation of a thrombus (clot).
Drugs for haemostasis and thrombosis:
Some drugs act as haemostasis promotion-rarely necessary except when defects:
Haemophilia
Extensive anticoagulation therapy
Haemorrhage after surgery
Menorrhagia
Some drugs act as Thrombosis prevention-extensively used
Drugs affect haemostasis and thrombosis by affecting:
•Platelet adhesion and activation
•Blood coagulation fibrin formation
•Fibrin removal fibrinolysis
What are platelets?
Maintain integrity of circulation
Essential for Haemostatsis, healing of vessels and inflammation.
Various properties:
•Adhesion following vascular damage
•Shape changes
•Secretion of granule content
•Biosynthesis of PAF and prostaglandins
•Aggregation
•Exposure if acidic phospholipid on surface.
Mechanism of platelet adhesion, activation and secretion?
Usually platelets are not active and just float around in the blood.
If platelets get exposed to damage they will become activated. Many pathways activate platelets.
Two components that activate platelets of the matrix are collagen and von willebrand factor and there receptors for both on the platelets so when exposed to these extracellular matrix components they can bind and start to activate platelets activation.
There are also soluble factors and there are lots of other receptors on the platelets and they bind different things, so things like thromboxane-A2
ADP, aIIbB3, GPIb/V/IX and many others.
Platelet aggregation leads to further platelets activation, receptors bind to fibrin and fibrin forms links between the platelets causing aggregation and further stimulating activation of platelets. Change in shape is driven by change in the cytoskeleton of the platelets.
*Platelet adhesion and aggregation:
Exposure of collagen or Von Willebrand Factor (vWF) will bind to receptors on the platelets and lead to activation. This leads to platelet activation will trigger platelets aggregation which will further stimulate activation of platelets around the plug or the activated aggregated mesh work forming and this will form a plug. Incase of bleeding plug stops bleeding but incase of thrombi without bleeding this will block blood vessel.
The platelets also contract and this is given by cytoskeletal changes and this will lead to concentration affect and further block the blood vessel.
Substances can stimulate aggregation or activation. Eg ADP, thromboxane A2, Von Willbrand factor or collagen . All lead to activation of platelets and aggregation.
There are also factors that prevent the activation of platelets and these include nitraic oxide and and prostacyclin both made by endothelial cells and they are released into the blood and these serve to inhibit aggregation and activation. Endothelial cells also reduce levels of ADP via AMP enzyme cleavage.
Platelet adhesion, activation, and secretion are crucial processes in hemostasis, the body’s mechanism for preventing excessive bleeding. Here’s a breakdown of each process:
-
Platelet Adhesion:
- Vascular Injury: When a blood vessel is damaged, exposing the underlying collagen and von Willebrand factor (vWF), platelet adhesion is initiated.
- Glycoprotein Receptors: Platelets express glycoprotein receptors on their surface, such as glycoprotein Ib (GPIb) and glycoprotein VI (GPVI), which interact with vWF and collagen, respectively.
- Initial Adhesion: The interaction between vWF and GPIb leads to the initial adhesion of platelets to the exposed collagen fibers in the injured vessel wall.
-
Platelet Activation:
- Agonists: Various agonists, such as thrombin, adenosine diphosphate (ADP), and thromboxane A2, are released or generated at the site of injury.
- Receptor Activation: These agonists bind to specific receptors on the platelet surface, triggering intracellular signaling cascades.
- Intracellular Signaling: Activation of receptors leads to an increase in intracellular calcium levels, activation of protein kinases, and phosphorylation of various proteins, ultimately resulting in platelet activation.
- Shape Change and Granule Secretion: Activated platelets undergo shape change, extending filopodia and lamellipodia. They also secrete granules containing factors such as ADP, serotonin, and thromboxane A2, which further amplify platelet activation and recruit additional platelets to the site of injury.
-
Platelet Secretion:
- Granule Release: Platelet granules, including alpha granules and dense granules, contain various molecules involved in hemostasis and wound healing.
- Alpha Granules: These contain factors such as fibrinogen, von Willebrand factor, and growth factors, which promote platelet aggregation, clot formation, and tissue repair.
- Dense Granules: These contain molecules like ADP and calcium, which enhance platelet activation and aggregation.
- Autocrine and Paracrine Signaling: The substances released from platelet granules act in an autocrine (affecting the releasing platelet) and paracrine (affecting nearby platelets and cells) manner, further enhancing platelet activation and aggregation.
Overall, platelet adhesion, activation, and secretion are tightly regulated processes that ensure rapid and effective hemostasis following vascular injury. Dysregulation of these processes can lead to bleeding disorders or thrombotic diseases.
How can we influence platelet aggregation and activation?
Inhibition of platelets activation and aggregation can occur via targeting of promoters like thromboxane A2 production or activity same for ADP.
Cell aggregation can also be inhibited via blockers that will block binding to Von willbrand factor or collagen the extracellular matrix components that lead to platelet activation.
The stimulation of inhibitor production like stimulation of HNO3 acid production but this strategy is short lived so not very effective. Increase of prostacyclin formation will inhibit platelet activation or increase removal of ADP which decreases platelet activation.
Platelet activation and aggregation via GP surface proteins eg GPIbeta bind to VWfactor extracellular matrix activation
GPIIalpha bind to fibrinogen and fibrinogen lead to platelets aggregation.
Antiplatelets drugs
Decrease platelet aggregation and inhibit thrombus formation in arterial circulation.
Aspirin
Thienopyridines: clopidogrel (prasugrel, ticlopidine)
Ticagrelor
Glycoprotein IIb/IIIa inhibitors
Eptifibatide
Tirofiban
Abciximab
Dipyridamole
What is the role of anti-platelet activity?
Inhibit pathways that activate platelet activation or aggregation.
So targeting thromboxane synthesis or TXA2 binding to receptors, ADP pathways or glycoproteins GPI or GPII
Or target aggregation set by nitric oxide which is very short lived so not a therapeutic option or target prostacyclin.
,
Pharmacology of aspirin
Aspirin irreversibly inactivates cyclooxygenase COX
COX1 and COX2
•COX1 is found in platelet
Homeostasis
Platelet aggregation
•COX2 is found in endothelial cells
Platelet aggregation
COX 1 important due to their ability to synthesis thromboxane A2 in platelets which will stimulate further activation of platelets.
In endothelial cells COX 2 is important for the production of prostacyclin which is an inhibitor of platelets activations and aggregations.
Aspirin irreversibly inactivates COX1 in platelets
Reduces thromboxane A2 formation
Reduces platelet aggregation
Irreversibly inactivates COX2 in endothelium
Reduces prostacyclin formation
Increases platelet aggregation
Net effect zero
Endothelial cells can synthesis new COX 2 and platelets can’t because no nuclei.
Lower doses just inhibit platelets
Higher doses both.
Clopidogrel, Prasugrel, Ticagrelor
Thienopyridines- pro drugs additive effects to aspirin, because they work on separate pathway.
Inhibit ADP induced aggregation ADP receptor antagonist
Antagonise the platelet P2Y12 receptor (purinergic receptor)
Ticagrelor
Nucleoside analogue- like adenosine
Blocks P2Y12 ADP receptors on platelets
Different binding sites than ADP so allosteric inhibitor and blockage reversible and therefore acts faster and for shorter period.
PLATO trial Ticagrelor less mortality from all CV causes than clopidogrel
Side effects- more non lethal bleeding effects more quickly reversible
Though.
Glycoprotein IIB/IIIA receptor anataginists
Antagonist antagonise the ability of the glycoprotein receptor to bind to fibrinogen and therefore lead to reduced or inhibition of platelet aggregation and activation.
• Inhibit all pathways of platelet activation because bind to glycoprotein
Ilb/Illa receptors, blocking fibrinogen binding so inhibiting aggregation.
• Abciximab - monoclonal antibody
• Adjunct with heparin and aspirin for prevention of complications in patients undergoing percutaneous coronary intervention
• Used ONCE only, very expensive - approx £260
*• Cyclic peptides - Eptifibatide and Tirofiban
• Adjunct with heparin and aspirin to prevent early MI in, patients with unstable angina or non-STEMI
Coagulation
Haemostasis and thrombosis:
Haemostasis is the arrest of blood loss from damaged blood vessels.
Thrombosis pathological formation of clot in vasculature in the absence of bleeding. Thrombosis leads to activation of platelets and the downstream activation of coagulation.
The formation of blood clot:
In endothelial cell damage if platelets are exposed to extracellular matrix such as VWF and collagen fibres the platelets will bind to and become activated and this will lead to platelet aggregation, platelets start to initiate the coagulation cascade to form a fibrin polymer.
Wound or injury leads to vasoconstriction then platelet activation and adhesion. This leads to the formation of a plug and this leads to fibrinolysis.
Coagulation:
Formation of a fibrin clot or thrombus
Reinforces platelet plug
May trap blood cells
•white thrombus
•red thrombus
Thrombus is insoluble, strong and traps RBC and WBC and this reinforces the platelet plug.
This formation of clot or thrombus is regulated by the coagulation cascade.
Coagulation cascade:
Complex enzyme cascade that ultimately leads to the conversion of soluble fibrinogen to insoluble fibrin.
Coagulation cascade
Coagulation cascade complex series of enzymic steps (proteolysis each enzyme will cleave and catalyse the next enzyme in the cascade).
Intrinsic or contact pathway all; components present in blood already
Extrinsic or in vivo pathway; component from outside of blood/requires external input eg tissue factor/gets activated due to tissue damage which induces tissue factor and thus activates coagulation cascade.
Both pathways converge at factor x (ten) and this leads to its cleavage to activated form xa and this is either initiated by factor 9a or 7a depending on whether it is intrinsic or extrinsic pathway activation. Xa cleaves prothrombin to thrombin. Thrombin will cleave fibrinogen to insoluble fibrin which will then form a polymeric system and mesh work that will form into blood clot.
Thrombi or atherosclerosis it is the extrinsic pathway and it is tissue factor release that gets switched on. Activation of factor x to xa leads to the conversion or cleavage of prothrombin to thrombin then cleaves soluble fibrinogen to insoluble fibrin the fibrin will then form polymers and this will lead to a highly insoluble plug which will trap the blood cells and form a clot.
How does the coagulation pathway further reinforce platelets activation/aggregation?
Platelet aggregation and platelet pathways interact with coagulation cascade at different levels.
Platelet activation/aggregation will lead to formation of platelet plug. Platelets secrete thromboxane A2 and ADP to stimulate aggregation. Platelet activation lead to the exposure of acidic phospholipids to the outside of the cell and this step switches on the coagulation cascade and it feeds into the in vivo pathway or the extrinsic pathway and also in the activation of 7a or 10 or 10a or cleaves of thrombin too.
The coagulation pathway or components of the coagulation feed back to further stimulate platelet aggregation and activation and factors that induce this step are thrombin and fibrinogen binds to GPII/IIIbeta to stimulate further aggregation so both pathways interact to form a thrombus and block a blood vessel.
What’s the role of thrombin?
•Thrombin cleaves fibrinogen to fibrin, producing fragments that polymerise to form insoluble fibrin.
•Activated factor XIII activates thrombin— strengthens fibrin links.
•Platelets aggregation.
•Cell proliferation.
•Regulates smooth muscle contraction.
What’s the role of liver in coagulation?
Liver synthesis many of the coagulation factors and liver is absolutely essential for the synthesis of these clotting factors.
Vitamin K lipid soluble (phytomenadione) and it is called “Koagulation” vitamin as its required for the synthesis of factors II, VII, IX, X
Vit K from Dietary sources and Synthesis in the GIT.
Bile salt synthesises is essential for Vitamin K absorption and vitamin K absolutely essential for these coagulation factors.
Anticoagulation agents
Drugs used in coagulation disorder
Warfarin and heparin anticoagulants low molecular weight and unfractioned
fractionated vs unfractionated heparin?
LMWH is obtained by fractionation of polymeric heparin. LMWH differs from unfractionated heparin in a number of ways, including the average molecular weight; the need for only once or twice daily dosing; the absence of monitoring the aPTT; and the lower risk of bleeding, osteoporosis, and HIT.
How do anticoagulants prevent thrombosis?
Main drugs used for platelet-rich white thrombi:
Anti-platelet drugs-aspirin
Main drugs to prevent or treat red thrombi:
Injectable anticoagulants (heparin and newer thrombin inhibitors) act immediately.
Oral anticoagulants (warfarin and related compounds) take several days
Patients with venous thrombosis given injectable anticoagulants until effects of warfarin established.
Warfarin act on factor XI, X and prothrombin (II) and factor VII in the extrinsic pathway.
Xa inhibitors act in Xa
Heparin acts on Xa and thrombin
IIa inhibitors act on thrombin IIa
tPA act on plasminogen
Anticoagulants prevent thrombosis in the coagulation cascade by targeting different steps of the clotting process. They inhibit the enzymes or factors involved in clot formation, thereby reducing the formation of blood clots. Some common mechanisms of action include inhibiting the activation of clotting factors, blocking the conversion of fibrinogen to fibrin, or interfering with platelet activation and aggregation. By preventing excessive clotting, anticoagulants help maintain blood flow and prevent the formation of dangerous blood clots.
Heparins pharmacology?
LWMH & unfractioned heparins
Extracted form the liver
Present in mast cells
Mechanism of actions of heparin- activates antithrombin III:
•ATIII inactivates thrombin and Xa and other serine proteases
•Heparin binds to ATIII and it changes conformation of ATIII this accelerates the rate of thrombin inhibition.
•Accelerates rate of action of ATIII accelerating thrombin inhibition.
Inhibiting a single molecule of Xa helps prevent the formation of 100s of thrombin molecules.
Heparins structure are highly acidic sulphate groups- administered as heparins
3 D-glucosamines
2 Uronic acid
Heparins are a family of GAGs (mucopolysaccharides)
Compounds:
•Unfractioned UFH
•Low molecular weight heparins (LMWH)
Unfractionated heparin inhibits both thrombin and Xa, however, LMWH inhibits mainly Xa and therefore its effect is more predictable.
Unfractioned heparin-Hospitals
Unfractioned Heparins work to inhibit multiple enzymes in the coagulation cascade whereas LMWH only inhibit specific enzyme Xa only.
Heparin + ATIII inhibit IXa, XIa, XIIa, Xa and IIa (thrombin) which inhibits XIII from producing XIIIa; converts fibrin into stabilised fibrin
Heparin pharmacokinetics
Not absorbed orally
Large size
Degradation
Partially metabolised in the liver by heprainase to uroheprain
20-50% is excreted unchanged
Parenteral administration
IV or SC
t1/2
40-90mins
Acts immediately
What are the advantages of LMWH over Heparin.
LMWH bind less to endothelium and plasma proteins hence greater bioavailability and plasma half life than unfractioned heparin.
Predictable dose response (only effect Xa)
Laboratory monitoring is rarely required.
Reduced frequency of dosing
Less side effects
Can be used at home (convenience/cost).
Oral anticoagulants
Warfrin
Pharmacology of warfarin
Inhibits vitamins K reductase
Competitive inhibition
Vitamin K essential for the synthesis for the coagulation cascade factor (2,7,9,10)
The enzyme warfarin targets is essential for the function of vitamin K by inhibiting vitamin K reductase this reduces or inhibits the synthesis of coagulation factors.
What are the effects of vitamin K inhibition?
Inhibits hepatic vitamin K dependent synthesis of factors II, VII, IX and X and of anticoagulation protein C and it cofactor protein S.
Since Warfarin acts in directly it has no effect on existing clots.
Takes at least 48-72hrs to achieve an antithrombolytic effect.
Meantime administer LWMH
Warfarin pharmacokinetics
Readily absorbed through GIT
Quite lipophillic
Placenta
Breast milk
Extensively bound to plasma proteins 99%
Plasma half life of 37 hours variable
Metabolised by cytochrome P450
Difficult drug to control so needs constant monitoring.
What’s the Fibrinolytic system?
The fibrinolytic system refers to the body’s natural mechanism for breaking down blood clots. It is a complex cascade of biochemical reactions that involves the conversion of inactive plasminogen into active plasmin, which is responsible for the breakdown of fibrin, the protein that forms the structure of blood clots.
When a blood clot forms in the body, it is necessary for it to be eventually dissolved to restore normal blood flow. The fibrinolytic system plays a crucial role in this process. The key components of the fibrinolytic system include:
- Plasminogen: This is an inactive form of the enzyme plasmin. Plasminogen is present in the blood and is converted into plasmin when it is activated.
- Tissue plasminogen activator (tPA): tPA is a protein that is released by the endothelial cells lining the blood vessels. It is responsible for initiating the conversion of plasminogen into plasmin. tPA binds to fibrin within the blood clot and activates plasminogen specifically at the site of the clot.
- Plasmin: Plasmin is the active enzyme that breaks down fibrin into smaller fragments called fibrin degradation products. Plasmin also degrades other proteins involved in clot formation, including fibrinogen and some clotting factors.
The activation of the fibrinolytic system is tightly regulated to prevent excessive clot breakdown or bleeding. Abnormalities in the fibrinolytic system can lead to an increased risk of clot formation or difficulty in clot dissolution.
Fibrinolytic drugs, such as alteplase or streptokinase, are synthetic or recombinant versions of tPA. They are used therapeutically to enhance the fibrinolytic process and rapidly dissolve blood clots in conditions like acute myocardial infarction or ischemic stroke.
