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Pharmacology 2060A/B Final notes.docx

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Pharmacology
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Pharmacology 2060A/B
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Angela Nissen

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Module 12 - Drugs to Lower Blood Cholesterol and Triglycerides 12.1 Introduction Coronary Heart Disease Occurs when coronary blood circulation fails to adequately supply the heart with blood Primarily caused by atherosclerosis Occurs when plaque builds up on the walls of the arteries Causes artery to narrow  decreases blood flow to the heart The risk of developing coronary heart disease is directly related to the levels of cholesterol in the blood (which forms the plaque) People with high blood cholesterol levels are at high risk and hence the large medical effort to design cholesterol lowering drugs In Canada cardiovascular disease causes one third of all deaths more than any other illness 12.2 Cholesterol Cholesterol is very important molecule supporting many physiological roles Component of cell membranes, precursor of steroid hormones, precursor of bile salts (help us absorb dietary fats) We obtain cholesterol through dietary sources (exogenous) of through endogenous synthesis which occur primarily in the liver Approximately 80% of cholesterol in the body is synthesized by the liver whereas 20% is obtained from dietary sources Therefore most drugs that decrease cholesterol target the liver to decrease the synthesis, rather than targeting dietary absorption High levels are linked to atherosclerosis Plasma Lipoproteins The basic structure is an outer hydrophilic shell made up phospholipids which allows them to be soluble in the blood plasma and a core composed of hydrophobic cholesterol and triglycerides Primary function is to transport cholesterol and triglycerides in the blood As cholesterol and triglycerides are hydrophobic they require lipoproteins in order to be soluble in the plasma All lipoproteins also apolipoproteins embedded in the phospholipid shell which serve several structures Allow recognition by cells which may bind and ingest lipoproteins Activate enzymes that metabolize lipoproteins Increase the structural stability of lipoproteins Lipoproteins that contain apolipoprotein A-I transport cholesterol from non-hepatic tissues back to the liver Lipoproteins that contain apolipoprotein B-100 transport cholesterol from the liver to non-hepatic tissues Classes of Lipoproteins Named based on their density – protein has a higher density than lipid so lipoproteins with a higher percentage of proteins will have a high density and vice versa 1 In terms of coronary heart disease and atherosclerosis three classes of lipoproteins are particularly important: 1. Very-low density lipoproteins (VLDL) 2. Low density lipoproteins (LDL) 3. High density lipoproteins (HDL) Very-Low Density Lipoproteins (VLDL) Deliver triglycerides from the liver to adipose tissue and muscle They have a triglyceride rich core and account for almost all of the triglyceride content in the blood The link between VLDL and atherosclerosis is controversial with some, but not all studies suggest that high VLDL contribute to it VLDL particles contain one B-100 apolipoprotein molecule which allows them to bind to adipose and muscle cells and transfer their lipid (triglycerides) to the cell Low Density Lipoproteins (LDL) Deliver cholesterol to non-hepatic tissue – have a cholesterol rich core and account for 60-70% of the cholesterol in the blood LDL particles contain one B-100 apolipoproteins molecule which allows them to bind to cell and transfer their cholesterol to cells There is a clear link between LDL cholesterol and development of atherosclerosis The higher the blood LDL level the greater the risk of developing coronary heart disease Reducing blood LDL levels halts or even reverses atherosclerosis and has been proven to decrease death from coronary heart disease Because of the role it plays in heart disease LDL are often referred to as ‘bad cholesterol’ High Density Lipoproteins (HDL) Deliver cholesterol from non-hepatic tissue back to the liver  HDL’s promote cholesterol removal from the blood Similar to LDL, HDL have cholesterol as their main core lipid and account or 20-30% of total blood cholesterol The effect of HDL on coronary heart disease is opposite to that of LDL Therefore elevated HDL decreases the risk of coronary heart disease HDL particles may contain multiple apoliporoteins including A-I, A-II and A-IV The A-I apolipoprotein is believed to mediate the beneficial effects of HDL cholesterol As HDL cholesterol protects against atherosclerosis it is often referred to as ‘good cholesterol’ The Role of LDL Cholesterol in Atherosclerosis Initiation of atherosclerosis begins with damage to endothelium – the cells lining the blood vessels Mediated by – hypertension, smoking, elevated blood lipids, hemodynamic factors and immune reactions LDL accumulate in the sub-endothelial space and are 2 oxidized Oxidized LDLs recruit monocytes (immune cells) to the sub-endothelial space Monocytes are converted to macrophages which are another type of immune cell Macrophages ingest oxidized LDL cholesterol and become larger and vacuolated – referred to as foam cells As foam cells accumulate under the endothelium a fatty streak appears Continued accumulation of foam cells causes the endothelium to rupture Collagen smooth muscle cells and platelets attach forming a fibrous cap If the fibrous cap is not strong enough moving blood can cause the cap to rupture A thrombus (aggregation of platelets will form which may partially or completely block blood flow, either at the site of atherosclerosis or further downstream 12.3 Cholesterol Screening and Risk Assessment Cholesterol Screening Screening guidelines, target levels and risk assessment parameters have been generated from the heart and stroke foundation of Canada and or the Canadian Cardiovascular society In Canada cholesterol screening is recommended for all males over the age of 40 and all females over the age of 50 or post-menopausal females Testing is recommended in all patients regardless of age who: Have diabetes Heart disease (or family history) Hypertension Waist circumference greater than 102cm (40 inches) for men and 88cm (35 inches for women) Smoke or have recently stopped smoking Inflammatory disease or renal disease Cardiovascular Risk Assessment Used by health care practitioners to estimate the risk a patient has of developing cardiovascular disease Although cardiovascular risk assessment is imperfect is provides health care professional with guidelines and treatment targets Most commonly used form of cardiovascular risk assessment is called the Framingham Risk Score (FRS) Uses gender, age, total blood cholesterol, smoking status, HDL cholesterol and systolic blood pressure in a formula to calculate risk score – represents patients 10 year risk of developing coronary heart disease Patients with FRS greater than 20% are considered high risk, medium risk if the score is between 10-19% and low risk if under 10% FRS has been shown to underestimate risk in youth women and patients with metabolic syndrome Tables represent scores developed through experimental studies which determine percentage risk Tables are different for men and women 3 Framingham Risk Assessment All high risk patients with <20% FRS, diabetes or heart disease should be treated with cholesterol lowering treatments LDL target concentration of <2mmol/L or greater than 50% decrease in LDL-cholesterol levels Moderate risked patients with FRS of 10-19% should have LDL lowering treatments is the concentration of LDL-cholesterol is >3.5mmol/L, ratio of triglycerides/HDL-cholesterol is >5.0 or there is significant inflammation present LDL target concentration of <2mmol/L or greater than 50% decrease in LDL-cholesterol levels Low risk patients with FRS of less than 10% should be treated only if their LDL-cholesterol is >5.0 mmol/L LDL target concentration of greater than 50% decrease in LDL-cholesterol levels Metabolic Syndrome Combination of medical disorders that cause increased risk of coronary heart disease and type II diabetes Metabolic syndrome is diagnosed when patients have three or more of the following: 1. Central obesity – wait circumference >102 cm for men or 89 cm for women 2. Elevated triglycerides – blood triglycerides > 1.7 mmol/L 3. Low HDL cholesterol – HDL cholesterol < 1.03 mmol/L in men and 1.29 mmol/L in women 4. Hyperglycemia – fasting blood glucose > 5.6 mmol/L 5. Hypertension – blood pressure > 135/85 Treatment of metabolic syndrome is targeted at decreasing the risk for coronary heart disease and type II diabetes Estimates suggest that 1 in 4 Canadians have metabolic syndrome 12.4 Non-Drug Treatments of LDL Cholesterol Drug therapy is NOT the first line of treatment for elevated LDL cholesterol The primary treatment for high LDL cholesterol is lifestyle changes including modification to diet weight exercise plan and smoking status 4 Diet – intake of less than 200 mg/day of total cholesterol and intake of saturated fats of 7% or less of total calories. Further recommendations suggest the intake of soluble fiber of 10-25 grams/day and plant stanols and sterols of 2 grams/day Weight Control – weight loss by dietary modification and exercise lowers LDL cholesterol and decreases the risk of coronary heart disease Exercise – cardiovascular exercise has many benefits which include decreasing LDL cholesterol elevating HDL cholesterol along with decreasing insulin resistance and blood pressure Cigarette Smoking – decreases HDL cholesterol and increases LDL cholesterol = increasing risk of coronary heart disease. Been called the leading preventable cause of death and disease and is an especially important risk factor in younger (<50) men and women 12.5 Drug Treatment of Elevated Blood Lipids Although the first line treatment for elevated blood lipids are lifestyle changes many patients are unable to reach target cholesterol levels with lifestyle changes alone When target cholesterol levels are not achieved by lifestyle changes drug treatment is initiated There are several classes of drugs used to treat elevated blood lipids: Statins, nicotinic acid, bile acid sequesterants, cholesterol absorption inhibitors, fibrates Must understand the mode of action in the body and any side effects of these drugs HMG-CoA Reductase Inhibitors (Statins) Cholesterol Synthesis Approximately 80% of total body cholesterol is actually synthesized by the liver Hepatic cholesterol synthesis occurs in what is known as the mevalonic acid pathway Acetyl CoA from the citric acid cycle is converted to 3-hydroxy-3-methylglutaryl (HMG-CoA) HMG-CoA is then enzymatically converted to mevalonic acid by the enzyme HMG Reductase - Most important step to remember After several other enzymatic steps cholesterol is formed Conversion of HMG-CoA into mevalonic acid is the rate limiting step in cholesterol synthesis and therefore HMG Reductase is mostly targeted by cholesterol lowering drugs Cholesterol is greatest during the night therefore medications are taken in the evening Mechanism of Action - Statins Statins decrease the hepatic synthesis of cholesterol by inhibiting the enzyme HMG-CoA reductase the rate limiting step of cholesterol synthesis Inhibition of HMG –CoA reductase causes an up-regulation of hepatic LDL receptors This allows the liver to remove LDL cholesterol from the blood The net effect is a decrease in LDL cholesterol levels in the blood and therefore increased metabolism in the liver 5 Benefits of statins 1. LDL cholesterol and triglyceride  2. HDL cholesterol concentrations  Primary prevention studies – targeted at preventing the developments of cardiovascular disease Statins are effective in the primary prevention of coronary heart disease Multiple recent studies have shown that statins decrease the incidence of coronary events (heart attack and stroke) even in low risk patients with no history of coronary heart disease Secondary prevention studies – aims to prevent the recurrence of cardiovascular events Preventing a patient who has had a heart attack from having another episode Statins are effecting drugs for preventing recurrent cardiovascular events in the higher risk patients Due to their remarkable ability to prevent the onset and progression of cardiovascular disease, statins are among the highest prescribed drugs in the world Atorvastatin (Lipitor) is the highest prescribed drug in Canada and the United States Rosuvastatin (Crestor) is the fourth highest prescribed drug in Canada Statin Pharmacokinetics Atorvastatin Pharmacokinetics Low oral bioavailability (~14%) Large fraction of absorbed dose is extracted by the liver the site of the drug action Distribution is primarily to the liver but also to the spleen adrenal glands and skeletal muscles Metabolized by CYP3A4 and predominantly excreted in the feces Rosuvastatin Pharmacokinetics Low oral bioavailability (~20%) Large fraction of absorbed dose is extracted by the liver the site of the drug action Distribution is primarily to the liver but also to skeletal muscles Predominantly excreted in the feces with minimal renal excretion Plasma Rosuvastatin concentrations are approximately two times higher in Asian patients when compared to Caucasians Initial dose in Asians should be 5 mg and caution should be used when increasing that dose Statin – Adverse Effects The most common adverse event in myopathy (muscle injury). Mild myopathy characterized by muscle aches and weakness occur in 1-5% of patients Rhabodomyolysis is a rare but serious adverse effect associated with statin use defined as muscle lysis and resultant release of its contents with severe pain 6 There is a low incidence of hepatotoxicity associated with statin use and therefore liver function tests should be performed before initiating therapy and periodically thereafter Cholesterol is required for the synthesis of cell membranes and many hormones and therefore statins should not be prescribed to women who are pregnant or are planning on becoming pregnant Potentially teratogenic drug Nicotinic Acid (Niacin) Inhibits the hepatic secretion of VLDL Since LDL is a by-product of VLDL degradation nicotinic acid effectively reduces both VLDL and LDL levels in the blood Also increases blood levels of HDL cholesterol Nicotinic acids are used much less in therapy relative to statins due to their side effects Intense facial flushing, hepatotoxicity, hyperglycemia, skin rashes and increased uric acid levels in the urine Bile Acid Sequesterants Background: Bile acids are negatively charged molecules produced in the liver from CYP7A1 mediated cholesterol metabolism Bile acids are secreted into the intestine and function to aid in the absorption of dietary fats and fat soluble vitamins Bile acids undergo enterohepatic recycling and are therefore reabsorbed from the intestine Over 95% of bile acids are normally reabsorbed Mechanism of action: Bile acid sequesterants are large positively charged molecules and they function by binding bile acids in the intestine and preventing their absorption Since over 95% of bile acids are reabsorbed this causes an increased demand for bile acid synthesis In order to synthesize more bile acids in the liver LDL cholesterol is required Liver cells increase the number of LDL receptors which results in increased uptake of cholesterol from the blood to the liver causing decreased blood plasma LDL cholesterol levels Adverse effects: Bile acid sequesterants are not absorbed at all and therefore do not have any systemic side effects Predominant side effects are limited to the GI tract and include constipation and bloating As bile acid sequesterants are designed to bind to negatively charged molecules they may decrease the absorption of some drugs such as thiazide diuretics, digoxin, warfarin, and certain antibiotics Cholesterol Absorption Inhibitor A specific thansport protein called NPC1L1 is responsible for the intestinal uptake of the majority of dietary cholesterol Ezetimibe is a cholesterol absorption inhibitor which has been shown to decrease intestinal cholesterol absorption by 54% and lower blood LDL cholesterol by 15-20% Decreased intestinal absorption of cholesterol by ezetimibe can produce a compensatory increase in hepatic cholesterol synthesis Ezetimibe is often prescribed as an adjunct therapy along with a statin A combination pill called vytorin contains a statin (simvastatin) with ezetimibe and can reduce LDL cholesterol by up to 60% 7 Fibric Acid Derivatives (Fibrates) The most effective class of drugs for lowering plasma triglyceride levels and also increase HDL cholesterol but have almost no effect on LDL cholesterol levels Fibrates act by binding to and activating a receptor in the liver cell nucleuses called PPARα (peroxisome- proliferator activated receptor-alpha) causing: Increased synthesis of the enzyme lipoprotein lipase that enhances the clearance of triglyceride rich lipoproteins Decreased apolipoprotein C-III production which is an inhibitor of lipoproteins lipase and therefore increases the lipase’s activity which degrades triglycerides Increased apolipoprotein A-I and apolipoprotein A-II levels which are responsible for the increased HDL levels associated with fibrates Fibrate Adverse Effects – increased risk of gallstones, myopathy (increased risk with statin use), and hepatotoxicity If patients are taking statins as well they should be especially monitored for myopathy and hepatotoxity to a lesser extent Module 13 – Drugs for Hypertension 13.1 What is Hypertension Simply defined as elevated systemic arterial blood pressure Blood pressure is a measurement of the force against the walls of your arteries as the heart pumps blood through the body Blood pressure is measured with a sphygmomanometer In order to accurately measure blood pressure 1. Patient should be seated for at least 5 minutes before 2. No caffeine of nicotine intake within 30 minutes of measurement 3. Feet should be touching the floor not dangling 4. Arm should be elevated to heart level 5. Two measurements in each arm should be taken 5 minutes apart 6. Before a diagnosis of hypertension the patients should have repeated this three times at least two weeks apart Blood Pressure Classified by looking at both the systolic and diastolic pressure Systolic blood pressure is the pressure of flowing blood when the heart contracts and forces the blood out Diastolic blood pressure is then the heart is relaxed and filling up In clinical practice blood pressure is read as the systolic pressure over the diastolic pressure John’ pressure is 120 (mmHg) over 80 (mmHg) (120/80) Classification of Blood Pressure 8 Classifying patients into groups based on their blood pressure Normal: systolic pressure <120 and diastolic pressure <80 Prehypertension: systolic pressure 120-139 or diastolic pressure 80-89 Stage 1 Hypertension: systolic pressure 140-159 or diastolic pressure 90-99 Stage 2 Hypertension: systolic pressure >160 or diastolic pressure >100 Types of Hypertension Primary Hypertension – no known cause with approximately 92% of all cases of hypertension 90% of people over the age of 55 have high blood pressure Secondary hypertension – cause is identifiable Causes include: Kidney disease, Hyperthyroidism, Pregnancy, the drug Erythropoietin, Pheochromocytoma (tumor on the adrenal gland causing excess release of epinephrine), sleep apnea and oral contraception use Causes of Hypertension Many factors influence blood pressure: The amount of water and salt in your body The condition of your kidneys nervous system and blood vessels The levels of certain hormones in your body The following are risk factors from developing hypertension: Obesity, smoking, stress, high salt diet, diabetes, African decent Certain medications are known to cause hypertension including: NSAIDs, oral contraception and cold medications that contain pseudoephedrine Consequences of Hypertension Hypertension is called the silent killer People go many years with no symptoms Chronic hypertension is associated with increased morbidity and mortality If untreated can cause myocardial infarction, kidney failure, stroke or retinal damage Why Lower Blood Pressure Lowering blood pressure saves lives Clinical trials have conclusively demonstrated that decreasing blood pressure decreases patient morbidity and mortality Lowering blood pressure decreases the incidence of stroke, (heart attack) myocardial infarction and heart failure It is estimated that decreasing blood pressure by just 5 mmHg can reduce the risk of stoke and heart attack by 20-35% Determinants of Blood Pressure Blood pressure = cardiac output * peripheral resistance Cardiac output is determined by heart rate contractility of our heart, blood volume and venous return 9 Peripheral resistance is determined by the constriction in our arteries, the greater the constriction of the arteries the greater the pressure 13.2 Blood Pressure Regulation There are three systems that our body has to regulate blood pressure 1. Sympathetic nervous system 2. The renin-angiotensin-aldosterone system (RAAS) 3. The kidney The Sympathetic Nervous System Branch of the autonomic nervous system and helps us respond to stress i.e. the fight or flight response Is also constancy active to help keep the body function in homeostasis including blood pressure Has a reflex circuit called the baroreceptor reflex that helps keep blood pressure at a set level The Baroreceptor Reflex Baroreceptors on the aortic arch and carotid sinus sense blood pressure and relay the information from the heart back to the brain stem If BP is perceived to be too low the brainstem sends impulses along sympathetic neurons that stimulate the heart and smooth muscle of vasculature Increases CO and smooth muscle vasoconstriction = increased BP If BP is perceived to be too high sympathetic activity is decreased Causes decreased cardiac output and vasodilation The activity of baroreceptors can oppose our attempts to lower blood pressure with drugs as the set point in patients with hypertension is higher The baroreceptor reflex responds rapidly within seconds to changes in blood pressure Renin-Angiotensin Aldosterone System (RAAS) Comprised of a series of protein hormones and enzymes Plays a critical role is regulating blood pressure blood volume and electrolyte balance Activation of RAAS effects the kidney and vascular smooth muscle to control blood pressure and is therefore a target of many blood pressure lowering drugs Unlike the baroreceptor reflex, activation of the RAAS may take hours or day to influence the blood pressure Pathway: angiotensinogen cleaved by 10 renin into angiotensin I (INACTIVE)  activated by angiotensin converting enzyme into angiotensin II (ACTIVE) which causes the release of aldosterone and antidiuretic hormone Renin Catalyzes the formation of angiotensin I from angiotensinogen Rate limiting step in angiotensin II formation Renin is synthesized and secreted by the juxtaglomerular cells of the kidney Senses the sodium and blood pressure around the glomerulus The following increase renin release: Decreased blood volume, low blood pressure, stimulation of beta 1 receptors on the juxtaglomerular cells of the kidney Angiotensin Converting Enzyme (ACE) Converts the inactive angiotensin I  active angiotensin II Angiotensin II is a very potent vasoconstrictor by binding to its receptor (AT1 receptor) on vascular smooth muscle Also stimulates release of aldosterone from the adrenal cortex - acts on kidneys to increase sodium and water retention This increases blood volume = increases cardiac output = increases blood pressure Also acts on the posterior pituitary gland to release antidiuretic hormone  water retention by the kidney = volume of blood = CO = BP RAAS Summary 1. Helps our body regulate blood pressure 2. When activated it causes vasoconstriction and retention of sodium and water 3. Vasoconstriction increases peripheral resistance 4. Water and sodium retention increase cardiac output 5. Causes an increase in BP Renal Blood Pressure Regulation The kidney is critical organ in terms of blood pressure regulation If blood pressure decrease for prolonged period of time the kidney responds by retaining water and therefore increasing blood volume = cardiac output = increasing blood pressure 13.3 Non-Drug Treatments for Hypertension Non-pharmacological intervention are the initial recommendations for patients with a diastolic blood pressure of approximately 90-95 mmHg Augment the effectiveness of drug therapy in patients with higher blood pressure Non pharmacological interventions: 1. Decreasing Body Weight There is a direct relationship between obesity and hypertension Obesity is thought to cause hypertension by two mechanisms Obese patients have increased insulin secretion causes tubular reabsorption of sodium causing expansion of extracellular volume (increases CO = increase BP) 11 Obese patients also have increased activity of the sympathetic nervous system causing vasoconstriction and increased blood pressure Weight loss lowers blood pressure in up to 80% of obese patients 2. Restricting Sodium Intake Salt is necessary to our bodies however when sodium intake is too high it has negative effect on blood pressure The kidney regulates the amount of salt in our body eliminating excess salt in the urine When salt levels are too high it causes water to be reabsorbed from the kidney into the blood Causes increased extracellular volumes and increased blood pressure Limiting salt intake to 5 g per day decreases systolic blood pressure by ~12 mmHg and diastolic by ~6 mmHg 3. Physical Exercise Regular exercise decreases blood pressure by an average of 10 mmHg Decreases extracellular fluid volume and circulating levels of plasma catecholamines (activate heart and cause vasoconstriction) The benefits of exercise are seen even if patients don’t restrict sodium or lose weight during the training period 4. Potassium Supplementation Just as total sodium levels are positively correlated with blood pressure, total body potassium levels are inversely correlated Total body potassium results in lower blood pressure High potassium diets decrease blood pressure by increasing sodium excretion, decreasing renin release and causing vasodilation Preferred sources of potassium are fresh fruits and vegetables Patients that are on ACE inhibitors should not be on high potassium diets as they accomplish the same thing Dietary Approaches to Stop Hypertension (DASH Diet) The dash diet was derived from the dietary approaches to stop hypertension studies These studies gave subjects one of three diets and evaluated blood pressure 1. Standard North American Diet – high fat and cholesterol 2. Standard North American Diet plus extra fruit and vegetables 3. A diet rich ins fruits vegetables, low fat diary, lean meats, whole grains, nuts and legumes with exclusion of high saturated fats and cholesterols The results were remarkable with most patients achieving lower blood pressure within 14 days without lowering salt intake The best results were seen in patients with prehypertension Patients with severe hypertension are encouraged to stick to the diet in combination with blood pressure lowering medications Smoking Cessation 12 Smoking acutely elevates blood pressure due to the nicotine content but has never been linked in the development of hypertension Despite this patients with hypertension should be encouraged to quit smoking Both hypertension and smoking are risks for developing cardiovascular disease Alcohol Restriction Excessive alcohol consumption increases blood pressure and can decrease response to some antihypertensive drugs Patients with hypertension of prehypertension should consume less than 2 drinks per day and less than 14 in men and 9 in women per week 13.4 Antihypertensive Medications Drugs that decrease blood pressure do so by decreasing cardiac output of peripheral resistance CO is determined by HR, contractility, blood volume and venous return PR is determined by arteriolar constriction Site of Action of Antihypertensive Medications Vascular smooth muscle – calcium channel blockers and thiazide diuretics RAAS – beta blockers, direct renin inhibitors, ACE inhibitors, angiotensin receptor blockers, aldosterone receptor antagonists Brainstem – centrally acting alpha 2 agonists Heart – beta blockers, calcium channel blockers Kidney – thiazide diuretics, loop diuretics, potassium sparing diuretics Diuretics The mainstay therapy for hypertension – three main classes of diuretics: loop, thiazide and potassium diuretics Work by blocking sodium and chloride ion reabsorption from the nephron of the kidney and therefore out of the urine By preventing reabsorption of the ions diuretics make an osmotic pressure within the tubule that prevents the reabsorption of water The retention of water within the nephrons promotes excretion of water and sodium and chloride ions Lowers the blood volume and therefore lowers the cardiac output = decrease blood pressure Diuretics – Sites of Action Loop diuretics – act on the thick ascending limb of the loop of Henle 20% of sodium is reabsorbed at this point which is a lot and therefore are very effective Thiazide diuretics – act in the distal tubule 10% of sodium is reabsorbed at this point making these drugs less effective than loop diuretics Potassium diuretics – act in the late distal tubule and mainly in the collecting duct of the nephron 13 Only 1-5% of sodium is usually reabsorbed here, therefore these are the least drastic and effective drugs Loop Diuretics The most effective diuretics available Act by blocking sodium and chloride reabsorption in thick ascending limb of loop of henle Usually reserved for situations that require rapid loss of fluid such as edema, severe hypertension that does not respond to milder diuretics, and in severe renal failure Adverse effects include: hypokalemia – may cause fatal cardiac dysrhythmia, hyponatremia – low blood odium levels dehydration and hypotension Thiazide Diuretics The most commonly used class of drug to treat hypertension Two mechanisms: Block sodium and chloride ion reabsorption in the distal tubule by blocking active transporters Decrease the vascular resistance (mechanism unknown) The maximum amount of diuresis is much less than loop diuretics For many hypertensive patients thiazide diuretics alone are enough Adverse effects include: hypokalemia, dehydration, and hyponatremia Potassium Sparing Diuretics/Aldosterone Inhibitors Produce minimal lowering of blood pressure, almost never used alone Act by inhibiting aldosterone receptors in the collecting duct Blocking aldosterone receptors causes increased sodium excretion and potassium retention in the body The main use is in combination with thiazide and loop diuretics to counteract the hypokalemia side effects Should no be used with ACE inhibitors or ARBs (angiotensin receptor blockers) as these drugs also conserve potassium The primary adverse event associated with potassium sparing diuretics is hyperkalemia which may result in fatal dysrhythmias Beta Blockers Blocking cardiac beta 1 receptors – binding of catecholamines (epinephrine, norepinephrine) to cardiac beta receptors causes increased cardiac output Blocking beta receptors decreases cardiac output and therefore decreased blood pressure Blocking beta 1 receptors on juxtaglomerular cells – cells release renin which activates the RAAS pathway causing vasoconstriction Beta blockers decrease renin release therefore decreasing RAAS mediated vasoconstriction Therefore its effects reduce both peripheral resistance and BP Beta blocker drugs all have the suffix ‘olol’ – example propranolol Classes of Beta Blocker Drugs Beta blockers can be classified as either first or second generation depending on their selectivity st 1 generation beta blockers – produce non-selective blockade of beta receptors Inhibit both beta 1 receptors (juxtaglomerular and heart cells) and beta 2 receptors (in the lungs) 2 generation beta blockers – produce selective blockade of only beta 1 receptors 14 Beta Blocker – Adverse Effects Selective beta 1 receptor blockers have the following adverse effects: Bradycardia (slow heart rate) decreased cardiac output, heart failure (rare), rebound hypertension if drug dosage is withdrawn too quickly – dosage should be decreased slowly Non-selective beta blockers have the same adverse effects as selective beta blockers but include: Bronchoconstriction due to the blockade of beta 2 receptors in the lung, inhibition of hepatic and muscle glycogenolysis (dangerous when too much insulin is taken in diabetic patients) Angiotensin Converting Enzyme Inhibitors (ACEI) Decreases blood pressure by two mechanisms 1. Decreasing the production of angiotensin II – a potent vasoconstrictor so decreasing it causes vasodilation Decreasing angiotensin II also decreases total blood volume therefore ACEI reduce cardiac output and peripheral resistance 2. Inhibiting the breakdown of bradykinin – elevated levels of bradykinin cause vasodilation ACEI drugs have the suffix ‘pril’ ACEI lowers total cardiac output and peripheral resistance to lower blood pressure Angiotensin Converting Enzyme Inhibitors – Adverse Effects Generally well tolerated however therefore are some adverse effects Can be linked to the reduction of angiotensin II or elevated bradykinin Side effects from decreased angiotensin II synthesis First dose hypotension – therefore first doses should be low Hyperkalemia – decreased angiotensin II = decreased aldosterone release which leads to potassium retention Potassium supplements and use of potassium sparing diuretics should be avoided Side effects from increased bradykinin Persistent cough in 5-10% of patients Angioedema rare but potentially fatal Use with certain NSAIDs may decrease the effect of ACE inhibitors Angiotensin Receptor Blockers (ARBs) Similar actin to ACE inhibitors in that the decrease the action of angiotensin II although the mechanism differs Act by blocking the bindings of angiotensin II to its receptors (AT1 receptors) ARBs block the actions of angiotensin II but DO NOT effect its synthesis 15 ARBs cause vasodilation by blocking the action of angiotensin II on arterioles and also decrease aldosterone release from the adrenal cortex causing increased sodium and water excretion All have the suffix ‘sartan’ Angiotensin Receptor Blockers – Adverse Effects ARBs don’t inhibit bradykinin breakdown as well as ACE inhibitors so they don’t produce persistent cough ARBs also do not cause hyperkalemia and the incidence of angioedema is much lower than ACE inhibitors Direct Renin Inhibitors (DRIs) Bind to renin and block the conversion of angiotensinogen to angiotensin I Since the conversion angiotensinogen to angiotensin I is that rate limiting step in the RAAS pathway DRIs can influence the entire pathway Despite DRIs decreasing plasma renin activity by 50-80% its blood pressure lowering effect is the same as other classes of drugs Direct Renin Inhibitors – Adverse Effects Hyperkalemia – should not be used in combination with other drugs that may cause hyperkalemia (i.e. potassium sparing diuretics, ACEI) and potassium supplements Very low incidence of persistent cough and angioedema (much lower than ACEI) Diarrhea Calcium Channel Blockers Calcium channels bring calcium from outside the cell to inside the cell In the heart and smooth muscle that surrounds arteries, calcium is essential for contraction Therefore the activity of calcium channels plays an important role for contraction of the heart and vasoconstriction of arterioles Calcium channel blockers block the entry of calcium into heart and smooth muscle cells therefore decreasing contraction rate and intensity Calcium channel blockers are classified into two categories: 1. dihydropyridine calcium channel blockers 2. non-dyhrydropyridine calcium channel blockers Dihydropyridine Calcium Channel Blockers Significantly decrease calcium influx into arteriolar smooth muscle Result in relaxation of muscle around the arteries and causes vasodilation At therapeutic doses these drugs do not act on the heart muscles, effect is exclusively on surrounding smooth muscle All drugs of this type end with the suffix ‘dipine’ Adverse Effects Flushing, dizziness, headache, peripheral edema, reflex tachycardia and rashes 16 Non-dihydropyridine Calcium Channel Blockers Block calcium channels both in the smooth muscle of the arteries and in the heart Therefore in addition to producing vasodilation of arteries and decrease cardiac output Adverse Effects Constipation dizziness, flushing, headache, edema, may compromise cardiac function and should be used with caution in patients with cardiac failure Centrally Acting Alpha 2 Receptor Agonists These drugs bind to and activate alpha 2 receptors in the brainstem Activation of these receptors decreases sympathetic outflow to the heart and the vascular smooth muscle Sympathetic activity normally causes increased cardiac output and vasoconstriction By inhibiting the sympathetic outflow centrally acting alpha 2 receptor agonists decrease cardiac output and peripheral resistance to lower BP Adverse Effects Drowsiness, dry mouth and rebound hypertension if drug withdrawn too quickly 13.5 Treatment Algorithms Deciding how to treat patients with hypertension can be difficult The target blood pressure that most patients should achieve is <140/90 mmHg Patients with diabetes or chronic kidney disease should achieve a blood pressure less than 130/80 Keeping blood pressure under this level in patients with kidney disease will help slow the progression of damage In patients with severe renal disease thiazide diuretics are ineffective so more potent loop diuretics should be used Treatment algorithms for patients with just hypertension and for patients with hypertension plus diabetes or renal disease help guide drug type and dosing – Refer to them Treatment Algorithm – Hypertension only If lifestyle modifications aren’t enough, so thiazide diuretics are added, and if necessary another class of drug added 1. Note: other classes may substituted if patients don’t respond 17 Treatment Algorithm – Diabetes and Renal Disease These patients are at high risk for developing heart disease so controlling blood pressure can be more difficult. 2. Note: other classes may substituted if patients don’t respond Module 14 - Central Nervous System Pharmacology 14.1 Introduction to Neuropharmacology Neuropharmacology is the study of how drugs affect the function of the central nervous system There are many disorders of the central nervous system and most of them have a component that is mediated by biochemical imbalance In neuropharmacology we attempt to treat this biochemical imbalance, usually referring to neurotransmitters, with drugs Unfortunately the drugs treat the symptoms of disease but not the cause The Brain The brain is composed of literally millions of neurons Neurons are cells in the brain that act to process and transmit signals and information Neurons are excitable cells that transmit information by electrical and chemical signaling The start of information transfer begins at the dendrite which receives a signal from another neuron This causes action potentials to propagate along the axon of the neuron When the AP reaches the pre-synaptic nerve terminal it causes the release of neurotransmitters which pass the signal along to the next neuron Action Potential Action potentials play a key role in cell to cell communication in neurons The resting membrane potential of cells is approximately - 70mV, the inside of the cell is relatively more negative to the outside During depolarization of the cell + sodium ions enter the cell through voltage gated sodium channels 18 The sodium channels then close and potassium channels open allowing potassium to leave the cell during repolarization The current overshoots resting membrane potential and then returns to baseline (-70mV) Synapse Once an action potential reaches the presynaptic nerve terminal it causes influx of calcium Causes vesicles containing neurotransmitters to fuse with the membrane The vesicles release neurotransmitters into the synaptic cleft which then diffuse across the space Neurotransmitters then bind to receptors on the post synaptic membrane to cause an influx of sodium and the relay of the signal continues Neurotransmitters in the CNS Neurotransmitters are chemicals that transmit a signal across a synapse Neurotransmitters can be broken down into classes: Monoamines – norepinephrine (depression and anxiety), epinephrine (anxiety), dopamine (Parkinson’s disease and Schizophrenia), Serotonin (depression and anxiety) Amino Acids – excitatory (glutamate and aspartate in Alzheimer’s disease) Other – acetylcholine (Parkinson’s and Alzheimer’s) Basic Mechanism of CNS Drug Action Drugs can act to treat CND disorders in several ways: Replacement – drugs act to replace neurotransmitters that are low in disease states Agonists/Antagonists – directly binds to receptors on the post-synaptic membrane Inhibiting neurotransmitter breakdown – NT metabolism is inhibited Blocking reuptake – NT reuptake into the pre-synaptic membrane for re-use is blocked Nerve stimulation – the drug directly stimulates the nerve causing it to release more NT 14.2 Parkinson’s Disease Was first described in 1817 by James Parkinson Parkinson’s disease is caused by a progressive loss of dopaminergic neurons in the substantia nigra of the brain Although progressive loss of dopaminergic neurons is normal through aging patients with Parkinson’s lose 70-80% of these neurons Without treatment, Parkinson's progresses in 5-10 years to a state where patients are unable to care for themselves Parkinson’s Disease – Symptoms Parkinson's is a chronic movement disorder with distinct symptoms: 1. Tremor – mostly in the extremities including hands arms legs jaw and face 2. Rigidity – due to joint stiffness and increased muscle tone 3. Bradykinesia – slowness of movement especially slow to initiate movements 19 1. Hallmark in Parkinson’s 4. Masklike face – patients cant show facial expression and have difficulty blinking and swallowing 5. Dementia – often develops later in the disease’s onset Parkinson’s Disease – Pathophysiology Parkinson's is a chronic movement disorder that is caused by an imbalance between acetylcholine and dopamine in the brain In healthy patients there is a normal balance of acetylcholine and dopamine which results in normal GABA release The symptoms of Parkinson's arise because of the following Dopamine release is DECREASED as dopaminergic neurons deteriorate therefore there is not enough dopamine present to inhibit GABA release So there’s a relative excess of acetylcholine compared to dopamine which result in INCREASED GABA release Excess GABA release cause the movement disorders observed in Parkinson's Parkinson’s Disease – Etiology The etiology is largely idiopathic (unknown) but there are some factors thought to be associated with development of the disorder: 1. Drugs – a by-products of illicit street drug synthesis produce the compound MPTP which causes the irreversible death of dopaminergic neurons 2. Genetics – mutation in 4 genes (alpha synuclein, parkin, UCHL1 and DJ-1) is known to predispose patients to Parkinson's 3. Environmental Toxins – certain pesticides have been associated with Parkinson's 4. Brain Trauma – direct brain trauma from injury (boxing, accidents) is linked with increased risk of developing Parkinson's (Eg. Muhammad Ali) 5. Oxidative Stress – reactive oxygen species (ROS) are known to cause degeneration of dopaminergic neurons 1. There is a link between diabetes which produce ROS and Parkinson's 14.3 Parkinson’s Disease – Drug Treatment The ideal treatment of Parkinson's would be to reverse the degeneration of dopaminergic neurons which does not exist Therefore we treat the symptoms of Parkinson's by trying to improve the balance between dopamine and acetylcholine Drug treatment of Parkinson's improves the dopamine and acetylcholine balance by either increasing dopamine concentrations or decreasing acetylcholine Parkinson’s Disease – Agents that Increase Dopamine Neurotransmission There are five different major classes of drug that act by increasing dopamine neurotransmission 1. Dopamine replacement 2. Dopamine agonist 3. Dopamine releaser 20 4. Catecholamine-O-methyltransferase inhibitor 5. Monoamine oxidase-B inhibitor Dopamine Replacement – Levodopa Levodopa is the most effective drug for treating Parkinson's The beneficial effect of levodopa decrease over time as the disease progresses Levodopa crosses the blood brain barrier by an active transport protein Levodopa is inactive but is converted to dopamine in dopaminergic nerve terminals Conversion is mediated by decarboxylase enzymes in the brain The cofactor pyridoxine (vitamin B6) speeds up this reaction Once converted into dopamine the molecules enter vesicles in the pre-synapse and act in synaptic transmission as dopamine usually would Do not administer pure dopamine to patients because it doesn’t cross the blood brain barrier and it has a short half life in blood Figure: L-Dopa (black circles), restricted entry by blood brain barrier. Transported into the brain by transport proteins. Then decarboxylase enzymes convert it to dopamine and then package it into vesicles. Increasing dopamine in neurons. L-DOPA – Adverse Effects Nausea and vomiting – due to dopamine mediated activation of the chemoreceptor trigger zone in the medulla Dyskinesis – abnormal involuntary movements Cardiac dysrhythmia – conversion of L-dopa to dopamine in the periphery can result in activation of cardiac beta-1 receptors Orthostatic hypotension – rapid drop in blood pressure when a patient stands up Psychosis – 20% of patients will develop hallucinations, vivid dreams/nightmares, and paranoid thoughts Peripheral L-DOPA Metabolism Only approximately 1% of L-DOPA doses reaches the brain The remaining is metabolized in the peripheral tissue (mostly intestine) before reaching the brain For this reason it’s almost always given with carbidopa, a decarboxylase inhibitor that inhibits the peripheral metabolism so more L-DOPA can reach the brain When combines approximately 10% of doses reach the brain Carbidopa allows lower doses to be administered and decreases the incidence of cardiac dysrhythmias and nausea and vomiting L-DOPA – Loss of Effect Patients taking L-DOPA may experience two types of loss of effect: 21 1. Wearing Off – usually occurs at the end of dosing interval, indicates drug levels might be low Can be minimized by: Shortening the dosing interval Giving a drug that inhibits levodopa metabolism (ie. COMT inhibitor) Adding a dopamine agonist to the therapy 2. On-Off – can occur even when drug levels are high Can be minimized by: Dividing the medication into 3-6 doses per day Using a controlled release formulation Move protein containing meals to the evening Dopamine Agonists Produce their effect by directly activating dopamine receptors on the post-synaptic cell membrane Not as effective as L-DOPA but are often used as a first line treatment for patients with milder to potentially moderate symptoms Adverse effects include hallucinations, daytime drowsiness, orthostatic hypotension (when they stand up abruptly) Figure: Purple dots in blood are dopamine agonists. In contrast to L-DOPA these cross the blood brain barrier and bind to dopamine receptors on post- synaptic membrane Dopamine Releasers Acts to stimulate release of dopamine from dopaminergic neurons and also block dopamine reuptake into presynaptic nerve terminal, it also blocks NMDA receptors Response develops rapidly usually within 2-3 days Not as effective as L-DOPA so usually used in combination with it or alone in milder symptom patients Blockade of NMDA receptors is thought to decrease dyskinesia side effect of L-DOPA Often if patients are having dyskinesia with L-DOPA, dopamine releaser drugs can be added to regimen Adverse effects include dizziness, nausea, vomiting, lethargy and anticholinergic side effects Figure: Block dopamine reuptake transporter. Doesn’t allow the dopamine to come back into the presynaptic neuron, so it can stay in the synaptic cleft and act longer Catechol-O-Methyltransferase Inhibitors COMT is an enzyme that adds a methyl group to both dopamine and L-DOPA Methylated dopamine and L-DOPA are inactive and do not activate dopamine receptors Inhibiting COMT results in a greater fraction of L-DOPA available to be converted into dopamine 22 COMT inhibitors are only moderately effective in treating symptoms of Parkinson's and are often combined with L-DOPA Adverse effects are similar to those experienced with L-DOPA including nausea orthostatic hypotension, vivid dreams and hallucinations Monoamine Oxidase-B Inhibitors MAO-B is an enzyme that oxidatively metabolizes dopamine and L-DOPA therefore inactivating them MAO-B is present in both the periphery and in the brain Inhibiting oxidative metabolism of L-DOPA allows more conversion to dopamine in the brain Similarly, inhibition of dopamine metabolism allows more dopamine to remain in nerve terminals and be released following an action potential MAO-B inhibitors are only moderately effective in treating symptoms of Parkinson's and are often combined with L-DOPA Adverse effects include: insomnia, orthostatic hypotension and dizziness At therapeutic doses MAO-B inhibitors used to treat Parkinson's do not inhibit MAO-A in the liver and therefore do not cause hypertensive crisis when patients eat tyramine containing foods What About Acetylcholine We must remember that the symptoms of Parkinson's are due to the relative imbalance of dopamine, being too little and the relatively high levels of acetylcholine The relative excess of acetylcholine in Parkinson's in part causes diaphoresis (excess sweating) salivation and urinary incontinence Anticholinergic Drugs Anticholinergic drugs block the binding of acetylcholine to its receptor and are also called cholinergic antagonists Anticholinergic drugs may increase the effectiveness of L-DOPA  causing decrease in the incidence of diaphoresis salivation and incontinence Figure: anticholinergic drug binds to cholinergic receptors, and any acetylcholine released by vesicles can’t bind and cause their effects. Anticholinergic Drugs – Adverse Effects Dry mouth, blurred vision, urinary retention, constipation and tachycardia Elderly patients may experience severe central nervous system side effects such as hallucinations, confusion and delirium and therefore these drugs are usually reserved for younger patients 14.4 Alzheimer’s Disease An irreversible form of progressive dementia and is the most common form of dementia Over 500,000 Canadians have Alzheimer’s 23 Approximately 1 in 11 people over the age of 65 have Alzheimer's Women account for almost 75% of all current cases of Alzheimer's Alzheimer's costs Canadians over 15 billion dollars per year in health care Symptoms of Alzheimer's disease include: memory loss, problems with language judgment behavior and intelligence Early symptoms of the disease include: confusion, memory loss and problems conducting routine tasks As the disease progresses, patients have difficulty completing dialing living activities including: eating, bathing, speaking and controlling bowel and bladder function The disease affects the frontal cortex important in controlling intelligence judgment and behavior, the hippocampus important for memory function and language Alzheimer’s Disease – Pathophysiology Characterized by a degeneration of cholinergic neurons in the hippocampus early in the disease followed by the degeneration of neurons in the cerebral cortex Linked to decreased cholinergic nerve function Patients with advanced Alzheimer's have only 10% of the cholinergic function of healthy subjects Structural changes in the brain include enlarged ventricles and decreased brain size Alzheimer’s Disease – Diagnosis A definitive diagnosis of Alzheimer's cannot be given until after death when a brain sample is analyzed The hallmarks of Alzheimer's are neurofibrillary tangles and neuritic plaques Neurofibrillary tangles – form inside neurons when microtubule arrangement is disrupted caused by abnormal production of tau protein responsible for cross-bridging between microtubules to help keep their structure Neuritic Plaques – found outside of neurons and are composed of a core of a protein fragment called beta amyloid which ahs been shown to kill hippocampal cells and cause Alzheimer’s like symptoms when injected into monkeys Alzheimer’s Disease – Etiology The cause of Alzheimer’s disease is still unknown Approximately 20% of cases are thought to run in families and therefore genetically determined There is some evidence that mutations in DNA can cause the development of the disease Ex. Patients with two copies of apolipoprotein E4 (ApoE4) are at increased risk for developing Alzheimer's Appears that ApoE4 promotes formation of neuritic plaques by binding to beta amyloid therefore promoting disposition There is also an increase incidence of Alzheimer's disease in patients with mutations in amyloid precursor protein gene which is involved in the production of beta amyloid, major component of neuritic plaques 24 Head injury is also a risk factor for developing Alzheimer's 14.5 Drug Treatment of Alzheimer’s Disease Drug treatment of Alzheimer's disease shows only minimal improvement in symptoms There are currently only two classes of drugs used to treat Alzheimer's 1. Cholinesterase inhibitors – inhibit the breakdown of acetylcholine 2. NMDA receptor antagonists – block NMDA mediated increases in intracellular calcium Cholinesterase Inhibitors These drugs inhibit the metabolism of acetylcholine by the enzyme acetylcholinesterase This allows more acetylcholine to remain in the synaptic cleft to exert its action Cholinesterase inhibitors are only able to enhance cholinergic neurotransmission in the remaining healthy neurons Cholinesterase inhibitors display minimal benefit on some measures of memory Only effective in approximately 25% of patients Cholinesterase Inhibitors – Adverse Effects Nausea and vomiting, diarrhea and insomnia The NMDA Receptor The NMDA receptor is a calcium channel that is blocked by magnesium at rest When glutamate binds to the NMDA receptor the magnesium dissociates allowing calcium to enter the post synaptic neuron When the glutamate dissociates, magnesium returns to block the entry of calcium Normal calcium influx is thought to be important in the process of learning and memory In Alzheimer's disease there is excess glutamate release so the NMDA receptor remains open allowing excess calcium to enter the cell Excess calcium in the cell is detrimental in two ways To learning and memory as it overpowers the normal calcium signal It causes degradation of the neurons as too much calcium is toxic NMDA Antagonists The NMDA antagonist is able to fill the pore of the calcium channel in the post synaptic cell and therefore block excess calcium from entering the cell This therefore prevents the degradation of the cholinergic neurons NMDA Antagonists – Adverse Effects NMDA antagonist drugs are well tolerated by the body Side effect observed in clinical trials had the same incidence as patients taking placebos and therefore non- existent 25 14.6 Schizophrenia Schizophrenia makes it hard to tell the difference between real and unreal experiences, to think logically, to have normal emotional responses and to behave normally in social situations Contrary to popular belief patients with schizophrenia usually DO NOT have duel or multiple personalities and are usually not violent Schizophrenia affects approximately 1% of the world’s population and usually begins in adolescence or early adulthood (16-30 years) Schizophrenia – Symptoms Symptoms of schizophrenia can be divided into positive and negative symptoms Positive – exaggerate or distort normal neurological function Negative – when a loss of normal neurological function Schizophrenia – Etiology The causes of schizophrenia is largely unknown yet risk factors are known 1. Family history – 10% of schizophrenics have parents with the disease and if both parents have the disease then there is a 25% chance that the offspring will also have it 2. Drug abuse – methamphetamine, phencyclidine (PCP –angel dust), and lysergic acid diethyamide (LSD) use are all known to cause schizophrenia 3. Low birth weight – babies born at less that 5.5 pounds have an increased risk of developing schizophrenia 4. Low IQ – the lower the person’s IQ the greater the risk they have of developing schizophrenia Brain Regions Affected by Schizophrenia Basal ganglia – involved in movements and emotion and in schizophrenic patients the abnormal activity is thought to play a role in paranoia and hallucinations Frontal lobe – involved in problem solving and insight and in schizophrenic patients the abnormal activity plays a role in difficulty planning actions and organizing thought Limbic system- involved with emotions and in schizophrenic patients the abnormal activity contributes to agitation Hippocampus – mediates learning and memory which are decreased in schizophrenia Occipital lobe – processes visual information and in schizophrenia its abnormal activity is involved in interpreting images, reading emotion on others faces and recognizing motion Auditory system – the over activity contributes to hallucinations Schizophrenia – Pathophysiology Usually schizophrenia is thought of as a disorder with increased dopaminergic nerve transmission 26 Drugs that block dopaminergic nerve function decrease some positive symptoms of schizophrenia Schizophrenia and Parkinson’s are often though of as on the opposite ends of the dopamine continuum because in schizophrenia there is excess dopamine and in Parkinson's there is too little Drugs that are used to treat Parkinson's disease may cause schizophrenia like side effects Although the dopamine hypothesis is helpful it is too simple as serotonin and glutamate as neurotransmitters also play a role Serotonin (5-HT) – patients with schizophrenia have decreased number of 5-HT and an increased number 1A of 5-HT receptors in the frontal cortex These changes are thought to play a role in the symptoms patients experience Glutamate – binds to and activates the NMDA receptor, PCP is a strong antagonist of the NMDA receptor and causes many of the symptoms of schizophrenia Patients with schizophrenia have a decreased number of NMDA receptors in some regions of the brain Schizophrenia – Diagnosis There is no definitive test of schizophrenia and is usually made by a psychiatrist after interviewing the patient and family The psychiatrist may evaluate several of the following before diagnosing schizophrenia Changes in function from before illness, developmental background, family history, response to medication, brain scans (some changes are typical in schizophrenics – enlarged ventricles and decreased frontal lobe activity) 14.7 Drug Treatment of Schizophrenia The basis for treating the symptoms of schizophrenia is blocking dopamine 27 serotonin and or glutamate neurotransmission in the brain Drugs used in treatment can be classified as conventional or atypical antipsychotics These classes differ in their mechanism of action and side effects Although it was once thought that the atypical antipsychotics would take over the market both conventional and atypical antipsychotics are in use today Conventional Antipsychotics Act primarily by blocking dopamine 2 receptors (D2) in the mesolimbic area of the brain Therefore the excess amount of dopamine in the synaptic cleft does not have its diseased effect and only a normal amount of response from the dopamine is experienced To a lesser degree they also clock receptors for acetylcholine histamine and norepinephrine The potency of conventional antipsychotics is directly proportional to their ability to inhibit D2 receptors These drugs are more effective at treating the positive symptoms of schizophrenia than the negative symptoms Initial effect of drugs may be seen in as few as 1 or 2 days but substantial improvement in symptoms usually takes between 2 and 4 weeks Conventional Antipsychotics – Adverse Effects Extrapyramidal symptoms, sudden high fever, anticholinergic effects, orthostatic hypotension, sedation, skin reactions Extrapyramidal Symptoms Extrapyramidal symptoms – movement disorders that resemble the symptoms of Parkinson's disease due to the blockade of D2 receptors Four types of symptoms occur: 1. Acute dystonia – involuntary spasm of the muscles in the face tongue neck and back and typically occurs early in therapy, occurs early in therapy 2. Parkinsonism – bradykinesia, mask-like face, rigidity and stooped posture and may treat with an anticholinergic drug to help relieve these symptoms (L-DOPA must be avoided). Occurs early in treatment 3. Akathesia – pacing squirming and a desire to continually be moving and typically occurs early in treatment, occurs early in treatment 4. Tardive Dyskinesia – occurs in about 20% of patients on long-term therapy and is irreversible with symptoms including involuntary twisting and writhing face and tongue along with lip-smacking. Patients should be switched to an atypical antipsychotic. Atypical Antipsychotics Atypical antipsychotics block both dopamine D2 receptors and 5-HT1A and 5-HT2A receptors 28 Despite having some activity to block D2 receptors the affinity is very low and therapeutic action is attributed to blockade of 5-HT (serotonin) receptors Compared to conventional, antipsychotics atypical ones have: The same efficacy versus positive symptoms Much greater efficacy versus negative symptoms Much lower risk of developing extrapyramidal symptoms especially tardive dyskinesia due to the decreased D2 receptor affinity Atypical Antipsychotics – Adverse Effects Sedation, orthostatic hypotension, weight gain (sometime severe- 75lbs), risk of developing type II diabetes and anticholinergic effects. Note: no extrapyramidal symptoms Module 14 – CNS Drugs Part II 14.8 Epilepsy Is a neurological disorder that produces brief disruptions in the normal electrical activity of the brain Epilepsy is characterized by sudden brief seizures, the nature and intensity of which vary from person to person Definitions Seizure – a sudden alteration of behavior that is caused by CNS dysfunction and are sudden and transient Epileptic Seizure – a seizure which is cause by primary CNS dysfunction due to excess depolarization and hypersynchronization of neurons Non-Epileptic Seizure – a seizure like episode but not the result of electrical activity in the brain Epilepsy – a tendency for recurrent and spontaneous epileptic seizures Status Epilepticus – a single unremitting epileptic seizure of duration longer than 30 minutes OR frequent without recovery of awareness in between. Medical emergency Types of Seizures Epileptic seizures can be classified into three main types – focal/partial seizures, generalized seizures and secondary generalized seizures 29 Focal/Partial Seizures These seizures arise in one localized area of the brain The terms partial and focal are interchangeable There are two types of partial seizures – simple and complex partial seizures 1. Simple Partial Seizures Involve no loss of consciousness and symptoms depend on where the seizure activity is in the brain Example case – 45 year old male started with chlonic movements of his right arm with progression to the right side of the face then right leg There was no impairment of consciousness and it lasted about 45 seconds As the seizure showed movement signs on the right side of the body the left side of the brain was affected due to the contralateral nature Figure: Shows the focal point of the seizure on the left side of the brain 2. Complex Partial Seizures A complex partial seizure involves a loss of consciousness Patients may appear to be awake (eg. Eyes open) but are not aware of surroundings Symptoms depend on where the seizure activity is taking place in the brain Example case – 37 year old male with right temporal lobe epilepsy Seizure focus in the right side of the brain but visible symptoms are on the left Whistling bicycling movements in the left leg, rising epigastric sensation with nausea, normal ictal (during the seizure) speech with no memory of the events after the seizure Lasted about 30-45 seconds Generalized Seizures These seizures have a bilateral diffuse onset seeming to arise from all areas of the brain at once 30 There are five different types of generalized seizures: 1. Absence 2. Tonic/clonic 3. Myoclonic 4. Tonic 5. Atonic seizures 1. Absence Seizure Once referred to as petit-mal seizures Involves loss of consciousness behavioral arrest and appear to be staring Are usually brief but may occur in clusters and can recur multiple times in a day Rarely associated with automatism (unusual purposeless movement) and usually very minor if there are any More common in childhood patients, can be misdiagnosed as children staring into space The events are measureable with an EEG represented by increased discharges and increased electrical activity during the seizure Figure: EEG of absent seizure 2. Tonic/Clonic Seizure The type of seizure most commonly associated with epilepsy Involve an abrupt loss of consciousness a tonic period when muscles become rigid lasting about a minute then a clonic period when muscles involuntarily contract lasting an additional 2-3 minutes Patients may become incontinent and have tongue biting In the post-ictal phase patients may be drowsy, confused and frequently complain of headaches Used to be called grand-mal seizures Myoclonic Tonic and Atonic Seizures 3. Myoclonic Seizures – involve sudden brief muscle contractions that can involve any muscle group Usually there is no loss of consciousness Sometimes associated with a later development of generalized tonic/clonic seizures 4. Tonic Seizures – often involves sudden muscle rigidity and impaired consciousness 5. Atonic Seizures – involve sudden loss of muscle tone and known as drop seizures as patients typically drop to the ground Potential for falling injuries Usually are brief lasting about 15 seconds Secondary Generalized Seizures A seizure that begins in one area of the brain like a focal seizure and then spread throughout the brain The preliminary focal phase is sometimes referred to as an “aura” Sometimes patients experience this aura and can predict that they’re going to have a seizure Localized Focal Seizures The location of a focal seizure can be determined by evaluating the patient’s symptoms and what we known about the various regions of the brain 31 Frontal Lobe Simple repetitive motor movements involving a localized muscle group are associated with seizure activity in the contralateral primary motor cortex Tonic posturing affecting the entire side of the body are associated with seizure activity in the contralateral Supplemental Motor Area and other higher level motor structures Very complex behavioral automatisms that involve odd bilateral movement such as swimming or bicycling movements are associated with seizure activity in the higher areas of the frontal cortex These behaviors often involve vocalizations laughter and or crying Temporal Lobe Experience emotions such as anger, fear, euphoria and psychic symptoms such as déjà vu, jamais vu or amnesia are associated with seizure activity in the temporal lobe Auditory hallucinations of buzzing or voices talking and olfactory and gustatory hallucinations are associated with the temporal lobe More complex sensory phenomena involving visual distortions, numbness and autonomic disturbances can also be associated with temporal lobe seizures Parietal Lobe Localized parasthesias such as numbness and “pins and needles” are associated with seizure activity in the contralateral somatosensory cortex More complex and wide spread parasthesias are associated with seizure activity in the somatosensory associated cortex Seizure activity in the higher order sensory association areas in the parietal lobe can be associated with complex multi-sensory hallucinations and illusions Can be hard to distinguish from temporal lobe seizures which is more common Occipital Lobe Visual hallucinations such as flashing or repeated pattern in the environment are associated with seizure activity in the occipital lobe The hallucinations are less likely to be of organized objects such as people or objects and more likely of things in the background Seizure activity in the occipital lobe can also produce temporary blindness or decreased vision as well as sensation of eye movement Patients may have reflex nystagmus (involuntary eye movement) Simple partial seizures in the occipital lobe can be mistaken for migraine headaches as many of the symptoms are similar to common migraine auras Epileptogenesis – the main causes Three main classifications of etiology of epilepsy: Symptomatic Epilepsy – arising form an identified physical cause such as a brain tumor, stroke infection or other injury Idiopathic Epilepsy – does not have an identifiable cause there is often a family history of seizures and genetics likely play a role 32 Cryptogenic Epilepsy – likely have an underlying cause that has not been identified The Seizure Threshold Seizures are caused by spontaneous uncontrollable discharges from hyperexcitable areas of the brain The seizure threshold can be though of as the balance between excitable and inhibitory forces in the brain Everybody has a seizure threshold and is affected by how susceptible the patient is to having a seizure Seizures a mediated by changes in electrical activity so the ability to reach the threshold and fire an action potential is important in the generation of a seizure Some factors that may affect the seizure threshold are stoke, head injury, drug/alcohol withdrawal, infection, tumor, severe fever, visual stimuli (flashing lights) 14.9 Antiepileptic Drugs (AED’s) Work by four distinct mechanisms of action 1. Blocking sodium channels 2. Blocking voltage dependent calcium channels 3. Glutamate antagonists 4. Potentiating the actions of GABA Can be classified as either being traditional (phenytoin, valproic acid) or newer AEDs (lamotrigine) The effectiveness of traditional vs newer appears to be similar Newer drugs tend to have decreased side effects and a decreased propensity to induce hepatic drug metabolizing enzymes Sodium Channel Blockers Sodium influx into the cell is a critical step in generation of an action potential Excess firing of AP’s is one of the causes of an epileptic seizure After sodium enters the cell the sodium channel enters an inactive state during which further sodium entry into the cell is prevented In normal causes the sodium channel very quickly returns to the active state to allow more sodium to enter the cell and generation of another action potential Sodium channel blocker antiepileptic drugs act to prolong the inactivation state of the sodium channel and therefore do not allow neurons to fire at a high frequency Phenytoin The most widely used antiepileptic drug and acts by blocking sodium channels Phenytoin is useful in treatment of all types of epileptic seizures EXCEPT absence seizures The metabolic capacity of the liver to metabolize phenytoin displays non-linear kinetics There is a small increase in dose may produce a large increase in plasma concentration Phenytoin has a narrow therapeutic range and often undergoes therapeutic drug monitoring Adverse effects – sedation, gingival hyperplasia, skin rash Phenytoin it is teratogenic Figure: for most drugs if we increase the drug linearly we get a predictable increase in steady state plasma concentration of the drug. However 33 phenytoin is non linear, so a small increase in the dose can produce a large change in the action or toxicity of the drug Voltage Dependent Calcium Channel Blockers Influx of calcium through voltage gated calcium channels promote neurotransmitter release from the presynaptic terminal Inhibition of calcium channels suppresses neurotransmitter release and therefore suppresses action potential transfer AP opens voltage dependent calcium channels causing release of neurotransmitter and activation of next neuron. Calcium blockers don’t allow calcium to go into nerve terminal so it can’t activate release neurotransmitter on the next neuron Glutamate Antagonists Glutamate is an excitatory CNS neurotransmitter Blocking its action decreases CNS excitation so it’s a treatment target for antiepileptic drugs Glutamate mediates its effect by binding to either the NMDA receptor or AMPA receptor Glutamate antagonists used to treat epilepsy block both the NMDA and AMPA receptors and therefore prevent excitation in the CNS The GABA Receptor GABA is an inhibitory CNS neurotransmitter Binding of GABA to its receptor cause negatively charged Chloride ions to rush into the cell This makes the inside of the cell more negative and therefore further away from the action potential threshold = more difficult to have an AP Potentiating the Action of GABA Drugs that potentiate the actions of GABA increase inhibitory stimuli in the CNS and therefore suppress seizure activity Drugs that potentiate the action of GABA can mediate their effecting in four main ways: 1. Enhancing binding of GABA to its receptor 2. Stimulating GABA release 3. Inhibiting its reuptake and metabolism 14.10 Depression Occasional feelings of depression are normal as are grief and sadness following any form of loss When these symptoms are prolonged and interfere with everyday life, depression may be diagnosed Depression is thought to occur to one third of people at some time in their life Current estimates suggest that 3% of Canadians currently have depression 34 Depression – Diagnosis For a diagnosis of depression at least five of the following symptoms must occur for at least two weeks Depressed mood most of the day nearly everyday Loss of interest or pleasure in all or almost all activities Significant weight loss or gain, insomnia or hypersomnia Psychomotor agitation or retardation Fatigue and energy loss Feelings of worthlessness or excessive guilt Decreased ability to think concentrate or excessive indecisiveness Recurrent thoughts of death or suicide. Types of Depression Depression can be classified into two major types – exogenous or endogenous Exogenous depression is triggered by external stimuli whereas endogenous depression may or may not be related to external events Exogenous Pathological grief Adjustment disorder Endogenous Major severe and atypical depression Dysthymia Seasonal affective disorder Postpartum depression Bipolar disorder Exogenous Depression Pathological grief – prolonged grieving coupled with excessive guilt Psychotherapy is usually more effective in terms of treatment than drugs Adjustment disorder – prolonged depression following failure or rejection with symptoms including hypersomnia (excessive sleep) and hyperphagia (over eating) Psychotherapy is usually more effective in terms of treatment than drugs Endogenous Depression Major depression – common symptoms include loss of interest and lack of response to positive stimuli with symptoms worse in the morning. Insomnia and weight loss are typical Severe depression – similar symptoms to major depression with the addition of severe suicidal ideation and psychoses Atypical depression – similar symptoms to major depression but patients have atypical symptoms of hypersomnia and hyperphagia and patients are usually obese Dysthymia – the patients mood is regularly low but symptoms are not as severe as major depression with them being noticed more by family and close friends than the patient themselves Usually responds better to psychotherapy than drugs Seasonal affective disorder (SAD) – mild or moderate symptoms of depression related to the lack of sunlight in winter months, symptoms go away in the summer 35 Post-partum depression – moderate to severe depression in women after they give birth Usually occurs within 3 months after delivery but can occur up to a year after Bipolar disorder – alternating periods of elevated or irritable mood and periods of depression The Monoamine Hypothesis The exact cause and pathophysiology of depression are unknown The major hypothesis with regards to the biochemical basis for depression is the monoamine hypothesis Suggests that altered monoamine release, receptor sensitivity or post-synaptic function lead to symptoms of depression Example – 20 year old university student takes ecstasy for a rave which depletes serotonin levels and for the next week lacks motivation to study and leave the house and feels his life is going no where Typical symptom for those who take ecstasy which depletes serotonin Drugs that increase monoamine neurotransmission are effective at treating symptoms of depression 14.11 Antidepressant Drugs Antidepressant drugs act to increase the synaptic levels of one or more monoamine neurotransmitters The efficacy of anti
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