CVR Pharmacology Year 1 PDF

PHARMACOLOGY  Drugs & Asthma Asthma Treatment of asthma focuses on the lung by targeting the bronchioles. The goal of asthma treatment is to improve airflow, measured by peak Expiratory flow (PEF). 1. Bronchodilation: its purpose...

PHARMACOLOGY  Drugs & Asthma Asthma Treatment of asthma focuses on the lung by targeting the bronchioles. The goal of asthma treatment is to improve airflow, measured by peak Expiratory flow (PEF). 1. Bronchodilation: its purpose is to relax smooth muscle around the bronchioles which widens the airway lumen improving airflow 2. Anti inflammation: reduce chronic inflammation that causes airway thickening, edema, and excessive mucus production that contributes to airway narrowing Drug Treatment of Asthma in Adults Step 1: Intermittent Reliever Therapy- quick Relief During an Attack use a short acting B2 agonist (SABA) like salbutamol through an inhaler (metred-dose aerosol) this relaxes the airway muscles quickly to ease breathing Step 2: Regular Preventer (maintenance) Therapy- prevent Symptoms with Low-Dose Corticosteroids a low-dose corticosteroid inhaler is added with the previous inhaler for daily use This reduces inflammation and prevents future asthma symptoms Step 3: Initial Add-In Therapy- Add a Leukotriene Receptor Antagonist if the symptoms persist, an oral leukotriene receptor antagonist like montelukast is taken This reduces inflammation further by blocking leukotrienes (chemicals that worsen asthma) Step 4: Additional Controller Therapy- Add Long-Acting Medicines introduce a long acting B2 agonist (LABA) via inhaler for sustained bronchodilation Alternatively or with it a long acting Muscarinic antagonist (LAMA) can be used to prevent airway tightening Theophylline (taken orally) can also relax airway muscles Step 5: Continuous Corticosteroid (oral)- Severe Cases- Advanced Treatment if the asthma is still not controlled, oral corticosteroids are used for long term control (have more side effects) For severe asthma, monoclonal antibodies (anti IgE or anti IL5) may be prescribed to target specific immune pathways STEP 1- INTERMITTENT RELIEVER THERAPY Adrenaline activates many receptors in the body (a1, a2, B1, B2) causing: bronchodilation (widening airways via B2 receptors) Increased heart activity (via B1 receptors) this can be risky Adrenaline was modified to create new drugs: isoprenaline: a non selective beta agonist that only acts on B1 and B2 receptors. Helps open airways via B2 but causes dangerous heart rhythms (arrhythmias) SABA drugs (salbutamol, terbutaline): further structural changes made these drugs selective for B2 receptors only, avoiding heart stimulation, making it much safer for asthma Adrenaline is quickly broken down in the body by an enzyme called Catechol-o-methyl transferase (COMT) SABA drugs avoid this breakdown because they are not catecholamines. This makes them last longer in the body providing better relief How Salbutamol Works: Classic cyclic nucleotide response 1. Salbutamol binds to beta 2 adrenoceptors found in the smooth muscle cells in the airway. These receptors are part of a system that spans the cell membrane 7 times 2. When salbutamol activates the beta 2 receptor, it triggers a G protein inside the cell. This G protein activates an enzyme called adenyl cyclase that increases levels of cAMP 3. Higher cAMP levels cause the smooth muscle to relax by lowering calcium levels in the cells (calcium is needed for muscle contraction) and switching off myosin light chain kinase (enzyme that helps muscles contract by activating myosin) SABA is mainly a bronchodilator May reduce the release of chemicals from mast cells that cause inflammation Clear mucus Also inhibits TNF alpha release from monocytes JOIN THE DARKSIDE  Adverse Effects of Salbutamol Common ones include: tachycardia (fast heartbeat), muscle tremors (effects on skeletal muscles), hypokalaemia ;low potassium (salbutamol pushes potassium into muscles which reduces potassium in the blood). Since it lowers potassium it can be used to treat hyperkalaemia (too much potassium) Tolerance: with constant use the body can become less responsive to salbutamol reducing its effectiveness How does Tolerance Happen? beta 2 receptors (on lung cells) detect salbutamol These receptors are made by the body when needed and placed on cell surfaces With repeated use of salbutamol the body may reduce the number of receptors (called downregulation) making the medicine less effective Genetics and tolerance- some people have slight differences in their Beta 2 receptors that affect how they respond to salbutamol 1. Variant at position C16 (glycine instead of arginine): higher tolerance and more common in people with worsening asthma at night 2. Variant position at C27 (glutamic acid instead of glutamine): less tolerance but higher chance of side effects (fast heartbeat) STEP 2- REGULAR PREVENTER (MAINTENANCE) THERAPY Corticosteroids are a type of medicine similar to the hormone cortisol. Usually delivered through ↑ an inhaler (brown) while salbutamol is blue They reduce inflammation and suppress the immune system - They don’t open up the airways like salbutamol so they don’t provide quick relief - When used regularly they reduce the number of asthma attacks and the need for quick relief I medicines like salbutamol Common ones include: beclometasone, flucticasone, budesonide Note these are used in very low doses Side effects: can cause fungal infections (candidiasis) of the mouth known as oral thrush because they suppress the immune system. Can cause systemic absorption because around 70% of the inhaled dose can end up in the GI tract. To prevent adrenal suppression fluticasone is designed to pass first pass liver metabolism before it spreads to the body There is also a concern that using some inhaled steroid may increase risk of pneumonia Salmeterol has partial agonist activity while STEP 3- INITIAL ADD IN THERAPY formoterol has a faster onset and has full If the above 2 are not that effective add in therapy may be required (oral leukotriene receptor agonist activity antagonist) and (LABA) Leukotrienes are chemicals in the body that cause inflammation in the airways the antagonist is a pill that blocks its effects Montelukast is a leukotriene receptor antagonist (taken orally) Leukotrienes are chemicals in the body similar to prostaglandins that are made from a fat called arachidonic acid. This process happens through an enzyme called lipoxygenase, not cyclo- oxygenase (used to make prostaglandins). Leukotrienes are made up of fatty acids and amino acids and the specific types of them (C4, D4, E4) together are called slow reacting & substance of anaphylaxis (SRS-A). Also note they can be chemotactic. Montelukast blocks the CysLT-1 receptor for cysteinyl leukotrienes. It reduces inflammation, prevents bronchi constriction, stops cells from moving into the lungs, reduces mucus production Side effects include GI tract problems, fever/headache, increased risk of upper respiratory & infection Risk of neuropsychiatric reactions include speech impairment and OCD symptoms & LABA Types include salmeterol and formoterol are not for quick relief they help keep airways open & over time They have to be inhaled with steroid if not they increase risk of asthma deaths They are more fat soluble than SABAs and this helps them stay in the tissues longer and bind to Beta 2 receptors better JOIN THE DARKSIDE  STEP 4- ADDITIONAL CONTROLLER THERAPIES - If the previous methods don’t work additional therapies like theophylline (pill taken orally) and a fourth inhaler containing long acting Muscarinic antagonist (relaxes muscles around airways to keep them open longer) are used The muscles around the airways in the lungs are controlled by the parasympathetic nervous system, which uses the vagus nerve. When the body wants to narrow & the airways (called bronchoconstriction), it releases a chemical called acetylcholine. This chemical works on muscarinic receptors to cause the airways to tighten. & Atropine is a drug that blocks these receptors, stopping the airways from tightening. Tiotropium is a similar drug to atropine, known as a long-acting muscarinic antagonist (LAMA). Tiotropium helps relax the airways for a longer time and is used as a treatment for asthma or other lung conditions, delivered through an inhaler. Theophylline is a bronchodilator used to treat asthma for a long time. It works by relaxing the muscles around the airways and making them less sensitive to & things that cause inflammation. Here’s how it was thought to work: 1. PDE Inhibition: Theophylline was initially believed to block the PDE enzyme, which helps increase cAMP levels in cells, leading to bronchodilation. 2. Adenosine Receptor: Later studies found that theophylline also blocks adenosine receptors at lower doses, which helps open the airways. 3. However, the exact mechanism is still unclear because some theophylline-like drugs (e.g., enprofylline) work as bronchodilators without affecting adenosine receptors. Theophylline belongs to the methylxanthine family, which includes caffeine (found in coffee and tea). - Key Points: Narrow Therapeutic Window: Theophylline needs careful monitoring because the dose is easy to get wrong. Too much can lead to heart arrhythmias and seizures. Liver Effects: It’s broken down in the liver, and if this process slows down, the drug can build up in the blood, causing side effects. New Theory: Recently, it’s been suggested that theophylline might also help overcome steroid resistance in treating asthma. STEP 5- CONTINUOUS CORTICOSTEROID SPECIALIST THERAPIES Taken orally but works the same way as the inhaler ones & Prednisolone is an example of one - Steroids like prednisolone work inside cells rather than on the cell surface. Inside the cell, they bind to a receptor in the cytoplasm, which is usually kept inactive by & a protein. When prednisolone binds to this receptor, the complex moves into the nucleus, where it affects DNA to change the cell’s activity. Here’s how it works: The steroid increases the production of lipocortin, a protein that stops the release of arachidonic acid (which is involved in inflammation) by blocking an enzyme called phospholipase A2. Steroids also reduce blood vessel leakage (helping reduce swelling). They can increase the number of beta-2 receptors on the cell, which helps with bronchodilation (opening airways). ↑ However, steroids also suppress the immune system by reducing the production of IL-2, a molecule that helps lymphocytes (immune cells) multiply. This helps control inflammation but also makes the body less able to fight infections. - Long-term use of steroids like prednisolone can stop the body from making its own natural cortisol because the body senses the steroids and reduces the - production of cortisol from the adrenal glands. If someone suddenly stops taking steroids, their body might not be able to produce enough cortisol, leading to a serious condition called an Addisonian crisis, & which can be dangerous. & To avoid this, it’s important for patients on long-term steroids to have a steroid treatment card that shows what steroids they’re taking, in case of an emergency. For some people with asthma, treatments aren’t fully effective, leading to problems like waking up at night, severe flare-ups, or needing emergency treatment. As a & result, many end up using oral steroids for a long time, which can have significant side effects. Evidence suggests that eosinophils (a type of white blood cell) play a major role in this process. When mast cells (another type of immune cell) are activated, they release prostaglandin D2 (PGD2), which does two things: 1. Activates eosinophils directly. & 2. Attracts more eosinophils to the area by releasing a chemical called IL-5 from T-helper cells. Since IL-5 is crucial for this process, it has become a target for new asthma treatments using monoclonal antibodies that block IL-5, helping reduce inflammation - and improve asthma control. Two monoclonal antibodies, mepolizumab and reslizumab, can help treat severe asthma by blocking IL-5, a chemical that causes the body to produce and attract eosinophils (immune cells that cause inflammation in the airways). Mepolizumab is given as a shot under the skin once a month. - Reslizumab is given as an IV infusion once a month. Both are used for severe asthma that doesn’t respond well to other treatments. Another drug, benralizumab, blocks the IL-5 receptor to reduce eosinophil activity. Adverse Effects JOIN THE DARKSIDE  Arrhythmias Cardiac Synctium Synctium- network of cells connected by gap junctions Action potentials are passed directly through gap junctions from one monocyte to another Cardiac Myocyte Action Potential 1. Rapid Depolarization (phase 0): sodium channels open allowing a large influx of sodium ions into the cell, this causes the cell to become more positive. 2. Partial Repolarization (phase 1): sodium channels close and potassium channels open briefly, allowing potassium to exit the cell. The cells start to depolarize slightly (become less positive). 3. Plateau (phase 2): calcium channels open allowing calcium to enter the cell, potassium continues to exit but since calcium is also entering they are balanced. This calcium influx triggers muscle contraction leading to heart muscle contraction (systole). 4. Repolarization (phase 3): calcium channels close and more potassium channels open causing potassium to exit the cell. The inside of the cell becomes more negative. This is when it returns to the resting membrane potential. 5. Rest (phase 4): resting state of the cardiac myocyte, the cell is stable and the negative charge is maintained by the sodium potassium pump (moves sodium out brings potassium in) and thus is preparing for the next action potential Cardiac Nodal Action Potential 1. Phase 0 (Depolarization): when the heart’s pacemaker cells (in the SA and AV nodes) are ready to send a signal, calcium enters the cell. This makes the inside of the cell more positive causing depolarization (action potential is fired) 2. Phase 3 (Repolarization): after the cell fires it needs to rest. Potassium leaves the cell making the inside of the cell negative again and ready for the next signal. 3. Phase 4 (Pacemaker Depolarization): pacemaker cells don’t have a stable resting state. They slowly depolarize on their own. This happens because of sodium and potassium slowly moving in and out of the cell making it more positive until it reaches a point where the cell fires again. Sympathetic stimulation (through β1/2 adrenergic receptors) increases the heart rate. This is because sympathetic input accelerates the pacemaker potential (faster depolarization), leading to faster action potential generation and thus a higher heart rate. Vagal (parasympathetic) stimulation (through muscarinic acetylcholine receptors or mAChR) has the opposite effect. It slows down the pacemaker potential (slower depolarization), leading to a slower heart rate. Terminology Chronotropic: altering the rate of the heart Inotropic: altering the strength of heart contraction Automaticity: property of heart cells to generate spontaneous action potentials Ectopic beats: action potentials are generated in the wrong place Common Causes of Tachycardias Rapid action potentials After polarization: too much calcium inside of the cell which causes the cell to fire extra action potential leading to extra heartbeats or ectopic beats. Re-entry: electrical signal in the heart goes around in a loop and re-excites the heart tissue that has already been activated. This can happen when there is damaged heart tissue causing abnormal heart rhythms Ectopic pacemaker activity: parts of the heart other than the normal pacemaker start to fire electrical signals on their own JOIN THE DARKSIDE Re-entry AP blocked in part of myocardium: If an electrical signal (action potential) is blocked in one part of the heart muscle, some cells can’t respond right away because they are in a refractory period (a resting phase where they can’t be triggered again yet). Refractory cells activated by backpropagation: When the signal moves backwards (backpropagation) into these refractory cells, it may cause them to depolarize (fire) when they shouldn’t. Out of phase depolarization: These cells fire at the wrong time, which causes them to be out of sync with the rest of the heart. May trigger additional contractions: This abnormal firing can lead to extra heartbeats or contractions that disrupt the normal rhythm of the heart. Example: Wolfe-Parkinson-White syndrome Atrial tachycardias transmitted to ventricles May cause retrograde re entry tachycardia (ventricular to atrial) Surgery can fix this Abnormal Automaticity caused by increased phase 4 depolarization and decrease in AP threshold Vaughan-Willians Classification Used to categorize anti arrhythmic drugs based on electro physiological effects Class 1 (a, b, c): voltage gated sodium channel blockers Sodium channel blockers are also used as local anaesthetics and anticonvulsants Slows down generation of action potentials Adverse effects include edema (feet/ankles) and dizziness It slows down heart rate drug does not bind when the channel is closed The faster the cell fires APs the more drug binds and slows AP generation, at low heart the drug has minimal effect because less AP generation is occurring so no need for so much drug binding class 1a drugs Qunidine, procainamide, disopyramide (main one) Can be used for atrial and ventricular tachycardias Anticholinergic side effects Negative inotropic effect=reduced contractility due to decreased calcium entry Avoid with hypotension (low BP) and low ventricular output (poor heart function) Class 1b drugs lidocaine (given through an IV, used in emergencies to treat ventricular tachycardias, not used often because there are better drugs). Mexiletine (similar to lidocaine but taken orally, used for long term control of certain arrhythmias). Tocainide (an older drug no longer used due to safety concerns) Rapid dissociation means the drug binds and unbinds quickly so it only works well when the heart is beating very fast. They are used for ventricular tachycardias and ventricular fibrillation, low effectiveness for atrial tachycardias Sympathetic innervation and nodal action potentials Class 1c drugs (APs): flecainide (can cause sudden death after myocardial infarction). Propafenone (additional B blocker The sympathetic nervous system stimulates effects) the heart through β1 and β2 receptors, increasing Used for atrial fibrillations and some ventricular tachycardias calcium (Ca²⁺) entry and speeding up action Can be used for chemical cardioversion (resetting heart to get it to beat normally again) potentials. Potent negative inotropes (if heart is already weak this can worsen and lead to heart failure) β-blockers: Class 11: Adrenergic β receptor antagonism: These drugs block β receptors, which are important for heart These drugs block β1 and β2 receptors, and lung function. slowing down the heart’s action potential β1 vs. β2 receptors: The heart has more β1 receptors, and they are more important for its function generation in the nodes (the heart’s natural than β2 receptors. pacemakers). How β receptors work in the heart: When something (like adrenaline) stimulates β receptors, it: They also reduce the amount of calcium 1. Increases cAMP (a signaling molecule inside cells). entering the heart muscle cells (myocytes), which weakens heart contractions (negative inotropic JOIN 2. Activates PKA (a protein that helps regulate cell activity). THE DARKSIDE 3. Increases calcium (Ca²⁺) entry, which makes the heart beat stronger and faster. effect). Uses: Class 1V: How they work: Atrial tachycardias: These drugs are good for controlling fast heart rhythms in They block L-type voltage-gated calcium the atria. channels. After a heart attack (MI): They help reduce the risk of death and arrhythmias The more the channels are used (like in fast caused by too much sympathetic activity (stress hormones). heart rates), the stronger the drug’s effect. Types of β-blockers: Effect on nodal action potentials: β1-selective: These mainly target the heart and are safer for most people Smaller APs: The action potential (AP) has (examples: atenolol, bisoprolol, metoprolol). less strength. Non-selective: These affect the heart and other organs (example: propranolol). Slower nodal firing: The AP lasts longer, Sotalol: A special β-blocker that also has class III effects (can control certain increasing the refractory period (ERP). arrhythmias by prolonging heart repolarization). Effect on other heart cells (myocytes): Side effects: Weaker contractions: They reduce calcium, Low blood pressure (hypotension): Can cause dizziness. so the heart doesn’t contract as strongly Fatigue: Common due to slower heart function. (negative inotropic effect). Peripheral vasoconstriction: Narrowing of blood vessels can make hands and feet Shorter AP duration: This can be risky, feel cold. especially in conditions like ventricular Avoid in asthma: Non-selective β-blockers can worsen asthma symptoms by tachycardia. affecting the lungs. Main Uses: Sotalol caution: Atrial fibrillation: Helps control heart rate. It’s useful for specific arrhythmias but can increase the risk of a dangerous Paroxysmal supraventricular tachycardia rhythm problem called Torsades de Pointes (TdP). (PSVT): Rarely used now. Class 111: Blood pressure control: These drugs dilate How these drugs work: blood vessels (vasodilation). They block potassium (K⁺) channels, which slows down repolarization (the Examples: process that resets the heart’s electrical activity after a beat). Verapamil: This extends the effective refractory period (ERP), making it harder for the heart Mostly affects the heart (cardioselective). to fire another beat too quickly. Also blocks alpha receptors and sodium Effect on the heart: channels. Myocytes and nodal cells: The action potential (AP) lasts longer, delaying the Diltiazem: next beat. Less heart-specific (non-cardioselective). Negative chronotropic effect: Slows down the heart rate. Has more effect on reducing blood pressure. Positive inotropic effect: Can increase the strength of heart contractions. Side Effects: Potential problems: Hypotension: Low blood pressure, leading to Reverse use dependency: These drugs can become pro-arrhythmic (cause dizziness. dangerous rhythms) at slower heart rates (bradycardia). Oedema: Swelling, often in the legs. Severe side effects: Despite being very effective, these drugs can have serious Constipation: Common with these drugs. adverse effects. Additional Uses: It is the most effective As medications for high blood pressure Class III Antiarrhythmic Drugs: Key Points (antihypertensive). Amiodarone: For chest pain relief (antianginal). Pharmacokinetics: Very lipophilic (accumulates in fatty tissues). Long half-life, so it stays in the body for a long time. Activity: Works on multiple classes: Class Ia, II, and III. Highly effective for treating both chronic and acute arrhythmias. Side effects: Can cause lung and liver damage, thyroid problems, and a serious rhythm issue (Torsades de Pointes, TdP). May also cause skin discoloration and photosensitivity (skin reacts to sunlight). Other options: Dronedarone: A safer version of amiodarone but less effective. Sotalol: JOIN THE DARKSIDE Less potent Class III activity but also works as a Class II β-blocker. This describes Digoxin, a drug that works by inhibiting the Na+/K+ pump (from the foxglove plant). Here’s a simple explanation: Na+/K+ Pump Inhibition: Digoxin blocks the pump that helps maintain the balance of sodium (Na+) and potassium (K+) across the cell membrane. This causes the cell to become depolarised (less negative inside the cell). Effect on the Vagus Nerve: Digoxin also stimulates the vagus nerve, which releases a chemical called acetylcholine (ACh). ACh acts on M2 receptors in the heart. M2 Receptor Effect: These receptors cause potassium (K+) to leave the cell, which hyperpolarises (makes it more negative) the cells, especially in the heart’s pacemaker cells (nodal cells). This can slow down the heart rate. Safety Concerns: Low therapeutic index (TI): Digoxin has a narrow margin between a safe dose and a toxic dose, making it unsafe in high amounts. Side effects: Dizziness, confusion, fatigue, nausea, and vomiting can occur if the drug levels are too high. Blocks the Na+/K+ pump in heart cells, which messes up the balance of sodium and potassium. This causes the cells to become more active (depolarized), making the heart contract harder. More calcium builds up inside the cells, which makes the heart beat stronger (positive inotropic effect). It also shortens the time the heart cells stay active, helping control the heart rate. Adenosine Adenosine is an emergency medication for fast heart rhythms (like supraventricular tachycardia). It’s given through an IV and works very quickly (in 8-10 seconds). It slows down the heart by making the AV node more negative (hyperpolarized), which helps control the heart rate. Side effects can include chest pain, shortness of breath, dizziness, and nausea. It also relaxes blood vessels but can cause bronchoconstriction (tightening of the airways). Bradycardia Atropine (IV): Blocks the vagus nerve to speed up the heart. Adrenaline (IV): Stimulates the heart to beat faster. Dopamine (IV): Increases heart rate, especially through β1 receptors. Dobutamine (IV): Similar to dopamine, but more focused on the heart. For long-term chronic bradycardia, a pacemaker is used to regulate the heart’s rhythm. Atrial Tachycardias For treating atrial fibrillation (A-fib) and atrial flutter: Rate control: Use drugs to slow the heart rate and prevent fast signals from the atria reaching the ventricles. Rhythm control: Use treatments like cardioversion (shocking the heart) or drugs to restore a normal heart rhythm. A-fib: Rate and Rhythm Control JOIN THE DARKSIDE Hypertension Antihypertensives High BP Normal range= 90/60-120/80 Pre hypertension: more than 120/80 High BP: more than 140/90 Severe hypertension: more than 180/120 even at rest, lying down, standing Essential hypertension is the most common meaning there is no identifiable disease or cause Secondary hypertension means there is an identifiable condition causing this Risks of Hypertension Heart attack, thromboembolism (blood clot formation blocking something) especially stroke, aneurysm (blood vessels swell and potentially burst), kidney failure, neurodegenerative diseases BP Regulation Autonomic Feedback Loop 1. Baroreceptors detect changes in blood pressure and send signals to brainstem (medulla oblangata) 2. The sympathetic nervous system then increases the heart rate, cardiac output, and vascular resistance when BP drops 3. The parasympathetic nervous system decreases the heart rate and promotes vasodilation when blood pressure is too high Hormonal Feedback Loops 1. Renin (enzyme) from the kidneys converts angiotensinogen into angiotensin 1 that is then converted to angiotensin 2 2. angiotensin 2 constricts blood vessels increasing vascular resistance Ways to Manage Hypertension BP=CO (amount of blood pumped by the heart in a minute) xPVR CO=HRxSV (how much blood is being pumped out) To reduce to PVR: dilate blood vessels To reduce CO: decrease the heart rate, decrease contractile force, decrease blood volume Renin-angiotensin System due to low BP 1. The liver produces angiotensionogen (protein that circulates the blood) 2. The kidney senses reduced blood flow, decreased sodium levels, or activation of the sympathetic nervous system and so the kidney releases renin (an enzyme) that converts angiotensinogen to angiotensin 1 3. Angiotensin 1 is then moved to the lungs and kidneys where the angiotensin converting enzyme (ACE) converts it to angiotensin 2 (active form) 4. Angiotensin 2 then has many effects as illustrated in the picture 5. As BP and fluid levels increase the body downregulates renin secretion via negative feedback Angiotensin 2 (AT1) Receptors Mediate actions of angiotensin 2. They are responsible for the classic effects of angiotensin 2 in regulating BP, and fluid balance. Key actions of AT1 Receptors are: 4. Antidiuretic Hormone (ADH) Release: 1. Vasoconstriction: In the hypothalamus, AT1 receptor activation Angiotensin II binding to AT1 receptors causes smooth muscle contraction in blood promotes the release of antidiuretic hormone (ADH), vessels, which leads to vasoconstriction, increasing blood pressure by raising peripheral which causes water retention in the kidneys, vascular resistance (PVR). increasing fluid volume. 2. Aldosterone Secretion: AT1 receptors in the adrenal cortex stimulate the release of aldosterone, which acts on the kidneys to increase sodium reabsorption, thereby retaining water and increasing blood volume. 3. Sympathetic Nervous System Activation: Activation of AT1 receptors in the brain increases sympathetic nervous system activity, leading to the release of noradrenaline (norepinephrine). This contributes to increased heart JOIN THE DARKSIDE rate, further vasoconstriction, and enhanced blood pressure. Angiotensin Converting Enzyme Inhibitors ACE breaks down pro inflammatory bradykinin (signalling molecule) ACE inhibitors are drugs that help lower BP by blocking ACE (thus enzyme narrows blood vessels and raises BP) ACE inhibitors are orally active drugs Examples: captopril (short duration), ramipril, lisinopril Side effects include: dry cough, angioedema (swelling around the heart), hyperkalemia, tetratogenic (inappropriate during pregnancy) Angiotensin Receptor Blockers (ARBs) Examples: losartan, candesartan, valsartan Similar clinical effects to ACEIs Similar adverse effects to ACEIs except no dry cough Generally used when patients are resistant to ACEIs (do not use both) Beta Blockers in Hypertension In the heart (B1) slow the heart rate and reduce the force of contraction this lowers the blood pressure In the blood vessels (B2) receptors cause blood vessels to tighten which can temporarily cause increased BP. But over time the body adjusts and blood vessel resistance decreases. In the kidneys (B1) receptors reduce release of renin Beta blockers decrease cardiac output, long term decrease in PVR Cautions: beta blockers can block B2 receptors in lungs leading to bronchoconstriction which can worsen asthma or COPD. They can also suppress insulin release and sometimes may not be perfect for arrhythmias Types include: atenolol, bisoprolol, (more B1 selective) labetalol Labetalol is safe during pregnancy and B1 selective drugs are more preferred Diuretics Medications that help reduce fluid buildup Types 1. Loop Diuretics: these are very powerful but not commonly used for high BP alone. They act on the loop of Henle in the kidney to remove large amounts of water and salt from the body. They are typically used in heart failure or severe fluid retention. 2. Thiazide Diuretics: most popular diuretics for high BP. They act in the distal tubule in the kidney to reduce salt reabsorption causing water loss and reducing BP over time. 3. Potassium-sparing Diauretics: weak diuretics that are usually added to prevent hypokalemia caused by other diuretics. They reduce potassium loss in the kidney while still helping with water removal. Thiazide Diuretics 1. thiazides inhibits the Na/Cl cotransporter which reduces reabsorption of sodium and chloride back into blood 2. Since the sodium and chloride stay in the nephron water follow leading to increased urine production (more water in urine and less in blood) 3. The loss of sodium, chloride, and water reduces blood volume and this helps lower blood pressure Additional Diuretic Aldosterone receptor antagonists like spironoclatone block the action of aldosterone (hormone that helps kidneys retain sodium and excrete potassium) 1. Block Aldosterone: Normally, aldosterone tells the kidneys to hold on to sodium and get rid of potassium. 2. Less Sodium Reabsorption: By blocking aldosterone, less sodium is kept in the body, and more is excreted in the urine. 3. More Potassium Retained: It also prevents too much potassium from being lost, so your body keeps more potassium. Effects: Helps reduce blood pressure by lowering sodium levels, reduces the risk of low potassium (hypokalemia). Vasodilators- Adverse Effects Edema, flushing, postural hypotension (dizziness), fatigue, reflex tachycardia, headache All these side effects are common with calcium channel blockers, alpha blockers, and directly acting vasodilators (nitrates, minoxidil, hydralazine) Calcium Channels in Hypertension L type voltage gated calcium channels are channels that allow calcium to enter cells and are activated by large changes in electrical potential across the cell membrane. They allow high levels of calcium influx and are very common. They are involved in blood vessel contraction Types of calcium channel blockers: 1. Dihydropyridines (DHPs): Selective for Blood Vessels: These drugs mostly block calcium channels in the vascular smooth muscle, helping to relax and widen blood vessels, reducing blood pressure. 2. Non-Dihydropyridines (Non-DHPs): Cardiac or Non-Selective: These drugs can block calcium channels in both the heart and blood vessels. JOIN THE DARKSIDE Cardioselective (targeting the heart): Reduce heart rate and contractility, useful for treating arrhythmias.  Alpha Blockers Examples: Doxazosin (main one) and prazosin They block Alpha 1 receptors that usually make blood vessels tighten. This causes them to relax lowering BP. Side effects include: edema, hypotension, and dry mouth Other drugs options 1. Centrally Acting Antihypertensives: Drugs: Clonidine, Methyldopa, Moxonidine. How They Work: Stimulate α2 receptors in the brain to reduce sympathetic signals, lowering blood pressure. When Used: Methyldopa is sometimes used in pregnancy. 2. Nitrates: Use: Commonly for angina (chest pain), less for hypertension. Mechanism: Relax blood vessels. 3. Potassium Channel Openers: Drug: Minoxidil (also promotes hair regrowth). How It Works: Opens K+ channels in vascular smooth muscle, relaxing blood vessels. When Used: Severe or resistant hypertension. 4. Renin Inhibitors: Drug: Aliskiren. How It Works: Blocks renin, reducing the production of angiotensin (which normally raises Severe Hypertension blood pressure). 1. Rapid Action: 5. Hydralazine: Same-day specialist referral is needed, Mechanism Not Fully Understood: Thought to relax arteries. especially if there are signs of organ damage or an Use: Emergency or resistant hypertension, often combined with other drugs. emergency (e.g., hypertensive crisis). Clinical Use 2. Organ Damage Assessment: A=ACEI or ARB (low cost) Check for damage to critical organs like the C= calcium channel blocker brain (stroke), heart (heart attack), kidneys, or eyes. D= diuretic 3. Treatment Options: 1. Lifestyle Changes First: Non-accelerated Hypertension (no organ Diet, exercise, weight loss, and reducing salt and alcohol intake should be the first steps. damage): 2. Drug Choices Depend on Comorbidities: Begin standard hypertension treatment. Arrhythmias: Use β-blockers or calcium channel blockers (CCBs). Monitor blood pressure weekly to ensure Decreased Kidney Function: Prefer diuretics. gradual improvement. Diabetes: Use β-blockers cautiously. Accelerated Hypertension (Hypertensive Heart Failure: Requires a complex approach with multiple drug types. Crisis): Benign Prostatic Hyperplasia (BPH): Alpha-blockers can help both blood pressure and BPH. Severe emergency with potential organ damage. 3. Pregnancy: Goal: Reduce BP by 25% within 1 hour. Avoid ACE inhibitors (ACEIs) and ARBs due to risks to the baby. Drugs Used (given by injection): Beta-blockers (e.g., labetalol) are preferred, followed by CCBs. Nitrates (e.g., nitroprusside). Calcium channel blockers (CCBs). Hydralazine. Beta-blockers JOIN THE DARKSIDE  Blood Coagulation Haemostasis - The process that stops bleeding by platelet adhesion & activation, fibrin formation, and concurrent action. E The body maintains balance between pro-coagulation (clotting) and anti coagulative (preventing clots) signals by: Heparan sulfate: prevents clot formation by aiding anti clotting proteins Signalling molecules like: & Prostaglandin I2 (PGI2) and Nitric Oxide (NO): prevents platelets from sticking and keep blood vessels open Tissue plasminogen activator (tPA): helps break down clots & & Endothelial cells convert ADP to adenosine to limit clotting Fibrin Formation Thrombin is an enzyme that cuts proteins called fibrinogen at specific spot. It cuts the ends of fibrinogen & and with those ends gone the remaining part is called fibrin (this doesn’t dissolve in blood). Fibrin strands assemble into fibrils and bind to platelets and each other forming a seal that closes the wound Platelet Aggregation 1. Activation: Platelets are activated by signals like collagen (exposed at the injury site) or molecules like ADP and thromboxane A2 (released by other platelets). 2. Shape Change: Activated platelets change shape to become sticky and better at clumping together. 3. Adhesion: Platelets stick to the damaged blood vessel using proteins like von Willebrand factor (vWF). 4. Aggregation: Platelets stick to each other using a receptor called GPIIb/IIIa, which binds to fibrinogen, forming a platelet plug. 5. Stabilization: Fibrin (produced by thrombin) reinforces the plug, making it stable and strong. Thrombosis Thrombosis happens when a pathological blood clot (thrombus) forms inside a blood vessel, causing a blockage. Key Features: 1. Types of Clots: Venous thrombi: Rich in fibrin (found in veins). Arterial thrombi: Rich in platelets (found in arteries). 2. Complications: A thrombus can detach and become an embolus, which might get stuck in a smaller blood vessel, causing further blockage (e.g., in the lungs or brain). Virchow’s Triad: Three factors that increase the risk of thrombosis: 1. Abnormal Blood Flow: Stasis (slow blood flow) in veins or turbulence in arteries. 2. Hypercoagulability: Blood is more prone to clotting due to conditions like genetic disorders, cancer, or certain medications. 3. Blood Vessel Damage: Injury to the vessel lining (endothelium) promotes clot formation. Causes and Risk Factors: Hypertension (high blood pressure). Atherosclerosis (plaque buildup in arteries). Myocardial infarction (heart attack). Vasculitis (vessel inflammation). Smoking, radiation, or chemical irritation. Inflammation, hypoxia (low oxygen), or infections. JOIN THE DARKSIDE Antithrombosis Drugs & Strategies Anticoagulants prevent clot formation by reducing thrombin. Antiplatelet drugs stop platelets from clumping. Fibrinolytics dissolve existing clots. Risk: All these drugs can cause excessive bleeding. Anticoagulants Prothrombin Time (PT): A lab test to measure how quickly blood clots (normal range: ~12-13 seconds). International Normalized Ratio (INR): A standardized ratio to compare an individual’s PT to a normal reference value. Warfarin Blocks VKORC1 enzyme, stopping Vitamin K from being recycled. Without active Vitamin K, the body can’t make key clotting factors (II, VII, IX, X). Why Vitamin K matters: Helps make clotting factors but needs to be recycled after each use. Antidote for overdose: 1. Vitamin K: Restores clotting factor production (slow). 2. Prothrombin Complex (PCC) or plasma: Provides clotting factors (fast). Problems High Risk: Small safety margin, needs regular monitoring. Drug Interactions: Many CYP450 interactions increase bleeding risk. Problems: Needs heparin bridging at the start. Teratogen: Unsafe in pregnancy. Hepatotoxicity: Can damage the liver. Soft tissue necrosis: Rare side effect. Gene polymorphisms: Genetic differences affect response. Synergistic bleeding: Risk increases with aspirin or heparin. Preferred Alternatives: Factor Xa inhibitors are now favored for most new patients. Direct Oral Anticoagulants (DOACs) 1. Factor Xa Inhibitors (”-xaban”): Examples: Rivaroxaban, Apixaban. Features: Orally taken, rapid onset. Caution in renal impairment. Antidote: Andexanet alfa. Favored as first-line anticoagulants. 2. Direct Thrombin Inhibitor: Example: Dabigatran. Features: Orally active, becoming more popular. Antidote: Idarucizumab. IV Anticoagulants 2. Hirudins: 1. Heparins: Examples: Lepirudin, Bivalirudin. Examples: Heparin, Fondaparinux. Admin: Injection only. Admin: IV or SC injection only. Uses: For patients who can’t tolerate heparin. Uses: How it works: Directly blocks thrombin. For acute situations (e.g., heart attack, stroke). Bridging to warfarin treatment. How it works: Activates antithrombin III, which inactivates clotting factors. Side Effects: Thrombocytopenia (low platelets). Hypersensitivity reactions. JOIN THE DARKSIDE Fondaparinux: More effective than regular heparin, synthetic form. Anti Platelet Drugs 1. PAR Activation: When thrombin activates PAR receptors on platelets, it starts a chain reaction inside the platelets. 2. Arachidonic Acid (AA) Production: This process leads to the production of a molecule called arachidonic acid (AA). 3. AA Turns Into TXA2: The AA is then converted into thromboxane A2 (TXA2) by an enzyme called cyclooxygenase. 4. TXA2 Activates Platelets: TXA2 binds to TP receptors on platelets. This makes the platelets stick together and become more active, which helps form a blood clot. It also activates a receptor called GPIIb, which helps the platelets stick to each other even more. Aspirin as a Blood Thinner 1. What it does: Aspirin blocks an enzyme called COX-1 in platelets, which prevents them from making a substance (thromboxane A2) that helps them stick together and form clots. 2. How it works: The effect of aspirin lasts for about 7-10 days, because it irreversibly blocks COX-1 in platelets. 3. Low Dose: Low doses (much lower than for pain relief) are used for clot prevention, with few side effects. 4. Resistance: Some people might not respond well to aspirin (aspirin resistance). 5. Combination with Other Drugs: Sometimes, aspirin is taken with other medications like clopidogrel to prevent clots more effectively. P2Y Receptors & PAR 1. What Happens: When ADP or thrombin bind to a specific type of receptor on platelets (GPCR), it triggers a signal inside the cell. 2. Effect on cAMP: This signal causes a decrease in a molecule called cAMP (which usually helps keep platelets inactive). 3. Increase in Ca2+: The drop in cAMP leads to the release of calcium (Ca2+) from the inside of the platelet. 4. Platelet Activation: Calcium triggers platelets to release substances from their storage (granules), such as ADP, which help activate more platelets and promote clotting. P2Y12 Receptor Antagonists 1. What are P2Y12 Receptors? Found mostly on platelets, these receptors play a key role in making platelets sticky to form clots. 2. P2Y12 Antagonists (”-grel-”): These drugs block P2Y12 receptors to stop platelets from clumping together. 3. Common Drugs: Clopidogrel: Irreversible blocker, but needs to be activated in the liver. Some people don’t metabolize it well, so it may not work for them. Prasugrel: Another irreversible option. Ticagrelor: Reversible blocker, works directly. 4. Use: Clopidogrel is the 2nd most used antiplatelet drug after aspirin. 5. Side Effects: Generally safe but can cause bleeding and stomach upset. JOIN THE DARKSIDE Phosphodiesterase Inhibitors (e.g., Dipyridamole 1. How It Works: Increases cAMP and cGMP in platelets, making them less likely to stick together and form clots. 2. When It’s Used: Often combined with aspirin to prevent strokes or after mini-strokes (TIA). 3. Why It’s Less Common: It’s not as effective as other options and can be expensive. 4. Other Effects: Phosphodiesterase Inhibitors (e.g., Dipyridamole Acts as a vasodilator (widens blood vessels), which can lower blood pressure but might cause issues like dizziness, migraines, or worsen a heart attack. 1. How It Works: GPIIb/IIIa Receptor Inhibitors Increases cAMP and cGMP in platelets, making them less likely to stick together and form clots. 1. GPIIb/IIIa Receptor Inhibitors: 2. When It’s Used: What they do: Block fibrinogen from binding to platelets, stopping clots from forming. Often combined with aspirin to prevent strokes or after mini-strokes (TIA). When they’re used: Specialist use during cardiac surgeries or with heparin. 3. Why It’s Less Common: Examples: It’s not as effective as other options and can be expensive. Abciximab: A monoclonal antibody, given by injection. 4. Other Effects: Eptifibatide and tirofiban: Peptides, also injection only. Acts as a vasodilator (widens blood vessels), which can lower blood pressure but might cause issues like dizziness, migraines, or worsen a heart 2. PAR Antagonists: attack. What they do: Block thrombin receptors (PAR) on platelets to stop clotting. Availability: New drugs like vorapaxar are approved in the USA, but not in the UK. Fibrinolytics/Thrombolytics 1. When They’re Used: Used to dissolve dangerous clots in conditions like stroke, DVT, pulmonary embolism, or heart attacks. 2. How Clots Break Naturally: The body converts plasminogen into plasmin, which breaks down the fibrin holding clots together. 3. How These Drugs Work: These drugs boost the body’s plasmin activity to dissolve clots quickly. Stroke 1. What is a Stroke? A serious condition where blood flow to the brain is blocked, causing brain cells to die. 2. Types of Stroke: Ischaemic stroke (85%): Caused by clots blocking blood flow. Haemorrhagic stroke (15%): Caused by bleeding in the brain, usually more severe and often fatal. 3. Transient Ischaemic Attack (TIA) (Mini-Stroke): Temporary blockage of blood flow without permanent damage, but it signals high risk for a major stroke. 4. Key Fact: Treatment must start quickly, ideally within 4 hours. Clot Breakdown 1. What Happens: The body activates plasminogen into plasmin, an enzyme that breaks down fibrin (the protein holding clots together). 2. Balance: The coagulation system forms clots, while the fibrinolytic system breaks them down. These processes are controlled by signals that keep clotting and clot breakdown in check. Fibrinolytics 1. How They Work: All are given IV and activate plasminogen to plasmin to dissolve clots. 2. Key Drugs: Alteplase (tPA): The only approved drug for strokes. Effective for general clot-busting. Streptokinase: From bacteria, used for clots in DVT and heart attacks. Urokinase: A natural enzyme, treats DVT and pulmonary embolism. JOIN THE DARKSIDE Procoagulants (restrict bleeding) 1. When Used: For bleeding disorders, surgery, heavy periods, poor nutrition, or to counteract anti-clotting drugs. 2. Key Drugs: Tranexamic Acid: Prevents fibrin breakdown, reducing bleeding. General anti-bleeding medication. Vitamin K: Needed for clotting factor production. Used as a warfarin antidote when combined with prothrombin. Desmopressin: Promotes release of clotting proteins (vWF) for haemophilia. Hyperlipidaemia Too much fat (lipids) or fat carriers (lipoproteins) in the blood. Key Problem: High cholesterol levels. Lipoproteins: HDL (High-Density Lipoprotein): “Good” cholesterol. LDL (Low-Density Lipoprotein): “Bad” cholesterol. Chylomicrons: Transport fat after eating. Artherosclerosis Oxidised LDL (bad cholesterol) builds up in arteries. HDL (good cholesterol) usually clears it, but too much LDL causes deposits. Result: Causes inflammation and cell damage. A clot forms over the damage, leading to atherosclerosis (narrowed arteries) Statins Block HMG-CoA reductase, which is the key enzyme in cholesterol production. Examples: Atorvastatin, Simvastatin. Side Effects: Generally well tolerated. Possible muscle pain. Rare liver damage, increased bleeding, or higher risk of diabetes. Fibrates Activate PPARα, a receptor that helps break down fats (lipid catabolism). Examples: Fenofibrate, Gemfibrozil. Side Effects: Generally well tolerated. Risk of gallstones (due to reduced bile production). Possible muscle pain. Others Ezetimibe Blocks cholesterol absorption in the intestines. Often taken with a statin. Side Effects: Generally well tolerated. Nicotinic Acid (Niacin) Reduces triglycerides and increases HDL (good cholesterol). Side Effects: Rarely used due to side effects. JOIN THE DARKSIDE  Cardiac Drugs II Angina & Heart Failure Angina & Angina occurs when the heart doesn’t get enough oxygen due to a mismatch between oxygen supply (blood flow) and oxygen demand (how hard the heart is working). This happens for two main reasons: 1. Angina Pectoris (90%): Fatty plaques (atheroma) narrow the coronary arteries. 2. Variant Angina (10%): Sudden spasms in the coronary arteries temporarily block blood flow. When the heart muscle lacks oxygen, it releases substances like potassium (K⁺) and lactate, which irritate nerves and cause referred pain in the chest. & The heart gets blood during its relaxation phase (diastole), and blood flows from the outer to the inner layers. In areas with reduced blood flow, small vessels & (arterioles) downstream of a blockage are already maximally dilated to try and compensate. Drugs that dilate coronary arteries don’t help much in angina pectoris because: ↑ They can’t improve blood flow to the ischemic areas. They might even reduce blood flow to these areas by diverting it to healthier parts of the heart. Instead, drugs relieve angina by reducing the heart’s oxygen demand—slowing the heart, reducing its workload, and improving overall balance. - Glyceryl Trinitrate (anti anginal drug) 1. How GTN is Taken: Glyceryl trinitrate (GTN) is taken under the tongue (sublingually) as a spray or tablet. This avoids it being broken down by the liver, allowing it to act quickly. 2. How GTN Works: GTN is a prodrug that is converted in the blood vessel walls into nitric oxide (NO) by enzymes. NO, a natural vasodilator, relaxes blood vessels by reducing calcium levels in smooth muscle cells, causing them to relax. 3. Effects of GTN on Blood Vessels: Venodilation (Veins): Widening veins increases their capacity (venous capacitance) to hold blood. This reduces the amount of blood returning to the heart (preload), which lowers: The heart’s filling pressure. Ventricular volume. End-diastolic pressure (the pressure in the heart before it contracts). Peripheral Vasodilation (Arteries): Widening peripheral arteries lowers blood pressure (afterload), reducing the resistance the heart has to pump against. Arterial Vasodilation: GTN relaxes arteries affected by spasms (vasospasm) and improves blood flow to areas of the heart by opening collateral blood vessels. 4. Positive Inotropic Effect: GTN has a weak positive inotropic effect, meaning it slightly improves the heart’s ability to pump. 5. How This Relieves Angina: By reducing preload (venodilation) and afterload (peripheral vasodilation), GTN lowers the heart’s workload and oxygen demand. At the same time, improved collateral flow and reduced vasospasm increase oxygen supply to the heart. 6. Using GTN: GTN can relieve angina attacks or be taken before activities like exercise to prevent pain. 7. GTN Tolerance: Using GTN too often can lead to tolerance because the enzymes that convert it into NO get “saturated.” To avoid this, GTN should be used intermittently, with breaks to let the body reset. Nitrate Alternatives 1. GTN and Continuous Delivery: GTN can be delivered continuously through skin patches or 2% ointment. To prevent tolerance, patches are used during the day and removed at night, giving the body a break. 2. Isosorbide Mononitrate: This is an oral nitrate taken daily. Unlike GTN, it is almost fully absorbed by the body (100% bioavailability) and works similarly by generating NO to relax blood vessels. 3. Nicorandil: Nicorandil has a dual action: It acts like a nitrate to produce NO and dilate blood vessels. At higher doses, it also opens special potassium channels (ATP-dependent K⁺ channels) in blood vessels, causing muscle cells to relax further (hyperpolarization). JOIN THE DARKSIDE Unlike GTN, nicorandil doesn’t cause tolerance and may directly activate enzymes (like guanylate cyclase) to relax blood vessels. Beta Blockers Main Use: Reduce the number of angina attacks in maintenance therapy. Mechanism: Block the action of adrenaline on the heart by inhibiting the sympathetic nervous system. Drug Development: 1. Beta-Adrenoceptor Agonist: Early modification of adrenaline → Isoprenaline (stimulates beta receptors). 2. Beta-Adrenoceptor Antagonist: Further modification of the ring structure → Propranolol (blocks beta receptors). Propranolol: A revolutionary treatment for heart disease, likened to the discovery of digitalis. How do Beta Blockers Reduce Anginal Pain 1. Reduce Oxygen Demand: Negative inotrope: Decrease heart muscle contractility. Lower afterload: Reduce systemic blood pressure. 2. Improve Oxygen Supply: Negative chronotrope: Slow heart rate → more time for blood to flow to the inner heart layers during diastole. 3. Effectiveness: Best for angina caused by atherosclerosis. Less effective for vasospasm-related angina. Beta Blockers: Cellular Mechanism Target: Block sympathetic nervous system effects and adrenaline. Action: 1. Reduce activation of adenylate cyclase. 2. Lower cAMP levels. 3. Decrease calcium entry into cells. Effects: Slow heart rate. Decrease cardiac conduction. Reduce myocardial contractility. Propranolol Side Effects bradycardia (B1) Bronchoconstriction (B2) Peripheral Vasoconstriction (B2) Hypoglycaemia (B2) Diarrhea CNS Beta 1 selective Beta Blockers 1. Atenolol: Selectivity: 30x more selective for beta-1 receptors. Properties: Water-soluble. Calcium Channel Blockers in Angina Treatment Doesn’t cross the blood-brain barrier. 1. Variant Angina: Excreted by kidneys. Accounts for about 10% of angina cases in the UK. 2. Bisoprolol: Caused by coronary artery spasm due to calcium influx. Selectivity: 75x more selective for beta-1 receptors. Can occur during sleep. Major beta-1 blocker used in the UK today. 2. Calcium Channel Blockers: 3. Propranolol: Diltiazem is particularly effective. Non-selective, still commonly used. Mechanism: 4. Primary Care Stats: Inhibit myocardial contractility → reduce oxygen demand. Usage stats don’t specify whether beta-blockers are for: Lower systemic blood pressure → reduce afterload on the heart. Angina. 3. Use in Angina Pectoris: Hypertension. May provide some benefit in reducing oxygen demand and Heart failure. improving blood flow. JOIN THE DARKSIDE Calcium Channel Blockers 1. Most Effective for Variant Angina: Dihydropyridines (DHPs): Amlodipine and Nifedipine (sustained release). Long duration of action → once-daily dosing. Work on L-type calcium channels to inhibit calcium entry into cells. 2. Amlodipine: Mechanism: Blocks calcium channels from the outside of the cell, affecting all channel states. 3. Dihydropyridines with Beta-Blockers: Can be used together but with caution (both are negative inotropes—decrease heart contractility). 4. Diltiazem: May have the best profile for relieving angina pectoris. 5. Verapamil: Should not be used in angina, as it’s a strong negative inotrope and can cause heart block. Chronotrope and Inotrope Effects 1. Chronotrope: Refers to heart rate changes. Positive chronotrope: Increases heart rate. Negative chronotrope: Decreases heart rate. 2. Inotrope: Refers to force of contraction of the heart muscle. Positive inotrope: Increases the force of contraction. Negative inotrope: Decreases the force of contraction. Starling’s Law of the Heart Describes the relationship between ventricular performance and ventricular fibre length. Normal Performance (Line a): Increasing fibre length increases heart performance (e.g., during physical activity like walking or running). Heart Failure (Line c): In severe heart failure, the heart cannot increase performance enough to supply tissues, leading to pulmonary and systemic congestion. Sepsis 1. Acute Heart Failure: Can occur during situations like surgery or intensive care. Septic Shock is a common cause. 2. Septic Shock: Caused by systemic infection that doesn’t respond to fluid resuscitation. 60% of patients experience decreased cardiac output, leading to poor tissue perfusion and damage to peripheral organs. 3. Drug Therapy Goals: Increase cardiac output to improve heart function. Increase systemic blood pressure to restore proper blood flow. Pharmacological Approach to Septic Shock 1. Goal: Stimulate beta-1 adrenoceptors in the heart to improve heart rate (positive chronotrope) and force of contraction (positive inotrope). 2. Sympathomimetic Amines: Noradrenaline and adrenaline are commonly used for this. Both also stimulate alpha-1 receptors to contract peripheral blood vessels, helping to raise blood pressure. 3. Choice of Drug: Noradrenaline is preferred in septic shock because it’s less likely to cause side effects. Adrenaline can stimulate beta-2 receptors in skeletal muscle, causing vasodilation, which might lead to lactic acid buildup and lactic acidosis. JOIN THE DARKSIDE Dobutamine in heart Failure Treatment 1. Development: Dobutamine is a beta-1 selective agonist developed from isoprenaline (originally for asthma treatment). 2. Mechanism of Action: Beta-1 receptor activation stimulates adenylate cyclase via a G-protein, increasing cAMP. This leads to more calcium entry into cells and release of calcium from the sarcoplasmic reticulum, which: Increases the force of contraction (positive inotrope). Increases heart rate (positive chronotrope). 3. Administration: Given via intravenous infusion (IV bag or syringe pump). Rapid onset of action. 4. Racemic Mixture: Dobutamine is administered as a racemic mixture, but only the positive isomer has inotropic (force of contraction) activity. Phosphodiesterase Inhibitors in Heart Failure Treatment 1. Mechanism of Action: Sympathomimetic amines (like dobutamine) increase cAMP by activating adenylate cyclase in the heart. Another way to increase cAMP is by preventing its breakdown with phosphodiesterase inhibitors. 2. Milrinone: Milrinone inhibits PDE type 3 in the heart, leading to increased cAMP, improving heart contractility (positive inotrope) and promoting vasodilation. Known as an inodilator (improves both contractility and vasodilation). Better vasodilator than dobutamine in both systemic and pulmonary circulations. 3. Sildenafil (Viagra): A well-known PDE inhibitor but selective for PDE type 5 (used for erectile dysfunction). Digoxin: Mechanism & Effects 1. Positive Inotrope: Increases force of contraction (positive inotrope), but does not increase heart rate (not a positive chronotrope). 2. Target Site: Sodium pump (Na/K ATP-ase) in heart muscle. Normally pumps 3 Na+ out and 2 K+ in to maintain membrane potential. 3. Action of Digoxin: Inhibits Na/K ATP-ase, increasing intracellular sodium (sodium transient). This high sodium is exchanged for calcium via a Na/Ca antiporter, leading to an increase in intracellular calcium. 4. Effect: More calcium inside the cell increases the force of contraction (positive inotrope), without directly affecting calcium transport. Digoxin in Heart Failure Treatment 1. Modern Use: Not first-line treatment for heart failure anymore. Used in combination with diuretics and ACE inhibitors. 2. DIG Trial: Conducted to see if digoxin reduced mortality in chronic heart failure patients on diuretics and ACE inhibitors. Result: No effect on mortality, but it reduced hospitalizations. 3. Benefits of Digoxin: Improves cardiac output and reduces fatigue, improving quality of life. Still important for symptomatic relief of heart failure, despite its decline in use. JOIN THE DARKSIDE Carvedilol in Heart Failure Treatment 1. US Trials (1990s): Improved survival in severe heart failure patients when carvedilol was added to treatment with loop diuretics, ACE inhibitors, and digitalis. 2. Carvedilol Characteristics: 3rd generation beta-blocker: Has an extra effect beyond beta-blocking. Non-selective beta blocker: Blocks both beta-1 and beta-2 receptors. Alpha-1 antagonist: Both isomers block alpha-1 receptors, leading to vasodilation. 3. Key Effects: Vasodilation without causing a reflex increase in heart rate. 4. Unanswered Question: Does the benefit come from all beta-blockers or is it unique to the specific properties of carvedilol? Beta Blockers In Chronic Heart Failure 1. Improving Mortality: Beta-blockers are a key treatment for improving mortality in heart failure patients. 2. Mechanism: Block beta-1 receptors to reduce sympathetic stimulation of the heart. This leads to: Improved left ventricular end-diastolic volume (LVEDV). Decreased ventricular mass. Reverse remodeling (fibrosis reduction, prevention of cellular hypertrophy). 3. Other Benefits: Reduces oxygen demand. Inhibits renin release and helps manage arrhythmias. 4. Careful Dosing: Titrate gradually to the therapeutic dose to avoid acute negative inotropic effects (reduced heart contractility). JOIN THE DARKSIDE