Lipid Lowering Medications PDF

# Lipid Lowering Medications ## Hyperlipidemia and atherosclerosis - A diagram of a coronary artery showing the different layers of the artery. - The lumen is narrowed with lipids, calcium, and cellular debris in it. > Coronary artery disease (CAD) has been shown to be correlated with the levels...

# Lipid Lowering Medications ## Hyperlipidemia and atherosclerosis - A diagram of a coronary artery showing the different layers of the artery. - The lumen is narrowed with lipids, calcium, and cellular debris in it. > Coronary artery disease (CAD) has been shown to be correlated with the levels of plasma cholesterol-and/or triacylglycerol-containing lipoprotein particles. ## Lipids and Lipoprotein - Diagram of a lipoprotein showing the different layers. - The inside of the lipoprotein consists of: - nonpolar lipids: - cholesterol ester - triglyceride - apolipoproteins: - apo C-2 - apo E - apo B100 - The outside of the lipoprotein consists of: - amphipathic lipids: - phospholipid - cholesterol ## Separation of lipoproteins by ultracentrifugation - Diagram showing a test-tube containing a layered mixture of lipoprotein. - The layers, from top to bottom, are: - chylomicrons - VLDL - IDL - LDL - HDL - free fatty acids/albumin > The greater the content of triglycerides in the lipoprotein, the lower the density of the lipoprotein. The greater the content of protein, the higher the density of the lipoprotein. ## What are chylomicrons? - Diagram showing that a chylomicron is mainly composed of triglycerides (85%), followed by phospholipids (17%) and proteins (7%). > Chylomicrons are huge but low-density; they are the majority. > Chylomicrons form in mucosal epithelial cells of the small intestine and contain mainly dietary lipids, which were transported to adipose tissue for storage. ## What are very low-density lipoproteins (VLDLs)? - Diagram showing that a VLDL is mainly composed of triglycerides (50%), followed by cholesterol (20%), phospholipids (20%) and proteins (10%). 1. VLDLs are synthesized in hepatocytes and contain mainly endogenous lipids. > Otherwise, they will be too big to pass through blood vessels, cells, etc. 2. Like chylomicrons, they lose triglycerides as their apo C-2 activates endothelial lipoprotein lipase and the resulting fatty acids are taken up by adipocytes for storage and by muscle cells for ATP production. > Triglycerides will be broken down wherever lipoprotein lipase is found. ## What are Intermediate Density lipoproteins (IDLs)? - Diagram showing that an IDL is mainly composed of cholesterol (32-37%), followed by triglycerides (24-30%), phospholipids (25-27%) and proteins (10-12%). > Also called ßVLDL or VLDL remnants. IDLs are derived from triglyceride depletion of VLDL. IDLs can be taken up by the liver for reprocessing, or upon further triglyceride depletion, become LDL. ## What are Low Density Lipoproteins (LDLs)? - Diagram showing that an LDL is mainly composed of cholesterol (50%), followed by proteins (25%), phospholipids (20%) and triglycerides (5%). > When present in excessive numbers, LDLs also deposit cholesterol in and around smooth muscle fibers in arteries, forming fatty plaques that increase the risk of coronary artery disease. For this reason, the cholesterol in LDLs, called LDL-cholesterol (LDL-C), is known as "bad" cholesterol. ## What are high density lipoproteins (HDLs)? - Diagram showing that an HDL is mainly composed of proteins (40-45%), followed by cholesterol (20%), phospholipids (30%) and triglycerides (5-10%). 1. HDLs are made in Liver 2. HDLs remove excess cholesterol from body cells and the blood and transport it to the liver for elimination. 3. Because HDLs prevent accumulation of cholesterol in the blood, a high HDL level is associated with decreased risk of coronary artery disease. For this reason, HDL-cholesterol is known as “good” cholesterol. ## Cholesterol transport in the tissues ### Exogenous Pathway - Diagram depicting the exogenous pathway of cholesterol transport. 1. The core triglycerides in chylomicrons are hydrolysed by lipoprotein lipase, and the tissues take up the resulting free fatty acids. 2. The chylomicron remnants bind to receptors on hepatocytes and undergo endocytosis. 3. Cholesterol is stored, oxidised to bile acids or secreted in the bile unaltered. Alternatively, it may enter the endogenous pathway of lipid transport in VLDL. ### Endogenous pathway - Diagram depicting the endogenous pathway of cholesterol transport 1. Cholesterol and newly synthesized triglycerides are transported from the liver as VLDL to muscle and adipose tissue. 2. The triglycerides are hydrolysed and the resulting fatty acids enter the tissues. During this process, the lipoprotein particles become LDL. 3. Cells take up LDL by endocytosis via LDL receptors that recognize LDL apolipoproteins. 4. Cholesterol can return to plasma from the tissues in HDL particles ## Classification of hyperlipoproteinaemias > aka dyslipidaemias | Type | Full name | cause | | :--- | :--- | :--- | | Type I | Familial hyperchylomicronemia | deficiency of lipoprotein lipase | | Type IIA |Familial hypercholesterolemia | decreased number of normal LDL receptors | | Type IIB | Familial combined (mixed) hyperlipidemia | overproduction of VLDL by the liver | | Type III | Familial dysbetalipoproteinemia | overproduction or underutilization of IDL | | Type IV | Familial hypertriglyceridemia | over production and/or decreased removal of VLDL triacylglycerol | | Type V | Familial mixed hypertriglyceridemia | either increased production or decreased clearance of VLDL and chylomicrons | | Type | Lipoprotein elevated | Cholesterol | Triglycerides | Atherosclerosis risk | | :--- | :--- | :--- | :--- | :--- | | I | Chylomicrons | + | +++ | NE | | IIa | LDL | ++ | NE | High | | IIb | LDL + VLDL | ++ | ++ | High | | III | BVLDL | ++ | ++ | Moderate | | IV | VLDL | + | ++ | Moderate | | V | Chylomicrons+VLDL | + | ++ | No effect | ## Dyslipidaemias: Treatment Strategies ### Diet/ Lifestyle - Omega-3 Acid Ethyl Esters - PCSK9 inhibitors - Reduce LDL receptor degradation ### Drugs used in hyperlipidemias - **Fibrates** - Increase peripheral clearance - **Resins** - Reduce fat absorption - **HMG-CoA Reductase Inhibitors (Statins)** - Increase peripheral clearance - **Ezetimide** - Reduce intestinal sterol absorption ## HMG-CoA reductase inhibitors > (Atorvastatin, Pravastatin, Simvastatin) > HMG: 3-hydroxy-3-methylglutarate ### Actions 1. **Inhibition of HMG-CoA reductase:** Their strong affinity for the enzyme compete effectively to inhibit HMG-CoA reductase, the rate-limiting step in cholesterol synthesis. > This results in cholesterol being formed. 2. **Upregulates LDL receptors on cell surface:** depletion of intracellular cholesterol causes the cell to increase the number of specific cell-surface LDL receptors that can bind and internalize circulation LDL-Cs. ### Clinical Uses - These drugs are effective in lowering plasma cholesterol (LDL-C) levels in all types of hyperlipidemias. - Reduce the risk of coronary events and mortality in patients with ischemic heart disease. ### Pharmacokinetics - oral, first-pass extraction - given in the evening > Why are statins best taken in evenings? (After finishing all meals → only source of cholesterol the body synthesises is HMG-CoA and it is most active.) ## HMG-CoA reductase inhibitors > (Lovastatin, Simvastatin, Pravastatin, Fluvastatin) ### Adverse Effects 1. **liver:** Biomedical abnormalities in liver function 2. **Muscle:** myopathy and rhabdomyolysis > This results in breakdown of muscles; symptoms include: intense muscle soreness & in extreme cases, the breakdown of the muscle. 3. **Contraindications in pregnancy, nursing mothers, children or teenagers:** affects neurodevelopment of fetus and child > Cholesterol is a large component of the brain; ## But, what if...... 1. Intolerant of statins? 2. Suboptimal cholesterol control even at maximal statin dose? 3. Severe hypercholesterolaemia? ## PCSK9 inhibitors > (Evolocumab, Alirocumab) ### Actions 1. Inhibition of hepatic proprotein convertase subtilisin-kexin 9 (PCSK9) which targets LDL receptors for degradation in lysosomes. 2. Reduced LDL receptor degradation: more cell-surface LDL receptors that can bind and internalize circulation LDLs. > This is the end step of the mechanism of action; it is somewhat the same as statins. ### Clinical Uses - Indicated for lowering plasma cholesterol (LDL-C) levels in familial hypercholesterolaemias, especially those intolerant to statins - Indicated in patients with clinically significant atherosclerotic CVD requiring additional LDL-C lowering after being on diet control and maximally tolerated statin therapy ### PK/PD Features - Monoclonal antibodies, thus administration via injection (abdomen, upper arm or thigh), reaches max serum concentration after ≥ 3 days, half-life 10-20 days, dosing every 2 or 4 weeks - PCSK9 inhibitors when combined with statins can lower LDL-C levels 50%-60% above that achieved by statin therapy alone ### Adverse Effects - Contraindicated in patients who develop hypersensitivity reactions, e.g., hypersensitivity vasculitis or serious allergies requiring hospitalization - Injection site inflammatory reactions (erythema, itchiness, swelling, pain or tenderness) - Increased incidence of nasopharyngitis and sinusitis ## Fibrates/Fibric Acid Derivatives > (Gemfibrozil, Fenofibrate) ### Action 1. They are ligands for the peroxisome proliferators-activated receptor-alpha (PPAR-α) protein. The interaction with PPAR-α results in increased activity of lipoprotein lipase. > This activation results from genetic upregulation. 2. By stimulating lipoprotein lipase activity, they cause a decrease in plasma triacylglycerol levels. 3. Levels of VLDL decrease, in part as a result of decreased secretion by the liver. 4. HDL levels rise moderately > Don't have to know ### Clinical Uses > It should show which type of high cholesterol they are used for. - treatment of hypertriglyceridemias with VLDL elevation, especially for dysbetalipoproteinemia. > For example: - Pure type I in cholesterol = statins - Type I in cholesterol + triglycerides = combination therapy ### Adverse effects - Gastrointestinal effects: Nausea - Skin rashes - gall-stones - myositis ## Omega-3-acid ethyl esters > (Omacor: eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) ethyl esters) ### Actions 1. Reduces hepatic triglycerides (TG) production and increases TG clearance from VLDL. > It still works; it acts at lower levels. 2. Functional inhibition of diglyceride acyltransferase (responsible for TG biosynthesis) as EPA and DHA are poor substrates for the enzyme. > This is because of a difference in structure. 3. Increase free fatty acid breakdown (via beta-oxidation) > This MOA has not been confirmed. 4. Increase lipoprotein lipase activity (?) > This will not be tested. ### Clinical Uses - Used (in conjunction with dietary measures) for Hypertriglycerideaemia (Type IV) monotherapy - Used for Familial Combined Hyperlipidaemia (Type IIb) in combination with statins (when control of TG is insufficient) - NOT indicated for Hyperchylamicronaemia (Type I) ### PK/PD Features - Oral (2-4g or more per day) taken with food - Metabolized by liver (as with all lipids) ### Contraindications and Adverse Effects - Contraindicated in patients who are allergic to fish (derived from fish oil) - Gastrointestinal symptoms (abdominal distension, pain, constipation, diarrhoea, dyspepsia, flatulence) are the most common adverse effects - In some patients, DHA may lead to increase of LDL-C (levels need to be monitored e.g., patients with familial hypercholesterolaemias) - Reduces production of thromboxane A2, may lead to increased bleeding time (special care needed for patients on anticoagulants such as aspirin and warfarin) > Watch this space! - Other congeners are under development or assessment (e.g., EPA-ester-only formulation, omega-3 carboxylic acids) - More may be approved for clinical use in future > Omega-3 FAs and esters are also available OTC: Are the efficacy or MOA between prescription and OTC versions expected to be significantly different? What other differences might there be between Omacor vs OTC? (They are made to very different standards, which results in a much lower level of the medicine in OTC; for example in terms of clinical efficacy, purity, etc.) ## Bile acid binding resins > (Cholestyramine) ### Action - Must only be one resin. 1. Anion exchange resins bind negatively charged bile acids and bile salts in the small intestine. 2. Lowering the bile acid concentration causes hepatocytes to increase conversion of cholesterol to bile acids. Therefore, the intracellular cholesterol concentration decreases 3. Activates an increased hepatic uptake of cholesterol-containing LDL particles, leading to a fall in plasma LDL. > Why? 4. May increase VLDL, but have little effect on HDL. ### Clinical Uses - Treatment of patients with primary hypercholesterolemia (IIA) > This is the preferred treatment. - +Niacin: treat LDL elevations in persons with combined hyperlipidemia (IIb) ### Pharmacokinetics - Oral only > This is administered orally only > A slower gut mobility is an important adverse effect, as well as diarrhoea because the large amount of bile remaining in the gut can act as a nutrient source for bacteria. ### Adverse Effects 1. GI effects: constipation, nausea and flatulence 2. impaired absorptions: vitamins A, D, E, K ## Inhibitors of intestinal sterol absorption > (Ezetimibe [Zetia]) ### Actions - Reduces cholesterol absorption at the small intestine by inhibition of the sterol transporter Niemann-Pick C1-Like-1 (NPC1L1). ### Pharmacokinetics - Readily absorbed, conjugated in the intestinal wall to an active glucuronide ### Clinical Uses - Reduction of LDL - Alone: 18% decrease in LDL - Vytorin: ezetimibe+simvastatin ### Adverse Effects - Common: Diarrhoea, flatulence - Rhabdomyolysis (more common when combined with statins) - Low incidence of reversible hepatotoxicity > Will ezetimibe still be effective in the absence of dietary cholesterol? # Anti-Hypertensive Medications ## A note on my CVS pharmacology lectures - Diagram showing a circle with the following drug types: - Lipid Lowering Drugs - Anti-Hypertensives - Anti-Arrhythmics - Anti-Anginals (Coronary) - Heart Failure Drugs - Arrows depict relationships between drug types. ## Objectives 1. Review mechanisms for regulation of vascular tone 2. Review the renin-angiotensin system (RAS) 3. Understand the classification of blood pressure lowering drugs 4. Understand the MOA of blood pressure lowering drugs ## What is Hypertension? | Blood Pressure Category | Systolic mm Hg *upper number* | Diastolic mm Hg *lower number* | | :--- | :--- | :--- | | Normal | Less than 120 | Less than 80 | | Elevated | 120-129 | Less than 80 | | High Blood Pressure (Hypertension) Stage 1 | 130-139 | 80-89 | | High Blood Pressure (Hypertension) Stage 2 | 140 or higher | 90 or higher | | Hypertensive Crisis (consult your doctor immediately) | Higher than 180 | Higher than 120 | > **Etiology:** Specific cause (<10%) - Essential hypertension (90%) - Family history ## Consequences (sequelae) of Hypertension - Congestive heart failure - Myocardial infarction - Renal damage - Cerebrovascular accidents ## Major factors influencing blood pressure > Arterial Blood Pressure = Cardiac output x Peripheral Resistance - Diagram outlining the factors influencing blood pressure: - **Cardiac output** - **Heart rate** - **Contractility** - **Filling pressure** - **Peripheral Resistance** - **Arteriolar tone** - **Venous tone** *(amount of contraction, ie, how dilated it is; more constricted = greater tone )* - **Blood volume** > **Preload**= Stretching of cardiac muscles before contraction > *Associated with ventricular filling* > **Afterload**= Force against which the heart has to contract to eject the blood > *Associated with peripheral resistance* ## Drugs used in hypertension | Tier | Topic | Drug Class | Module Drugs *all PO unless indicated* | Case Drugs | |:---:|:---|:---|:---|:---| | 1 | Hypertension | ACE-Inhibitors | Captopril, Enalapril, Lisinopril, Perindopril | Lisinopril | | | | Angiotensin Receptor Blockers | Candesartan, Losartan, Valsartan, Irbesartan, Telmisartan | Losartan | | | | Beta-blockers | Atenolol, Bisoprolol, Carvedilol, Nebivolol, Propranolol | Bisoprolol | | | | Calcium Channel Blockers (Dihydropyridines) | Amlodipine, Nifedipine (vs Verapamil) | Nifedipine | | | | Diuretics (Thiazides and thiazide-like) | Metolazone, Hydrochlorothiazide, Indapamide | Indapamide | | | | Hydralazine | Hydralazine | - | | | | Mineralocorticoid receptor antagonists | Spironolactone, Eplerenone, Finerenone | Spironolactone | | | | Alpha-blockers | Prazosin, Alfuzosin, Terazosin | - | > **Hydralazine, Mineralocorticoid receptor antagonists and alpha-blockers are second-line medications for hypertension** ## Mechanisms for Controlling Blood Pressure - Diagram showing the pathway of the renin-angiotensin system - Arrows depicting relationships between different components of the system. > This is the mechanism for regulating blood pressure from moment-to-moment and in the long-term > **Decrease in BP** - **Sympathetic Activity** - **Activation of β1-AR of heart** - **Activation of α1-AR in SM** *contraction of smooth muscle to ensure that only bleeding in peripheral leg limbs are stopped* - **Renal blood flow** - **Renin** - **Aldosterone** - **Ang II** *this acts to increase BP in both the short-term and the long-term* - **Glomerular filtration rate** *whole process of filtration slows down; less water loss* - **Na+, H₂O retention** - **Blood volume** > **Increase in BP** - **Cardiac output** - **Peripheral Resistance** >*B1-AR is the predominantly expressed beta-adrenergic receptors in cardiac myocytes* ## Determinants of vascular tone - Diagram showing the different pathways and their effects on vascular tone. > **MLCK:** Myosin light chain kinase active form. > **Myosin-LC#:** Myosin-LC phosphorylation. > **Contraction** - The pathway leading to constriction: - **Ca2+ channel** - **Calmodulin** - **Ca2+-calmodulin complex** - **MLCK** *this promotes myosin light chain phosphorylation which leads to contraction* - **Myosin-LC** - **Actin** - **Contraction** > **Relaxation** - The pathway leading to relaxation: - **β-agonists** - **Adenylyl cyclase*:** *via ẞ1 receptors in cardiac myocytes; leads to increase in contractility* - **cAMP** - **ATP** *via ẞ2 receptors in SM; leads to vasodilation* - **MLCK-(PO4)2** *this is the de-activiated phosphorylated form of MLCK; causes vasodilation by removing MLCK* - **Myosin-LC#** - **Actin** - **Contraction** - **Nitrates** - **Nitric Oxide** - **Guanylyl cyclase*** - **cGMP** - **GTP** - **Myosin-LC** - **Relaxation** ## Inhibitors of Angiotensin - **ACE-I** - **AT1 blockers** ## Formation of Angiotensins I-IV - Diagram outlining the process of angiotensin formation. > **C-terminal** > (Angiotensinogen → Angiotensin 1) > **Renin** *this enzyme acts to cleave angiotensinogen to form Angiotensin I* > (Angiotensin I → Angiotensin 11) > **ACE** *this enzyme acts to cleave Angiotensin I to form Angiotensin II* > **Angiotensin III** > **Angiotensin IV** > **N-terminal** > **V L L H F P H I Y V R N** > **Angiotensin II – strong basal activity** > **Angiotensin I – little basal activity** > **Angiotensinogen** *anything that ends in "-ogen" is a pre-peptide* ## Angiotensin Converting Enzyme Inhibitors (ACE-I) > E.g.: Lisinopril, Captopril, Enalapril ### Actions - Diagram depicting the mechanism of action. > *This is essentially a peptide signaler* > **Angiotensinogen** > **Renin** *this enzyme acts to cleave angiotensinogen to form Angiotensin I. It is increased due to a decrease in BP* > **Ang I** > **ACE** > **Ang II** *this is the active form of angiotensin which is a powerful vasoconstrictor and leads to an increase in BP* > **Amino-peptidase** > **Ang III** *this is also a little bit active in aldosterone release* > **Angiotensin converting enzyme Inhibitor** *inhibits the conversion of Angiotensin I to Angiotensin II* > **Bradykinin** *this accumulates at the site of action due to the ACE-I and reduces vascular resistance, increasing blood flow. It also prevents breakdown of bradykinin* - **NO, PG** *this is formed due to activation of bradykinin* > **Inactivate** *ACE-I prevents activation of angiotensin which leads to vasodilation* > **Vasodilation** > **BP** *this decreases due to vasodilation.* ### Clinical Uses 1. Hypertension 2. Cardiac failure 3. Following myocardial infarction > Are there protective effects against subsequent MIs? 4. Renal insufficiency ### Adverse Effects 1. Severe hypotension 2. Acute renal failure 3. Hyperkalemia 4. Angioedema* & dry cough** (bradykinin and substance P) 5. Contraindication: pregnancy > *Bradykinin & Substance P induced “inflammation like" responses: vasodilation, plasma extravasation -> angioedema* > **Bradykinin & prostaglandin idiosyncratic reactions. Increased sensitivity of bradykinin-dependent airway sensory nerve fibers?** ## Ang II type 1 (AT1) blockers > E.g.: Valsartan, losartan, candesartan, irbesartan, telmisartan - Diagram depicting the mechanism of action. > **Will it inhibit Ang II from being broken down into Ang IIZ?** - **AT1 blocker** - **Ang II** - **AT1 receptor** ### Adverse Effects 1. Less/no dry cough 2. Contraindication: pregnancy ## Beta-adrenoceptor Antagonists > **“Beta-Blockers”** ## MOA of Beta-Blockers - Diagram showing the pathways of β-blocker activity. > **MLCK:** Myosin light chain kinase active form. > **Myosin-LC#:** Myosin-LC phosphorylation. > **Contraction** - The pathway leading to constriction: - **Ca2+ channel** - **Calmodulin** - **Ca2+-calmodulin complex** - **MLCK** *this promotes myosin light chain phosphorylation which leads to contraction* - **Myosin-LC** - **Actin** - **Contraction** > **B1-blockade** > **Adenylyl cyclase*:** *this is inhibited by β-blockers, leading to a decreased in contractility* > **cAMP** > **ATP** > **MLCK-(PO4)2** > **Myosin-LC#** > **Actin** > **Contraction** > **Relaxation** - The pathway leading to relaxation: - **Nitric Oxide** - **Guanylyl cyclase*** - **cGMP** - **GTP** - **Myosin-LC** - **Relaxation** ## MOA of Beta-Blockers in cardiac myocytes - Diagram showing the pathway of β-blocker activity in myocardial cells. > **CICR = Calcium Induced Calcium Release** - **β-Blocker** - **β1** *this is part of the Gs protein complex* - **Gs protein** - **ATP ** - **Adenylate cyclase** *inhibited by β-blockers* - **5' AMP** - **cAMP** *reduced by β-blockers* - **PK A** - **PDE** - **Ca2+** *this causes SR to release Ca2+ at a faster rate* - **Sarcoplasmic Reticulum** - **Ca2+** *the level of Ca2+ inside the cardiac cell* - **Calcium channel blocker** *this prevents entry of Ca2+ into the cell* - **Actin-myosin complex** > **Beta-blocks prevent this from happening HOW?** ## MOA of Beta-Blocker associated bronchoconstriction* - Diagram showing the pathways of β-blocker activity in bronchial smooth muscle cells. > **MLCK:** Myosin light chain kinase active form. > **Myosin-LC#:** Myosin-LC phosphorylation. > **Contraction** - The pathway leading to constriction: - **Ca2+ channel** - **Calmodulin** - **Ca2+-calmodulin complex** - **MLCK** *this promotes myosin light chain phosphorylation which leads to contraction* - **Myosin-LC** - **Actin** - **Contraction** > **Β2-blockade** > **Adenylyl cyclase*:** *this is inhibited by β-blockers, which prevents vasodilation* > **cAMP** > **ATP** > **Via ẞ2 receptors in bronchial SM. Leads to vasodilation.** >**MLCK-(PO4)2** > **Myosin-LC#** > **Actin** > **Contraction** > **Relaxation** - The pathway leading to relaxation: - **Nitric Oxide** - **Guanylyl cyclase*** - **cGMP** - **GTP** - **Myosin-LC** - **Relaxation** > **Reduced inactivated form of MLCK = less bronchodilation = more prone to bronchoconstriction** > ***Similar effects in other vascular smooth muscle cells* ** ## Beta-Blockers: Main Types ### Non-Selective 1. Propranolol 2. Pindolol 3. Carvedilol > *This is contraindicated in slow metabolizers who have asthma* ### Cardioselective (β1) 1. Atenolol 2. Bisoprolol 3. Metoprolol XL > *This is metoprolol succinate* ### Mixed (3rd generation) - **Nebivolol** - **Beta1 selective in low dose / fast metabolizers (majority of population)** > *The body quickly converts it, resulting in a lower systemic dose of the drug and a more β1 selective effect at a lower dose* - **Non-selective in high dose/slow metabolizers** >*The body slowly converts it, resulting in a higher systemic dose of the drug and a more non-selective effect* - **Also has vasodilatory effects through increase NO release** > *This is important to remember because the drug has a different effectivity depending on the dose*. ## Beta-Blockers: Clinical Uses 1. Hypertension 2. Cardiac failure 3. Following myocardial infarction >*Has a protective effect against subsequent ones*. 4. Abnormal heart rhythm 5. Anxiety disorders >*Partially boosts beta-blocker effects and causes a decrease in HR. This makes a patient feel less anxious* ## Beta-Blockers: Adverse Effects 1. Hypotension 2. Bradycardia 3. AV nodal block 4. Reduced exercise capacity >*This is important because the heart is not pumping enough to satisfy metabolic requirements.* 5. Bronchoconstriction (esp. asthmatics) >*This is notably important for asthmatic patients* 6. CNS: Vivid dreams, clinical depression ("beta-blocker blues") ## Calcium Channel Blockers > **Dihydropyridines (DHPs)** > *Covered in IHD / Coronary artery disease Lecture* ## Diuretics > *(specifically....Thiazides)* ## Structure & Function of the nephron - Diagram showing the structure of a nephron - **Renal cortex** - **Renal medulla** - **Renal papilla** - **Renal pyramids** - **Renal columns** - **Afferent arteriole** - **Glomerulus** - **Arcuate artery and vein** - **Proximal convoluted tubule** - **Loop of Henle** - **Distal convoluted tubule** - **Collecting duct** *urine is collected by this time* - **Vasa recta - **Fibrous capsule** ## Distal Convoluted Tubule - Diagram showing the key components and functions of the distal convoluted tubule 1. This segment is relatively impermeable to water, and the NaCl reabsorption therefore further dilutes the tubular fluid 2. The mechanism of NaCl is electrically neutral Na+ and Cl- cotransport. > **Lumen-urine** > **Na+** > **Cl-** - The distal convoluted tubule is the site of the reabsorption of Na, K and Ca. > **Distal convoluted tubule** > **R PTH** *parathyroid hormone* > **Interstitium-blood** > **Na+** > **K+** > **Ca2+** > **Ca2+** *this is reabsorbed by the distal convoluted tubule epithelial cell* > **Ca2+** > **parathyroid hormone (PTH)** ## Thiazides > (the most widely used diuretic agents) > **Hydrochlorothiazide, Indapamide** > **Less water travels out of the tubule and into the interstition via osmosis at the collecting ducts. Salt remains in the interstition** ### Actions 1. Thiazides inhibit NaCl reabsorption by blocking the Na+/Cl- transporter. 2. Thiazides enhance Ca2+ reabsorption in the distal convoluted tubule. > **urine down collecting duct epithelium** > **Na+** > **Cl-** >> **Distal convoluted tubule** >> **R PTH** >> **K+** > **Ca2+** > **Ca2+** > **Less Na+** > **Na+ exchanger works better so more Ca2+ is moved out of the tubule.** 3. The action of thiazides depends in part on renal PGs synthesis. NSAIDs (eg, aspirin, indomethacin) interfere with the actions of thiazide diuretics by reducing the PGs synthesis. ### Clinical Uses 1. Hypertension > (this is the preferred use of thiazides) 2. Congestive heart failure > *Kidney stones are made up of excess Ca2+, and therefore it makes sense that thiazides would be used for the condition* 3. Nephrolithiasis due to idiopathic hypercalciuria 4. Nephrogenic diabetes insipidus ### Adverse Effects 1. **Hypokalaemic metabolic alkalosis** 2. **Hyponatraemia** 3. **Hyperuricaemia** 4. **Hyperglycaemia** > *This is important to remember as thiazides are possibly contraindicated in diabetic patients* 5. **Hyperlipidaemia** 6. **Hypercalcaemia** ## Selected MOAs of thiazide diuretics-associated adverse effects ### Hypokalaemic metabolic alkalosis > *Adapted from* https://www.ncbi.nlm.nih.gov/books/NBK532918/ > Patients on thiazide diuretics may experience a hypokalemic metabolic alkalosis due to the increase in aldosterone-mediated K+ and H+ ions excretion in the intercalated cells of the collecting duct (note this is not the location of thiazide action, ie, distal convoluted tubule). ### Hyponatraemia > *Adapted from* https://www.ncbi.nlm.nih.gov/books/NBK532918/ > The MOA of thiazide diuretics is to decrease sodium reabsorption and therefore decreased fluid reabsorption; this directly causes decreased levels of circulating sodium. If hyponatremia were to occur, it would happen during the first 2 to 3 weeks of therapy; after this time, the patient is in a new steady state in which further sodium and water losses do not occur. ### Hyperglycaemia > *Adapted from* https://www.ncbi.nlm.nih.gov/books/NBK532918/ > Thiazide diuretics cause hypokalemia; at the level of the pancreatic B cells, decreased K+ in the interstitium keeps the K+ channels open for an extended time, which causes the hyperpolarization of the cell. This hyperpolarization does not allow the voltage-gated calcium channels to open, in turn reducing exocytosis of insulin granules which is activated by calcium influx. As a result, insulin response to hyperglycaemia is impaired. ### **Hyperuricaemia** > *Adapted from* https://www.ncbi.nlm.nih.gov/books/NBK532918/ > Thiazide diuretics cause hyperuricemia and increase the risk of developing gout. Thiazides directly increase urate reabsorption in the proximal tubule by using the OAT 1 anion exchanger on the basolateral membrane and the OAT 4 urate anion exchanger on the luminal membrane. At the OAT 1 exchanger, thiazides enter the proximal convoluted tubule in replace of urate, for an anion, increasing urate in the interstitium. The OAT 4 exchanger exchanges thiazides for urate in the lumen, causing increased urate in the proximal convoluted tubule that then crosses the basolateral membrane and therefore increases urate in the interstitium. ## Second-line Antihypertensives ## Second-line antihypertensives ### Hydralazine > **Covered in the Heart Failure Lecture** ### Mineralocorticoid receptor antagonists - Spironolactone - Eplerenone - Finerenone > **Covered in the Heart Failure Lecture** ### Alpha-adrenergic antagonists - Prazosin - Alfuzosin - Terazosin ## Hydralazine > **Covered in Heart Failure Lecture** ## Alpha-adrenergic antagonists ### Target - Postsynaptic alpha1 adrenergic receptors on vascular smooth muscles mediate vasoconstriction, leading to increased peripheral vascular resistance, in turn increasing BP ### MOA - Alpha-andrenergic antagonists oppose alpha1-mediated vasoconst