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Queen's University
Pharmacology and Toxicology
PHAR 100

Lecture 15- Cocaine andAmphetamine (stimulant drugs) -Stimulant drugs effect mental functioning Cocaine -Increase in dopaminergic activity in the brain -Positives: euphoria, alertness, energy, decreased appetite -Negatives: irritability, anxiety History -indigenous to South America, found in leaves of coca tree -Natives of Peru and Bolivia chewed leaves -Sigmund Freud used cocaine to treat depression and chronic fatigue on himself Forms Cocaine hydrochloride  absorbed through nasal or injected (25mg-100mg) Cocaine Base (crack)  inhaled (water soluble) (250mg-1gram) Pharmacokinetics Intranasal, inhalation, iv -Penetrates brain, freely crosses placenta -Half life of 50 mins (removed by enzymes in liver  benzoylegonine is metabolite) -Alcohol potentiates cocaine effects Mechanism ofAction Three unique features to cocaine: 1. potent local anesthetic 2. vasoconstrictor (constricts blood vessels and raises blood pressure) 3. powerful psychostimulant with strong reinforcing effects Cocaine blocks active reuptake of dopamine and serotonin into presynaptic nerve terminals  can develop tolerance and dependence Amphetamines Synthetic organic compounds (structurally similar to dopamine, epinephrine) Mechanism ofAction Sympathetic stimulants increase synaptic activity of dopamine and norepinephrine transmitter taken up by cell and interferes with vesicular monoamine transporter End Result: increased neurotransmitter in synaptic cleft  increased receptor activation  increased DAand NE-mediated effects Dependence and Tolerance Physical dependence  withdrawal syndrome: dysphoria, more sleep, lethargy Psychological dependence  strong compulsion for frequent use Tolerance develops to euphoric and lethal effects (needs higher doses) Methamphetamine Synthesized from readily available chemicals -Hydrochloride salt (speed) broken down by heating and then being inhaled Nonamphetamine Stimulants Don’t have basic amphetamine nucleus but have sympathetic effects -Ephedrine herbal medicine  release of epinephrine  used for weight loss -Ritalin  blocks DAreuptake  treatment forADHD/ADD  CNS stimulants are used to treatADD and ADHD to reverse many of the symptoms -Pseudoephedrine  in cough and cold medicines  relieves nasal congestion Lecture 16 + 17- Cancer Incidence: number of new cases diagnosed per year Prevalence: number of cases existing during the year Mortality: number of deaths attributed to certain type of cancer in one year Statistics -Lung cancer leading cause of cancer death -Most common types in Canada: lung, breast, colorectal, prostate Females: chance of developing cancer  1:2.4, chance of dying from cancer  1:4.2 Males: developing  1:2.2 and 1:3.6 Survival rate (highest to lowest): prostate, breast, colorectal, lung Cancer Incidence in Countries Liver  higher in southeastAsia and centralAfrica  hep B infection Features of Cancer 1. Uncontrolled cell growth and dividiosn 2. Invasion of surrounding normal tissue 3. Metastatis  ability to spread throughout the body Carcinogens: substance capable of causing cancer in living tissues -Procarcinogen: becomes carcinogen after altered by metabolic processes -Ultimate carcinogen: result of metabolized procarcinogen  causes DNAdamage, if DNArepairs then normal cell, if damage is permanent then cancer is caused Carcinogenesis  multi step process Initiation: carcinogen alters genetic message Promotion: stimulation of rapid cell growth Progression: increase in malignancy Normal Cell  Initiated cell  pre-cancerous lesion  cancerous tumour Causes Genetics: contributes to variation in response to carcinogens -genetic based deficiency in DNArepair, some people are prone to mutations therefore when the DNAdamage is done from the carcinogen, DNAcannot be repaired thus leading to cancer Environmental: anything that is non-genetic -environmental chemicals, diet, lifestyle, infections Most common causes: tobacco use (1/3 cancer deaths, 20 year latent period), diet (1/3 cancer deaths, fruit and veggies decreases, read meat increases), infections (hep b and c, HIV, HPV, Epstein-barr virus, helicobacter pylori) Detection of Carcinogens Long term tests in humans  good proof, long and costly Short term tests in animals  officially recognized, costly, sometimes non-transferrable results Ames test  low cost, short term, uses mutant bacteria that regain ability to grow when exposed to mutagenic chemicals- known carcinogen = positive result Prevention of Cancer -Inhibition of carcinogen activation and enhancement of carcinogen detox -Vaccinations Hep B and HPV -Anti-estrogens -Antioxidants and anti-inflammatory agents Cancer Treatment Goals: Cure  Prolong life  relieve symptoms  psychological support research Treatments: Surgery, Chemo, Radiation, Bone marrow transplants, biological and hormone therapies Chemotherapy Anti-cancer drugs: kill/slow growth of rapidly dividing cells (also kills normal) -inhibits DNAsynthesis or cell division, act against abnormal proteins Side effects: decrease in red and white blood cells, hair loss, diarrhea, toxicities -control vomiting: serotonin receptor antagonists -control pain: opioids (morphine) Drugs Used in Chemo Alkylating agents  Bind to DNAand interfere with DNAreplication Antimetabolites  inhibits certain chemical used for metabolism to halt cell growth Mitotic Inhibitors  affect microtubule function, prevent cell division Topoisomerase Inhibitors  interfere with enzyme responsible for maintaining supercoiling of DNA, DNAstrand breaks thus leading to cell death Anti-tumour Antibiotics  natural products, inhibit topoisomerase Hormones and HormoneAntagonists  suppress cell proliferation Lecture 18- Hypertension Blood pressure  force that blood exerts on walls of arteries -circulating blood carries nutrients and oxygen to tissues, waste and carbon dioxide back to the heart Normal blood pressure is 120/80 mmHg -120  systolic BP (SBP)  heart in contraction -80  diastolic BP (DBP)  heart in relaxation Factors Controlling Blood Pressure Higher blood volume = higher blood pressure (and vice versa) Vasoconstriction= increased peripheral resistance= higher blood pressure Vasodilation= decreased peripheral resistance= lower blood pressure -SNS activity increases with vasoconstriction and vice versa Hypertension: Blood pressure greater than 140/90 Mild  SBP: 140-160 and DBP: 90-99 Moderate SBP: 160-180 and DBP 100-110 Severe  SBP more than 180, DBP more than 110 Risk Factors -Age, male gender, genetics, obesity, smoking -Usually no symptoms show for hypertension Treatment Dietary: low salt and fat diet, weight loss, no smoking or alcohol, exercise, reduce stress Drugs can be taken Diuretics: act on the kidney to remove excess salt and water -Thiazide diuretics drug of choice in elderly, increase salt and water excretion while decreasing blood volume and resistance of blood vessels -side effects: hypokalaemia, hyperglycemia, hypercalcemia, hypercholesterolemia, hyperuricemia Sympatholytics: decrease SNS activity -ex.Ablockers, B blockers, adrenergic neuron blockers, central acting drugs B blockers decrease SNS effect on cardiovascular system -either non selective B antagonist or selective B1 antagonist -side effects: bronchospasm, heart failure, impotence Calcium Channel Blockers: prevent calcium flow into heart muscles, which decreases myocardial contractility Angiotensin converting enzyme inhibitors: inhibit conversion of angiotensin 1 to the active angiotensin 2 -safe in asthma, no impotence, useful in diabetes Angiotensin receptor blockers: block action of angiotensin 2 at AT-1 receptsors -similar effect as above Vasodilators: dilate blood vessels Protocol -start therapy with diuretic,ACE inhibitor,ARB, CCB or beta blocker -can be used in combination Lecture 19- CoronaryArtery Disease Narrowing or blocking or coronary arteries, decrease in blood flow and oxygen to heart Manifestations: -asymptomaticmyocardial infarction, sudden death -angina pectoris: sudden chest pain due to myocardial ischemia (decreased blood to heart) --treatment: rest and antianginal drugs organic nitrates, B-blockers, calcium channel blockers Organic Nitrates -nitrates used reductase to become nitric oxide, which relaxes smooth muscles -it does 3 types of vasodilatation: --venous, coro
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