CSB601 Exam Notes PDF

lOMoARcPSD|48481542 CSB601 Exam Notes Introduction to Clinical Therapeutics for health (Queensland University of Technology) Scan to open on Studocu Studocu is not sponsored or endorsed by any colle...

lOMoARcPSD|48481542 CSB601 Exam Notes Introduction to Clinical Therapeutics for health (Queensland University of Technology) Scan to open on Studocu Studocu is not sponsored or endorsed by any college or university Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 CSB601 Lecture - Week 2 Likelihood of drug interactions increases - 5-6% if 2 drugs - 50% if 6 drugs - 100% if 8 drugs - Not all interactions are clinically significant Clinical significance - when a therapeutic combo could lead to an unexpected change/complication Susceptible patients include; - Anyone taking more than 1 drug (poly-pharmacy) - Patients on long term therapy for chronic disease - hepatic/renal disease patients - Intensive care (transplant recips) - Patients w/ more than one prescriber (difficult to obtain medication history) Not all interactions are easy to predict - Need to be able to spot the red flags An interaction is said to occur when; The effects of one drug are changed by the presence of - Another drug - Herbal medicine - Food, drink - Medical condition - Some environmental element Interactions are avoidable - Knowing how they occur and how to manage them is important Often are not anticipated, may manifest as; - Enhanced effect due to increased metabolism etc - increases side effects - Decreased effects or exposure Can cause serious outcomes - Not all interactions are bad - Certain drugs are frequently implcated - E.g wharfirin - In the majority of cases, when hospitalisation occurs, majority could have been avoided w/ early intervention Clinically important interactions Often includes; - Drugs w/ a narrow therapeutic index - E.g warfarin, digoxin, lithium - Drugs w/ steep dose response curve - Levodopa, verapamil - Little difference between clinical & toxic dose Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Need to consider patients clinical state & timeline - Effects may not be immediate Examples - Postural hypertension & tricyclic antidepressant - Chronic renal failure & long term NSAID - Benzodiazepine to treat insomnia, anxiety Many attempts at making a hit list - Beers explicit - START & STOPP criteria - Drug burden index Drug food & drug-herb interactions - Food can cause clinically important changes - Vitamin K decreases warfarin effects Some drugs can be given together, provided there are no other safer options - Can be given provided there is no risk of serious harm Repeat offenders include; Warfarin, ACE inhibitors The Dosing institute Video Series Introduction to Pharmacokinetics Pharmacokinetics & pharmacodynamics (two branches) - Pharmacodynamics is the effects of drugs on the body - What does it do to the body - What effects does it have - What receptors does it activate - Pharmacokinetics is the effect of the body on drugs - How does it get into the body - Where does it go - What does the body do to it - How does it get rid of the drug Pharmacokinetics ADME A- absorption D- distribution M- metabolism E - excretion 2 sections of drug interactions - Drug enters the body faster than it is being removed (at first) - Drug exits faster than it is entering (conc starts decreasing) - Point @ top of graph is called maximum concentration (CMAX) Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Time at which C Max occurs is called Tmax Halflife is the time it takes to remove half the current concentration to be removed from the body - Half Life often denoted T1/2 Area under the curve - Represents the total exposure to the drug the body gets Pharmacokinetics Absorption Specifically look at routes of drug administration - Follow blood from digestive system through to arterial circulation Flow - Gut to liver (via hepatic portal system) - Liver to venous circulation into the right side of the heart - Through pulmonary arteries to lungs - Lungs to left side of heart - Out of heart into arterial circulation Going to follow drug concentrations over a certain period (drug amounts are all identical) Oral administration Move through whole system Go into gut - See a slow rise and slow fall - Cmax quite low, Tmax quite large IV administration Drug doesn't have a long journey - No digestion - Quick rise of concentration - Cmax is larger, tmax is smaller - IV more direct route of administration Inhalation Many anaesthetics given this way - See concentration shoot up very quickly - Very large Cmax, very small Tmax Drugs that are toxic at high concentrations are better given at oral doses Area under the curve is the same for all types, the dose (or exposure) is all the same - Rate of excretion is proportional to the current rate of the drug - Excreted faster if there is more - NOTE: half life of the drug is the same regardless of administration - A property of the drug, not the route Pharmacokinetics: Distribution Can consider the body is made up of 4 major compartments & numerous minor compartments Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Blood (plasma) - Fat - Extracellular fluid - Intracellular fluid - Minor compartments - CSF - Peritoneum - Synovial fluid - Fetus If a drug is placed into one compartment, we can see how it may be distributed through into other compartments - Often placed into the blood (IV) Often associated with binding molecules (e.g proteins) - E.g albumin - Process sequesters the drug within the compartment - Effectively increasing the compartments storage capacity - An equilibrium is maintained between the bound and unbound drug - Unbound drug moves into new compartment - In that compartment, it binds until reaching equilibrium - This occurs throughout all compartments - Occurs until free drug matches bound drug in each compartment Balance between each compartment is determined using an equilibrium constant - Number that shows whether balance is in a forward or back direction Kc is dependant on - Permeability of barriers - pH of compartments - Binding capacity in each compartment Volume of distribution - Vd - Shows how much drug needs to be within the body to get a certain concentration of plasma - Is the total amount of drug in the body/conc of drug in the plasma - Vd of morphine is about 5L per kg - Trying to achieve 3/70 mg per L - Vd X desired plasma concentration Pharmacokinetics: Metabolism Drugs often get metabolised by the liver - Metabolism can occur elsewhere e.g lungs/gut Oral drugs may be metabolised by liver before reaching systemic circulation - Called first pass metabolism - Can be so dramatic it may cause need for IV - This happens with morphine Cytochrome P450 - Enzymes that are abundant in the liver Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Different types metabolise different drugs Variety of processes includes; - Oxidation - Hydrolysis - Hydroxylation Drug w/ hydrogen attached (Phase 1) - Hydrogen is the target of P450 - Hydroxylation turns the hydrogen into a hydroxyl group - New hydroxyl group is good for attachment UDP glucuronidation (Phase 2) - Glucoronic acid attaches to the group - This has many polar groups attached (3OH’s and 1 carboxyl) - Makes the drug extremely water soluble - Can be easily excreted by kidneys Example - E.g with aspirin - CYP hydrolyses the molecule - Resulted product is salicylic acid (active drug) - Aspirin needs to be metabolised before it has any effect - Is a pro drug - The UDP attaches a UDP group instead of an OH group Pharmacokinetics: Excretion Irreversible removal of drugs from body 2 main ways - Hepatobiliary system - Liver excretes drug into bile which is excreted with faeces - E.g refambicin - Kidneys Kidney excretion - Once in the nephron, it flows through into connecting ducts and out of the body in the urine - Cp (conc in the plasma) - Cu (conc in urine) - Rate of urine production (Vu) - Can determine the clearance of the drug with these values Cu x Vu Clearance = Cp Equation asks: how much plasma contains the amount of drug being cleared at this time How much is being cleared at any given time - 500ml of plasma is being cleared of the drug per minute Filtration rate and clearance are related - Good example is penicillin Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Higher the concentration in the plasma, the faster it is excreted - Half life is the same When half life is the same, this is first order kinetics If drug needs to be metabolised, it normally confirms to first order kinetics - If there isn't enough enzyme, it saturates - Too much drug, creates a bottleneck - In this situation, half life is always differing as the excretion is no longer dependant on concentration in the plasma When the half life is different, it is called zero order kinetics - Drugs w/ this are more easily overdosed - E.g ethanol (only metabolise 10g/hour) - Once no longer saturated, it reverts to first order kinetics Special Populations Lecture Lecture will focus on older adult populations Around 2-3% of hospital admissions each year are due to medication - 20-30% of admissions in older adults are medication related In aged care facilities, there is an average of 3-4 medicated problems 11-12% of adverse events are considered severe, with 5% requiring hospitalisation Medication related admissions - Very significant Drug induced issues are bound - Can worsen/mimic or cause a medical condition/disease - This is why medication histories are essential In aus, approx 1 in 3 unplanned hospo admissions are medicines-related Older populations - >65 years, or >50 for Aboriginal and Torres Strait Islander people - Rights include the right to refuse treatment Issues that need to be considered include; - Reduced life expectancy - Cognition - Social isolation - Cost of treatment - How they live their health-related lives Other factors include; - Limited evidence in people aged over 80 in clinical trials - Age related changes, need to carefully plan and monitor Renal impairment in older age Pharmacokinetic changes Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Need to monitor renal function before prescribing any renally excreted drugs - Can become toxic in patients - Dosages often need to be reduced - Certain medical conditions can also cause decline in renal function Pharmacodynamic changes - Altered sensitivity due to changes in receptors - Reduced physiologic reserves - Impairment in secondary compensatory mechanisms Polypharmacy - Higher chance of disease means multiple drugs - Geriatric syndromes can also increase, frailty, falls, disability Super Polypharmacy - Some are prescribed by a specialist - Some by GP - Some available over the counter or at a pharmacy - Some are complementary self prescribed medicines - Defined as having 10 or more medicines Older australians account for 13% of population but receive twice the number of prescriptions Adherence - Agreed treatment plan - Active collaboration with clinician - In developed countries, adherence is only about 50% Maximising adherence - Open, non-judgemental approach - Allow them to express concerns - Aim to improve patients understanding of medical management - Try to keep treatment simple - As few medicines possible - Discuss the potential for adverse effects - Encourage follow ups & keeping in touch Medicines & falls - Drowsiness, dizziness, confusion etc increase falls risk - Permanent withdrawals may not be possible - Benefits may outweigh risk Case Study Mr Henry - Adherent, didn't understand his medicines or the reasons for them - Takes >10 per day, didn't want an administration aid (sense of autonomy) - Main concern was SOB - Not appropriate storage - Potential for ineffective therapy - Patient was taking a trial drug too - Patient recently hospitalised Hepatic Impairment - If the patient has hepatic impairment - Dosing interval lengthened or dose needs to be reduced Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Special Populations - Pregnancy Lecture Almost every pregnant woman is exposed to some type of medication - Drug needs to be proven to increase baseline risk beyond the 2-3% malformation to be considered dangerous Many diseases that affect pregnancy - Asthma - Diabetes - Depression Critical periods of development Teratogenic exposure; - Exogenous agent that can modify any embryonic or foetal functional or structural development Drug safety in pregnancy - MIMS and drug sponsor info is not the only resource - Need to consider factors affecting placental transfer - It is unethical to conduct clinical trials in pregnant women Need to assess risks & benefits of treating or not treating the medical condition Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Week 3 - Allergies & Immunology Allergy & Anaphylaxis Lecture Allergic response; - body's immune response to allergens including food, chemicals, environment, insects, ocular - presence of these causes an inappropriately large response On first exposure, - Allergen presents to an APC (e.g macrophage) - These APC’s migrate to T cells (natural naive antibodies) - Migrate into TH2 (T helper 2 cells) - These synthesise IgE antibodies specific to the antigen - IgE antibodies sit in mucosal surfaces bound to mast cells When the IgE cells are triggered by their specific antigen AGAIN; - They releases inflammatory mediators including - Prostaglandins - Histamines - Cytokines - Leukotrienes Causes local symptoms or systemic symptoms - itching , swelling etc Antihistamines - Pharmacotherapy - Block the effects of histamine by binding to the H1 receptor - Therefore receptors cannot be activated - This blocks the effects of histamine including; - Vasodilation - Inflammation - Increased vascular permeability - Contraction of smooth muscles in heart - Available in topical or local form - Taken orally - Including older (sedating) - Phenergan - Cause sedation because they cross blood-brain barrier - Block H1 receptors and have anticholinergic properties - Can use to treat motion sickness - Newer (less-sedating) - Claratyne - With older ones, need to be careful with giving them to certain groups - Elderly (falls) - Children (risk of sedation) - need to be over 2 years, sometimes 6 years - Pregnancy (sedation of infant in breastfeeding) - Gastric obstruction (urinary retention) - Newer ones - Less risk in elderly - lower doses - Hepatic impairment - they can increase liver enzymes - Safe from 6 months in children, 1 year in others Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Fine for breastfeeding - Reduce dose in renal impairment - Intranasal have a faster effect - Effects tend to be localised - Very good drug absorption from nasal mucosa, can see systemic effects - Can cause local irritation - No cautions for elderly or hepatic, renal impairments - Corticosteroids intranasally - Act as a local anti inflammatory - Lower mucous production - Lower vasodilation - Don't immediately relieve symptoms (can take days to weeks) - Can see systemic absorption - Dont have to worry about hepatic, renal, pregnancy - Contraindicated for anyone with nasal infection or bleeding disorders - Decongestants - Block alpha-adrenal receptors - Cause vasoconstriction of nasal mucosa - Reduce tissue swelling - Intranasal or oral - May increase blood pressure and heart rate - w/ oral decongestants; have some cautions (w/ pseudoephidrine) - Elderly more likely to have cardiovascular issues - No use under 6 years - No use in 1st trimester - Contraindication within 2 weeks of an maoi - No use w/ hyperthyroidism, hypertension, hypertrophy - w/ intranasal - Avoid use in kids under 6 - Theoretical contraindication w/in 14 days of stopping MAOI - Have rebound congestion due to irritation in nasal mucosa - Monteleukast - Leukotriene antagonist - Blocks the cysteinyl leukotriene receptor - Stops the effects of leukotrienes - Stop smooth muscle contraction of airways (used in asthma) - Only avail in oral tablet - Often given along w/ antihistamines - Called singulair in AUS - Has systemic ADR’s inc hallucinations, mood changes etc Allergy Allergic rhinitis - Seasonal problems w/ itchy red watery eyes - Itchy or sore throat - Can cause cough, ears etc - All linked through sinuses - Can be in response to chemical contact - E.g cleaning products - Latex - Nasal involvement usually due to enviro allergens - Some drugs that induce rhinitis are; - Aspirin Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - NSAIDs - Any vasodilator antihypertensives (ACE inhibitors) - Oral contraceptives - Asthma is associated, pregnant women - Often have ocular involvement - Classified by duration (intermittent/persistent) - Severity (how much it impairs daily activities & sleep) Seasonal allergies - Rhinitis - Swelling or nasal mucosa - Itchy eyes/throat - Prefer antihistamines - Go for newer ones rather than older - Can be used for duration of the season w/out any issues - Long term decongestants are not recommended Anaphylaxis Most severe form of allergy - Acute and potentially life threatening response Often in peanuts, stings, latex Common misconception is that is develops immediately - Can take up to several hours - As there is more exposure, usually gets quicker & more severe - Can be worsened by exercise, current infection, comorbidities, certain drugs Pathophysiology - Similar to normal allergy reaction - Production of IgE that sits on mast cells - Mast cells release inflammatory mediators - Can get swelling, itching etc Lots of systemic symptoms - Swelling of lips and tongue (angioodema) - Eyes swelling - CNS & respiratory symptoms - Due to swelling - Hives & itchiness - GI symptoms - Can make heart rate faster or slower - Usually drops the bp (shock etc) Management - If known to have hypersensitivity, have a plan in place - Keep medications on hand - Emergency contact - How to use certain meds Pharmacotherapy - IM adrenaline - Subcutaneous tissue has erratic absorption - Get it immediately at full dose - Adrenaline Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Acts as an adrenoceptor antagonist at alpha and beta receptors around body - Lifts bp, causes vasoconstriction - Stops bronchoconstriction - Have epipens - No absolute contraindications - Life saving effects far outweigh the risks - Always refer for monitoring afterwards - Is dose by weight - If adrenaline is not enough, can give extra IV volume - Or short acting Beta 2 agonists - Restores blood pressure - Especially for people taking beta blockers - Corticosteroids - Takes 4-6 hours to take effect - Only used as adjunct therapy - After adrenaline wears off, if allergen is still present it can trigger another response Antihistamines - No clinical trials to say that H1 or H2 antagonists are helpful in acute anaphylaxis Antibiotics Lecture Bacterial Cells - Have a cell wall in addition to a plasma membrane - DNA is a little different - Eukaryotic cells have no cell wall - Bacterial cell dna is just in the cell - Ribosomes for protein synthesis are different between 2 types of cells Antibiotic targets - Can inhibit cell wall synthesis - Penicillins, vancomycins - Folate synthesis - Humans can’t synthesis it, they have to make it - Folate essential for synthesis of DNA - Protein synthesis inhibitors (translation) - DNA synthesis (transcription) Antibiotics can be active against; - Gram + Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Gram - - Gram negative can be harder to treat, have an extra outer membrane Bactericidal or bacteriostatic - Cidial - kills the bacteria for us (penicillins) - Cephalosporins - Aminoglycosides - quinolones - Static - inhibits the growth out of the bacteria so our own defence can kill it - Macrolides - Lincosamides - tetracyclines Broad vs narrow spectrum - What range does the antibiotic have action against - Narrow - Against a single or limited amount of organisms - Clindamycin, penicillin G - Extended - Gram positive and many of the gram negative - Cephalosporins, fluoroquinolones - Broad - Wide variety of microbial species - Have antibiotic resistance - Tetracyclines, amoxycillin + clavulanic acid Antimicrobial Creed (MIND ME) - M (microbiology) to guide therapy - I (indication) - evidence based - first line therapy - N (narrowest) - no resistance to newer drugs - D (dosage) - oral therapy wherever possible, site & type - M (minimise) duration of therapy - E (ensure) oral therapy wherever possible Antibiotic resistance - Only kills bacteria that are not drug resistant - Only have the bad drug resistant bacteria that are left - Bacteria can share their drug resistance - Penicillin resistant bacteria - Used to reserve quinolones & vancomycin - Now have resistant strains to those too - MRSA: Methicillin resistant Staph Aureus - VRE: Vancomycin resistant enterococci - Fewer antibiotics being developed - When they get released, we need to reserve them wherever possible Cell wall inhibitors Gram neg bacteria have an extra membrane Inhibit the bacteria's ability to build/maintain the cell wall - Beta-lactams - Have a beta lactam ring - Glycopeptides Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Act against cell walls too Penicillins - A beta lactam - Inhibitors of cell wall synthesis - Include amoxicillin - Penicillin - Flucloxacillin - Common to see anaphylaxis and intolerance to them - Resistance due to bacterial enzymes - Called beta lactamases - They attack beta lactam drugs - Clavulanic acid is a beta lactamase inhibitor - Assists cillins (extends their life) - Stops the breakdown of penicillins Cephalosporins - Inhibit cell wall synthesis - Bactericidal - Include; - Cefalexin - Cefaclor - Ceftriaxone - Closely related to penicillins - Wouldn't use if they were anaphylactic to penicillin Glycopeptides - Bactericidal - Inhibits cell wall synthesis - Vancomycin - Reserved for serious or life-threatening infections, usually given IV - Used for MRSA, meningitis, endocarditis Non-cell wall inhibitors Affect DNA production, protein synthesis Aminoglycosides - Inhibit bacterial protein synthesis - Attack their specific ribosomes - Bactericidal - need high concentration - Gentamicin - Used for serious hospital acquired infections - Higher the concentration - more side effects Macrolides - Inhibit synthesis, also have anti-inflammatory effects - Bacteriostatic - Include clarithromycin, erythromycin, azithromycin - All end in mycin (except vancomycin isn’t included) Tetracyclines - Inhibit protein synthesis - Bacteriostatic - Often used for skin infections - Acne, upper resp tract infections - Prophylactic for malaria Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Include doxycycline, tetracycline - All end in cycline Quinolones - Inhibit bacterial DNA synthesis - Bactericidal - All end in oxacin - Ciprofloxacin - Norfloxacin - Reserved for severe or complicated infections - Recurrent complicated UTIs - Can no longer use them to treat gonorrhea Immunology & Vaccination Immunity has different types - Innate - Adaptive (natural or artificial) Innate - First line of defence - Different cells and the compounds the secrete - Skin - Enzymes - Cytokines - Phagocytic cells - NK cells - Non specific type of immunity - Kills non self Passive & active immunity - Active - Immune response with production of antibodies - Can be natural or due to vaccination - Passive - Either mother to fetus - Administration of artificial immunoglobulin (e.g tetanus through injection) - If time doesn't permit vaccination alone - If they have immunosuppression Adaptive - When we build immunological memory - Need to build it Divided into 2 types; - Humoural - Antibody response by b lymphocytes - Once b lymphs are activated they produce antibodies to bind to pathogens & neutralise - For extracellular pathogens - Some form memory cells (they response to subsequent exposure) - Cellular - Against intracellular pathogens Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Not accessible to innate cells - T lymphocytes (search & destroy) - Get infections out of cells - Recognise self from non-self - Some form memory t cells Each antibody can usually only fit with one antigen Immunisation Rendering a person protected from an infectious agent - Introduction of an antigen to a person without causing disease - Usually a weakened version Antibodies - Usually only recognise one type of antigen Vaccine - Preparation of a weakened or killed pathogen - Not an active virus Vaccinations mimic natural infection - Used to eradicate smallpox, diphtheria & polio Herd immunity - When large numbers of people in the population are vaccinated - Indirectly protects the unimmunised - Requires 40-90% for herd immunity to take place - Really important for immunocompromised people Vaccines Lots of types 1. Live attenuated 2. Inactivated - part of or whole killed 3. Toxoid - inactive bacterial toxoids 4. Subunit - use proteins from an antigen from a pathogen 5. Conjugated - part of a pathogen not recognised to a carrier protein that is recognised Live attenuated - Cannot cause disease - Virus or bacteria is alive but weakened - Usually single exposure is sufficient for lifelong immunity - Can cause more mild side effects than other vaccines - Cannot be used in immunocompromised people - E.g measles, mumps, yellow fever, tuberculosis, typhoid Special populations - Should receive yearly influenza, pneumonia, varicella zoster - Pregnant should receive yearly influenza, pertussis (before pregnancy or 3rd trimester) Inactivated vaccines - Often require multiple doses to establish lifelong immunity - Use booster doses at varying time intervals - No symptoms of the disease are possible - Safe & encouraged in immunocompromised patients - Contain complete or parts of virus or bacteria - Inactivation with chemicals or heat - Include polio, influenza & hep A Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Toxoid vaccines - Inactivated toxins that are secreted by pathogens - Inactivated with heal or chemicals - Recognises entire bacterium - Diphtheria & botulism Subunit - Certain parts of the virus - Usually proteins of the virus - Faster & more safely than eggs - Tend to be recombinant Issues around immunisation Must be studied & proven to not cause disease or death - May show a few symptoms but no disease Needs to be stored correctly Immunisation failure - Don't maintain refrigeration - Not always 100% guaranteed effective - Incorrect injection site Getting antigenic shift - Mutation & evolving to create new forms & types - Change of antigens Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Week 4 - Asthma, COPD Asthma 1/10 have asthma at one stage in their life - 1 death per 21 hours Chronic airway inflammatory stimulated by antibodies - When mast cells activated they release inflammatory mediators Inflamm mediators can result in - Increased mucous - Wheeze - Thickened bronchial walls - SOB - Chest tightness - Cough - Expiratory airflow limitation (inability to breathe out) - no CO2 and O2 exchange Pathophysiology Can be; - Exercise - Stress - Chemicals and medications - Predisposing genetics - Allergens Mast cells begin to degranulate due to IgE antibodies An attack is a flare of asthma - Acute (immediate) - Over days, weeks or months Get increased releases of; - Prostaglandins - Cytokines - leukotrienes ^ all lead to chronic inflammation Bronchospasm happens - Air cannot flow through Can have; - Acute (bronchospasms) - Chronic inflammation (non specific hyperreactivity) - worsening of symptoms - Airway remodelling (constant bronchial restriction) Goal is control!!! - No limitation of activity - Daytime symptoms 160/100mmHg Choice of therapy; - Consideration for a patients pre-existing comorbidities - Stepwise approach - Adding drugs on if not bettering - Majority require 2 or more drugs - Following drug classes; - Angiotensin converting enzyme (ACE) inhibitor - Angiotensin receptor blockers (ARBs) - Calcium channel blocker - Thiazide diuretics - Beta blockers ACE inhibitors - ramipril , perindopril, lisinopril, enalapril - Inhibit angiotensin converting enzyme (cannot raise MAP) - Cannot convert angiotensin I to angiotensin II - Reduce vasoconstriction, reduce everything in RAAS - Reduces stroke volume, HR and SVR - Often the first line selection - So effective at reducing MAP - Adverse effects; Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Hypotension - Hyperkalaemia (increase in plasma potassium) - Stopping sodium and water retention - Potassium is kept in blood because sodium and water are staying in the urine - Persistent dry cough - Triple whammy interaction (results in acute renal failure) - Should NOT be used in combo with ARBs Angiotensin receptor blockers (ARBs) - Candesartan, telmisartan, olmesartan, irbesartan - Antagonise the angiotensin type-1 receptor - Prevents angiotensin II from binding & causing downstream effects - Sit in receptor preventing binding - Block out RAAS - ADRs; - Hypotension - Hyperkalaemia - Often reversed if you don't tolerate an ACE inhibitor - Involved with triple whammy - NO use with ACE inhibitors - Doing the same thing - Can cause lots of harm Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Calcium channel blockers - Calcium is required for muscle contraction - INCLUDES THE HEART - 2 subclasses; 1. Dihydropyridine 2. Non-dihydropyridine - Dihydropyridine - Amlodipine, felodipine, lercanidipine, nifedipine (dipine) - Inhibits influx of calcium into ONLY arteriolar smooth muscle - Selective, prevent calcium going into smooth muscle of arteries - Therefore arteries cant constrict - Net increase in vasodilation (increased SVR) - ADRs; - Due to vasodilation - Headache - Dizziness - Hypotension - Peripheral oedema - Narrow range of indications - Non-dihydropyridines - Diltiazem & verapamil (no naming convention) - Inhibits influx of calcium into arteriolar smooth muscle AND cardiac muscle - Reduction in heart rate and contractile force (SV) - ADRs; - Vasodilatory - Constipation (also affect some GI) - Bradycardia (slow HR) - NON-selective Ca2+ blockers - Broad range of indications (beyond just hypertension) - Very serious interactions w/ beta blockers Thiazide diuretics Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Hydrochlorothiazide - Inhibits reabsorption of sodium and chloride within the distal convoluted tubule - End section of the nephron - Block sodium and chloride from getting back into the blood - Wherever sodium goes, water follows - More water = more urine = less volume in the blood - Reducing stroke volume - ADRs; - Very well tolerated at low doses - Get electrolyte disturbances at higher doses - Often taken within a fixed dose combination - Most patients take as part of a single product - Come in combo with an ABR Beta blockers (ONLY BETA 1) - Rehash: what does noradrenaline do - Binds to adrenoreceptors - Atenolol, bisoprolol, metoprolol, carvedilol - Selectively antagonizes Beta1 adrenoreceptors - 1 heart, 2 lungs - Therefore prevents noradrenaline from binding to the receptor - No increase in heart rate, decrease instead - No increase in stroke volume, decrease instead - Give adrenaline for alpha 1 - causes vasoconstriction (shut down peripheral blood vessels) - ADRs; - Bradycardia - Bronchospasm (start to lose selectivity as you increase the dose) - Mask hypoglycemia - Weak antihypertensives - VERY SERIOUS interaction w/ non-dihydropyridine CaCBs - Life threatening bradycardia Additional applications for antihypertensives 1. Stable angina 2. post-MI 3. Heart failure Stable angina; - Retrosternal chest discomfort - Commonly triggered by stress or physical activity - Typically goes away with rest Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Myocardial O2 demand exceeds supply - Short acting nitrates for treatment - Beta blockers, non-dihydro and nitrates for prophylaxis of acute episodes - All meds reduce amount of O2 that myocardium requires Nitrates - GTN, isosorbide mononitrate - Produce vaso and venodilation - Reduction in venous return and preload Post-MI - Most patients benefit from long term combination therapy - MI-5; - Ace inhibitors (decrease cardiovascular mortality) - Beta blockers (decrease myocardial O2 requirements) - Statins - P2Y12 inhibitors - Aspirin Heart failure - Most patients benefit from long term combo therapy - Include; - Ace inhibitors (increase all cause survival, decrease hospitalisations) - Beta blockers (increase all cause survival, decrease hospitalisations) - Aldosterone antagonists - ARN inhibitors - Digoxin - Loop Diuretics (reduce the symptoms of heart failure - breathlessness/oedema) Loop Diuretics - Furosemide - Do the same thing as thiazides - Only do it in Loop of Henle instead of distal portion - Very very effective diuretics - Can see dehydration, hypotension, electrolyte disturbances - Need to be mindful of diuresis & adherence Nitrates - Glyceryl trinitrate, isosorbide mononitrate - Produce vasodilation & veno dilation - Reduction in venous return therefore reduce preload - Therefore reduce stroke volume - ADRs; - Vasodilatory - Headaches - Dizziness - Hypotension - Short acting (spray) or long acting (patch) - Nitrate tolerance develops if there is no nitrate-free period for 24 hours - FOR LONG ACTING - Very serious interaction with PDE-5 inhibitors e.g sildenafil (viagra) - Reducing the O2 demand of the heart Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Triple whammy - Happens for many reasons - Especially when combining particular drugs 1. ACE inhibitors (treat hypertension) - Causes dilation of efferent arterioles - Reduces blood pressure - More full of blood - Reduces GFR (glomerular filtration rate) 2. NSAIDs - Inhibit enzymes - Interferes with prostaglandins - Constricts blood flow into the glomerulus - Less input into the glomerulus with a higher output - Reduces GFR 3. Diuretic - Reduce the plasma volume - Remove water from the blood - Whole CV system under less pressure - If all 3 of these happen, eventually just to keep up with everything, there will be very little to nothing going through them - If you give ACE inhibitors and NSAIDs that is dehydrated they are very likely to suffer from triple whammy - Main effect of the triple whammy, get renal impairment - May lead to renal failure etc - Downhill effect as soon as kidney failure occurs - Much more vulnerable to be immunocompromised As soon as we retain water - LOOP DIURETICS For people with asthma and anaphylaxis Give cardioselective beta blockers Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Week 6 - Cardiovascular 2 Arrhythmias Epidemiology - Caused by problems with electrical impulses in the heart - Caused by CHD and other medical conditions - Atrial fibrillation (AF) is the most common - Always there, sustained arrhythmia - Higher incidence of stroke or heart failure - Can be worsened by medications Normal heart rhythm is called a sinus rhythm - Normally originates in SA node - Atria contract first and pump blood into ventricles - If the original signal is thrown off, isn't as efficient ECG’s - Often speak of QT intervals - Shorter the interval, faster the heart bate Arrhythmia - Any abnormal rhythm (not sinus rhythm) of the heart - Arises from abnormal impulse formation or abnormal conduction Signs/symptoms of arrhythmia; - Palpitations - breathlessness/fatigue (o2 not being transported properly) - falls/blackouts - Chest pain (similar to angina) - Can be fatal if its a ventricular arrhythmia - May be asymptomatic and not need treatment Classification Tachyarrhythmia - heart beating too fast - Sinus - Atrial flutter - AF - Ventricular tachy Bradyarrhythmia - heart beating too slowly - Under 60 beats per minute - Sick sinus syndrome - AV block (electrical signal is blocked) AF (atrial fibrillation) - Can be persistent, paroxysmal, permanent - Try to remove any underlying causes - Pneumonia - Thyroid imbalance - Alcohol Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Caffeine - Medications - Normally atrial contractions only account for 10% of ventricular fill - Can contribute up to 40% - Worsens when exercising - Major concern is the increase threat of clot (due to stagnant blood) Always always always try no treatment option first - Try drug therapy if its life threatening - If there are systemic symptoms or haemodynamic effects - Presence of an underlying heart disease Drug therapy Usually start with; - beta-blocker (atenolol or metoprolol) OR - Non-dihydropyridine CCB (diltiazem or verapamil) BOTH slow heart rate and force of contraction - Hope to reduce effects of arrhythmia Digoxin - Slows the heart rate - Reduces AV nodal conduction - Increase in tone and reducing sympathetic activity - Good at controlling ventricular heart rate - Helps increase force of ventricular contraction and reduce rate - Patients need to be assessed regularly for toxicity - Very serious - Narrow therapeutic index - Indications - AF and atrial flutter - Heart failure - Adverse effect - Bradycardia, need to be very aware are reassess - Cautions/contraindications - Safe in pregnancy - Preferred in geriatric or less active patients - VERY careful in reduced renal capacity - Careful with electrolyte or thyroid imbalances - Careful in use with beta or calcium blockers - Interactions with a lot of drugs Amiodarone - Slows how quickly the heart can contract (and therefore heart rate) - Acts on the refractory period of muscle contraction - Cell needs recovery time - Blows out the recovery time - Blocks potassium from coming through - Side effects - Thyroid dysfunction - Lots of iodine - Pulmonary toxicity - Liver dysfunction Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Corneal microdeposits - Neurotoxicity - Photosensitivity - Bradycardia - Metallic taste in mouth, photosensitivity, skin pigmentation - Needs to be monitored very very closely - Contraindications; - Lung disease (COPD or asthma) - Renal impairment - Contra in long QT interval - Not used in breastfeeding or pregnancy Non-drug treatment - If drug options are not appropriate or tolerable Options include; - Pacemakers - Implantable cardiac defibrillators - Cardioversion (usually in hospital situations) - Drugs and electrical stimuli to shock pre-arrhythmia - Catheter ablation - Surgery (valvular problems) Anti-Coagulants & Antiplatelets Coagulation cascade - Starts with a damaged blood vessel - Due to atherosclerotic plaques - Mechanical tissue injury - Triggers release of clotting factors - End result of clotting factors is factor 10a - Converts prothrombin to thrombin - Thrombin produces fibrin - Fibrin are the strains adhering to the platelet plug - Platelets need to be activated - Fibrin coats the whole thing to make a clot Antiplatelets stop formation of platelet plugs - Platelets do not become activated and cant stick together Anticoagulants stop formation of clots - No fibrin Factor 10 is written as the roman numeral X - If you see a it means it is activated Have extrinsic or intrinsic pathways - Need vitamin K to produce many of the clotting factors Anticoagulants Work in the venous system - Antiplatelets work in arterial system DO NOT refer to anticoagulants as blood thinners - No effects on the thickness of the blood Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Target our clotting factors - Considered more aggressive than anti-platelets Clots are ticking time bombs - Want to avoid getting them - Especially in patients w/ vasoconstriction or high bp Need to make sure patient knows how to adhere - Also need to watch for signs something is wrong - They need to avoid other drugs which cause bleeding Need to monitor their INR All anticoagulants need to be ceased prior to surgery Warfarin - Works by antagonising vitamin K - Stops synthesis of clotting factors that require vitamin K including factor 10 - Can't be activated, therefore cant form thrombin - Can't form fibrogen, can’t form a clot - Acts high up in the clotting cascade - Very high risk of bleeding - Food interactions - Green leafy vegetables - Changes vitamin K levels - Need to take the same dose at the same time each day - Every time they get an INR, their dose may change - Blood tests every 4 weeks - Not appropriate for pregnant women Heparin - Inactivates factor 10a and thrombin LMWH (low weight molecular heparin) - Works on thrombin - Faster onset but shorter half-life - Used when action is needed quickly - Heparin is preferred in severe liver impairment or disease - Can be contra - Can cause heparin induced thrombocytopenia - Not making enough thrombocytes - Can occur very quickly - Used and safe in pregnancy and breastfeeding - Used to treat thromboembolism Factor Xa inhibitors - Selectively inhibit factor Xa - Bleeding is the only adverse effect (further down in cascade) - Better tolerated than heparin or LWWH - Do not need INR monitoring - Available orally - Include; - Apixaban - Rivaroxaban - Fewer side effects Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - No antidotes - Not suitable with high risk of bleeding - Short half-life - Increasing number of drug interactions - Not suitable in severe RF - Metabolised by CYP3A4 Direct thrombin inhibitors - Selectively inhibit thrombin - Careful in liver failure & renal disease - Orally available, capsules cannot be opened - High risk of bleeding if they get the full dose at once - Includes; - Dabigatran Antiplatelets When platelets aggregate, they attach to blood cells and clot Work in the arterial system - NOT blood thinners - Stop platelets from being able to stick together Drugs include; - Aspirin - Clopidogrel - Dypirimadole Goal to inhibit platelet aggregation - Often used to prevent stroke - Usually ceased before surgery Also used in acute coronary syndromes Aspirin dose for pain 300mg - For CV prevention is 100mg a day - Lower dose every day A few different steps; 1. Adhesion - Artery wall with an atheroma (atherosclerotic plaque building/bursting) - Collagen often sticks off - Platelets stick to collagen and start to become activated 2. activation - Arachidonic acid is converted to thromboxane - Thromboxane a2 - COX-1 enzymes helps convert it - Activates its receptors which activate the ADP receptor - ADP receptor activates the IIb/IIIa receptor - Helps with fibrin & fibrinogen 3. Aggregation - IIb/IIIa receptors help with fibrin and fibrinogen - Give cross-linking of fibrinogen which causes aggregation and sticking together Aspirin - Blocks COX-1 Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Cant activate thromboxane Clopidogrel - Blocks ADP receptor - Cant activate IIb/IIIa Dipyridamole - Works on cyclic AMP - Energy form of platelets - Platelets can’t become activate and aggregate Aspirin - Inhibits platelet aggregation - Irreversibly inhibits cyclo-oxygenase (COX-1) - Stops synthesis of thromboxane A2 - Platelets cant aggregate - Works for the lifetime of the platelets - Circulate for 3 months at a time - Turns off the ability for lifetime - Can be combined with clopidogrel or dipyridamole - Can cause; - Gastric upset - GI bleeds - Ulcer - Severe skin reactions - Haemorrhage Clopidogrel - Binds to platelets ADP receptor (also known as the P2Y12 receptor) - Names are interchangeable - Inhibits platelet aggregation for the life of the platelet - Clopidogrel is a prodrug - activated by CYP enzymes - ADRs; - Multi organ hypersensitivity - anaemia - thrombocytopenia/neutropenia - Need to avoid grapefruit juice Dipyridamole - Inhibits function by inhibiting the platelets phosphodiesterases - Necessary for activation - Can hause headache, GI upset, hypotension, tachycardia - Avoid in patients w/ unstable angina or recent MI Dyslipidemia Cholesterol & triglycerides = lipids Aim to reduce the risk of atherosclerosis - Reduce the comorbidities Some terms; - TC: total cholesterol - HDL: high-density lipoproteins - LDL: low density lipoproteins Cholesterol Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - LDL is the bad cholesterol - Carries cholesterol from liver to peripheral tissues for physiological functions - Carry excess into the vascular tissue - Where atherosclerosis likely to develop - HDL - Does the opposite to LDL - Carries from vascular tissues to the liver where it is removed - Aim to lower LDL and increase HDL - IMPORTANT to know the cholesterol levels - LDL 2mmol> - HDL >1mmol Dietary change - Plant sterol - Limit alcohol & lose weight - Limit dairy & cheese Synthesis of Cholesterol Fats and cholesterol taken up from the diet - Into liver - Cholesterol also made in liver HMG CoA - Once of the steps in making cholesterol - HMG CoA reductase - If this is inactivated we don’t make our own cholesterol - If we don't get enough from the diet, LDL receptors are upregulated - Less you eat, the more LDL is uptaken from body Drug-therapy Statins are the first line treatment Statins - Block action of HMG CoA reductase - The rate limiting step in our bodies synthesis - Stops bodies from making excess cholesterol - Lowers LDL levels - Include; - Simvastatin - Atorvastatin (lipitor) - Rosuvastatin - All end in statin - Can’t make as much cholesterol - Pulls more in using LDL receptors, lowers cholesterol in blood stream - Indications; - Hypercholesterolemia - High risk of coronary heart disease, with or without hypercholesterolemia - ADRs; - Myalgia - Elevated chance of liver dysfunction - Myopathy - Rhabdomyolysis (serious side effect) - Lots of pressure on the kidneys - Leads to kidney disease - Must monitor for liver dysfunction and muscle problems Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Need to seek advice is urine is dark (brown) or if there is any muscle pain, tenderness or weakness - Most people can achieve reduction with half the max dose - Contraindications; - 1st trimester - Caution for hepatic issues - Lots of drug interactions, metabolised by CYP enzymes CYP enzymes - Statins are a substrate of CYP3A4 enzymes - Inhibitors of enzymes stop the enzymes from working - Stops breakdown of any drugs relying on these enzymes - Increased effects and increased ADRs - If there's an inducer, it increases breakdown and clearance of drug - Decrease conc in body and effects - E.g clarithromycin is a strong inhibitor of the enzyme - Increases levels of atorvastatin Ezetimibe - If statins are not enough - If there are contraindications to statins - Reduces the absorption of cholesterol from our diet - stops transport of cholesterol across the intestinal wall - Increased reuptake into the liver - ADRs; - Diarrhoea (fatty) - myalgia/myopathy - Raised liver enzymes - Pancreatitis - Contraindications; - Not with any hepatic conditions - Avoid in pregnancy, no data - Not for patients with fibrates - Pancreatitis or gallbladder disease Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Week 7 - Endocrinology Thyroid Disorders Thyroid - Sits anterior to the trachea, sits below thyroid cartilage - made up of thyroid follicles consisting of; - Follicular cells - Filled with thyroglobulin (precursor of T3 and T4) - Parafollicular (c cells) - Produce calcitonin T3 & T4 made from tyrosine - When combined with iodine - T3 has 3 iodine atoms - Higher binding affinity than T4 - More potent than T4 - Made in lower quantities - T4 has 4 iodine atoms - Less potent - Secreted in larger quantities - Cleaved into active T3 Thyroid - Under control of the hypothalamus - Hypothalamus releases TRH (thyroid releasing hormone) - This stimulates anterior pituitary to produce TSH (thyroid stimulating hormone) - T3 has a direct negative feedback on TSH - T4 has negative feedback on TRH and TSH Most T4 is converted to T3 - Both increase the basal metabolic rate - Results in; - Faster reflexes - Breakdown of muscle and liver energy stores - Increased body temp Epidemiology >12% of the population develops a thyroid condition Most thyroid cancers respond well to treatment Hypothyroidism Low levels of thyroid hormones Primary hypothyroidism is caused by; - Autoimmune thyroiditis (Hashimoto's) - Most common cause of immune is hashimotos - Iatrogenic - Usually secondary to treatment for hyperthyroidism - Radiation or surgical - Iodine deficiency - Enzymatic defects - Cretinism (congenital disease) - Postpartum thyroiditis Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Secondary hypothyroidism - Issue with pituitary or hypothalamus - Pituitary (lack of TSH) - Hypothalamus (lack of TRH) Hashimotos disease - More common in women - Antibodies against the thyroid gland leading to destruction of tissues - Can be genetic or due to environmental radiation - Comorbid autoimmune diseases increase likelihood Iodine deficiency - Trace element - Need to absorb from the food we eat - If we lack iodine, can't make thyroid hormones - No T3, no negative feedback - Leads to goiters (expansion due to no negative feedback) - Higher need for iodine in pregnancy and breastfeeding Symptoms - dry/coarse hair - Puffy faces or goiters - Weight gain - Slow heartbeat - Infertility or heavy periods - Problems with concentration - Dry skin - Cold intolerance - Depression Diagnosis - Through blood tests - If autoimmune, antibodies will be present - In primary, see high TSH and low T3 or T4 - In secondary, see low TSH and low T3 or T4 - May take symptomology into account when diagnosing Treatment - Main treatment is replacement - Usually T4 (levothyroxine or L-thyroxine) - More shelf stable than T3 - For primary; - Supplement - Restore T3/T4 levels - Unlikely to see shrinkage of tissue if going on for too long, surgery to remove excess tissues Pharmacology - Liothyronine (T3) - Start slow with elderly patients - Can use T3 in children and pregnancy but prefer T4 - Caution in diabetics - Caution in cardiovascular disorders - Thyroid hormones can increase heart rate - levothyroxine (T4) Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Preferred for children & in pregnancy - Need dose adjustments if hypothyroidism present before pregnancy - Often adjusted up and down - Slower dosage in elderly - Same cautions w/ diabetes and cardiovascular Hyperthyroidism Women 10x more likely - Less common than hypothyroidism though Have subclinical hyperthyroidism in around 3% - More common in african americans Pathology - Excess of thyroid hormones - Can be due to; - Graves disease (most common cause) - TSH-secreting pituitary tumour - Multinodular goiters AKA plummer disease - Hyperplasia of thyroid tissue - Thyroiditis - Secondary to a bad viral syndrome - Can be painful and subacute, painless and sporadic or postpartum - Can also be; - Drug induced - Amiodarone type 1 (excessive iodine) or type 2 (destructive thyroiditis) - Exogenous thyroid hormone (overreplacement) - Toxic adenomas - Genetic mutation in TSH receptor gene - Ectopic thyroid tissue - Struma ovarii - Tumour on the ovary that secretes its own thyroid - Not stimulated by TSH Symptoms - Enlarged thyroids/goiters - Rapid heart beat - Sweating - Heat intolerance - Insomnia - Infertility (lack of menstruation) - Weight loss - overactive metabolism - Hair loss - Muscle weakness - Irritability - Frequent bowel movements Graves disease - Own distinct set of symptoms - Classic triad; 1. Exophthalmos (oedema within the eye) - Bulging of the eyes 2. Thyroid dermopathy - Swelling and lumpiness under the skin - Itchy and red Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - HLA builds up - Causes pitting oedema 3. Thyroid acropachy - Clubbing of fingers and toes - Inflammation around connective tissue Diagnosis - Usually do blood tests - Hyperthyroidism; - Low free TSH - High levels of T4 - Subclinical; - Low free TSH - Normal T4 - Hyperthyroidism secondary to tumours; - High TSH - High T4 Treatment - 3 main options including; 1. Pharmacotherapy - Beta-1 selective or non-selective blockers to control symptoms (beta cells in charge) - Carbimazole - Propylthiouracil (PTU) 2. Surgery 3. Radioactive iodine - Carbimazole and PTU - Thioureas - Inhibit biosynthesis of thyroid hormones - Divert iodine away from iodination sites - Stops MIT and DIT from coupling to form T3 and T4 - Stop iodine molecules from incorporating into tyrosine - PTU added mechanism - Stops activated form in periphery - PTU contraindications; - Avoid in children (specialist monitoring) - Preferred in pregnancy due to added mechanism - Only in 1st trimester - Switch to carbimazole in 2nd and 3rd - Watch for agranulocytosis - Fever, mouth ulcers, sore throat, rash, abdo pain, jaundice - Can cause hepatotoxicity - Carbimazole - Avoid in children - Monitor in poor hepatic function - Watch for agranulocytosis - Radioactive iodine - Usually only one dose is needed - Uptaken by thyroglobulin - Biologically inactive bc it is radioactive isotope - Damaged tissue can no longer produce and secrete thyroid hormones Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Pathophysiology and pharmacology of Diabetes Many exceptions Epidemiology - 1 in 11 adults have diabetes (415 million people) - 1 person dies every 6 seconds from diabetes - 1 person develops it every 5 minutes Pathophysiology Need to understand normal physiology before abnormal physiology - Glucose the most important fuel for cellular energy - Consume glucose as part of our diet Polysaccharides - Come in most vegetables - Cannot use in cellular energy as humans - Body cleaves individual molecules to produce monosaccharides (e.g glucose) When we consume glucose; - Glucose enters blood (that isnt used for energy) and is packaged as glycogen - Placed in liver, adipose tissue - Insulin packages glucose into glycogen and places it in storage - Glucagon causes breakdown of glycogen - Glycogen gets broken down into glucose - Glucose put back into blood, the unused gets stored - Also excrete glucose as necessary - Through kidneys Pancreas - Alpha cells secrete glucagon - Beta cells secrete insulin Homeostasis of glucose incredibly important - No glucose = no energy - High glucose in plasma = series of complications - When there isn't enough glucose, use fats - Acute ketoacidosis (ketones are released from fat breakdown) - Glucose makes blood quite thick & viscous - Microvascular & macrovascular complications - Risk of MI, nephropathy etc - Hypoglycaemia - Adrenergic and neuroglycopenic sides - Adrenergic - Pallor, diaphoresis - Anxiousness - Neurglycopenic - Confusion, agitation, altered LOC When blood glucose levels rise (Insulin homeostasis) - Due to food or breakdown of glycogen - Something requires energy and body needs fuel - Pancreatic beta cells release insulin (due to too much glucose in the blood) Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - This process is called glycogenesis - Glucose is removed from blood and stored as glycogen in muscle, liver and adipose Glucose dependent insulin secretion - Consume food and it ends up in intestines - Ends up in blood, rising plasma conceentration of glucose - Consume foods (the physical process) - Causes secretion of incretins (GIP) - Incretins released in response to the consumptions of food - Dipeptidyl peptidase-4 enzyme occurs in body naturally - Finds and destroys incretins - Both of these processes tell pancreas to release insulin - GLUCOSE dependant Prandial insulin secretion - breakfast, lunch & dinner - See big spikes on insulin after each meal - Direct relation of secretion of insulin in response to food - Baseline line is NOT 0 - Basal and always existing level of insulin that pancreas is always producing When blood glucose levels are low (Glucagon homeostasis) - Due to not eating - Glycogen production - Blood concentration too low - Alpha cells release glucagon - Glycogen broken down into glucose (called glycogenolysis) Diabetes 2 types - Type 1: insulin deficiency - There is no insulin - Autoimmune destruction of beta cells (cannot make insulin) - Get hyperglycaemia Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Type 2: insulin insufficiency - Progressive beta cell dysfunction and insulin resistance - Insulin is less effective and cells less functional - Amount and effectiveness reduces - Get hyperglycaemia Pharmacodynamic management of Type 1 Diabetes Want to achieve 4 major goals; - Manage hyperglycemia - Avoid acute complications of hyperglycemia - Reduce chronic implications of hyperglycemia - Avoid hypoglycemia Insulin - Deficient in insulin - The major therapy is reintroducing exogenous insulin - Mimics the effects of endogenous insulin - Insulin is a huge protein - Not orally bioavailable - Cannot be in a tablet - Must be injected - Variety of different formulations Formulations of insulin - 2 primary insulins; - Ultra short acting (insulin aspart) - Big spike - Reduces quite quickly - Long acting (insulin glargine) - Smaller peak that lasts quite long and then drops off - Try to mimic normal process Pharmacotherapeutics of insulin - Insulin replacement therapy - Most common approach is the basal-bolus regime - Big dose and long acting background - Long acting and ultra short acting in combination Basal insulin - Long acting - Insulin glargine - Mandatory background effects - Injected independent of carbohydrate intake - Around 40% of individuals total insulin requirements Bolus insulin - Short acting - Insulin aspart - Mimics glycogenesis effect of insulin - Injected before each meal to cover carbohydrate intake - Typically 60% of the requirement, given in divided doses Adverse effects can include hypoglycemia Practice points; - Hypoglycemia - recreational substances - E.g alcohol inhibits glucose production, cannot break down glycogen - Changes in awareness and consciousness Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Compromise ability to recognise hypoglycemia - Fasting (e.g for religious purposes) - Recommendation to NOT fast - Temperature sensitive - Must be refrigerated - Delivery options include injection or insulin pumps - Monitoring on blood glucose conc Pharmacodynamic management of Type 2 Diabetes 4 main goals; - Manage hyperglycemia - Avoid acute complications of hyperglycemia - Reduce chronic complications of hyperglycemia Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Avoid hypoglycemia Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Management of T2D does not follow a hierarchy - Lots of considerations - Stepwise therapy - Add in drugs - Progressive accumulation Primary choices; - Biguanides - Sulfonylureas - DPP-4 inhibitors - SGLT2 inhibitors - GLP-1 analogues Secondary choices; - Acarbose - Pioglitazone - Insulin Biguanides - Only 1 (Metformin) - First line therapy, principle drug - Mechanism; - Reduces intestinal absorption of carbohydrates (less glucose) - Increases sensitivity of insulin (converted more) - Increases uptake into peripheral tissues Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Hepatic glucose production decreased (glycogenolysis) - Less glucose, can't break down glycogen - Reduces the breakdown of glycogen in the liver - Adverse effects; - N/V/D - nausea, vomiting, diarrhoea - Reduces likelihood of micro and macrovascular complications - Cannot cause hypoglycemia on its own - Immediate or extended release - Need to consider lactic acidosis (hasn't been shown in metformin but still be precautious) Sulfonylureas - E.g gliclazide, glipizide, glibenclamide (prefix gli-) - Increases pancreatic insulin secretion (independent of food) - Problematic as you may see hypoglycemia - Esp if you havent eaten - ADRs; - Weight gain and hypoglycemia - Will cause hypoglycemia on their own IF not taken with food - NEED to be taken with food - DO NOT take if you aren't eating DPP-4 inhibitors - Linagliptin, sitagliptin, saxagliptin (suffix -gliptin) - Inhibit DPP-4 - DPP-4 breaks down incretins - Inhibits the enzyme that breaks down incretins - Increase concentration of incretins - Increases glucose-dependent insulin secretion - Increase glucose dependent insulin secretion - Nothing happens if you haven't eaten - ADRs: pretty well tolerated, may get musculoskeletal pain (expect to see it) - Very unlikely to cause hypoglycemia on their own - Ties into mechanism on action SGLT2 (sodium-glucose co-transporter 2) inhibitors - Empagliflozin, dapagliflozin, ertugliflozin (suffix -gliflozin) - Mechanism; - Inhibit renal SGLT2 - Reduce co-transporter within the kidney - Pulls glucose and sodium from urine back into blood - Drugs stop this - Glucose and sodium stay in the urine - ADRs; - Polyuria (increase sodium, where sodium goes, water follows) - Genital infections (favourable environment for bacteria to grow) - Euglycemic ketoacidosis - Untypical for DKA - Pathophysiology not well understood - Practice points; - Unlikely to cause hypoglycemia on their own - Mild blood pressure reductions - Mindful of dehydration - Renal impairment Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Giving a drug that relies solely on kidneys, but do their kidneys work? Glucagon-like peptide 1 (GLP-1) analogues - GLP-1 is one of our incretins - Dulaglutide, liraglutide, exenatide (-tide) - Injecting you with incretins - Mimic the effects of GLP-1 - Increase glucose dependent insulin secretion - ADRs; - Gastrointestinal (N/V/D) - 40-50% of people get side effects - Injection site reaction (only avail in subcut) - Unlikely to cause hypoglycemia on their own IMPORTANT* - Combining drugs Secondary management Acarbose - Prevent carbs moving from intestine to blood - Very significant GI issues Pioglitaozne - Increase glucose uptake into peripheral tissues - Increase risk of Heart failure and bladder cancer Insulin - Sometimes just use the basal routine - Not only used in type 1 Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Week 8 - Mental Health Depression and Bipolar Affective disorders Includes; - MDD (or unipolar) - Mood swings into the same direction - Bipolar - Both directions, mania and depression Major Depressive Disorder (MDD) - Not situational - Interferes with daily functioning - Symptoms must occur or 2 weeks including; - Lethargy - Depressed mode - insomnia/hypersomnolence - Suicidal ideation - Feelings of worthlessness - Loss of apathy/personal neglect - May be triggered or may arise without cause - Risk factors include; - Genetic - More common in 1st world countries - Higher in women (includes post-natal depression) - 18-24 most common - In older patients, exists with chronic comorbidities - Thought to be caused by deficiency in neural signalling of 2 amine neurotransmitters; - Serotonin (5HT - structure is 5 hydroxytryptophan) and - Noradrenaline (NA) - Thought they couldn't signal properly - now know pathophysiology includes dopamine, glutamate, hormones inc cortisol and melatonin and BDNF (brain derived neurotrophic factor) - what builds up neurons - Neuronal connectivity altered - imbalance between growth factor (BDNF) and glutaminergic activity - Leads to cell death - Alterations in melatonin and cortisol - Changes in hippocampus which regulates mood - Focus on increasing monoamines in synaptic cleft - Monoamines bind on postsynaptic neuron - Left over monoamines degraded by MAO and COMTs MDD treatment: lifestyle & individualisation Always include; - Reduce stress - Cognitive behavioural therapy - Cease drugs and alcohol Pharmacotherapy; - History of successes and failures Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Concurrent illnesses - Risk of suicide TCA (tricyclic antidepressants) - Block presynaptic reuptake of %HT, NA and DA - Also block receptors in periphery - Lots of ADRs - Dry mouth - Blurred vision - Constipation - Tachycardia - Confusion - Sedation - Reduced seizure threshold - Weight gain - Toxic and fatal in overdose - Do not give in high suicide risk - Include; - amitriptyline, imipramine, nortriptyline - Contraindications; - Category C pregnancy - Not to be used in 14 days of an MAOI SSRI (selective serotonin reuptake inhibitors) - Selectively block presynaptic reuptake of 5HT (serotonin) - Better side effect profile - ADRs; - Hyponatremia (low sodium in the body) - Can be toxic but not as bad, can get serotonin toxicity - Serotonergic - Increased temp, agitation, sweating, diarrhoea, mania - Pseudoephedrine over the counter can contribute to serotonergic effects - Include; - Citalopram, fluoxetine and sertraline - Contraindications; - Fewer than TCAs - Not to be used in 14 days of MAOIs - Hepatically cleared - Category C for pregnancy - Careful in elderly - Higher risk of bleeds - Hyponatremia SNRIs (serotonin and noradrenaline reuptake inhibitors) - Block presynaptic reuptake of 5HT and NA - Similar ADR profile to SSRIs, both due to blocking - NA has more cardiac ADRs - Contraindications; - Caution in heart disease - Don't use in MI - Need to monitor BP regularly - Risk of serotonin syndrome - Contra in patients w/ high risk of bleeds - May lower seizure threshold - Not associated with weight gain Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Include; - Venlafaxine, desvenlafaxine and duloxetine - Contra; - Category C for pregnancy - Not to be used in 14 days of MAOI - Contra in unstable heart disease or hypertension MAOI (monoamine oxidase inhibitors) - Non selective - Work on MAO-A and MAO-B - Irreversible - Last line - Many adverse reactions and contraindications - Cannot be used in; - Patients w/ diabetes - Patients w/ cardiac disease - Patients w/ epilepsy - Interact w/ foods containing tyramine - Anything aged or fermented - Matured cheese - Ages yeast - Any soy beans - Cause weight gain and sleep disturbance - Include; - Phenelzine - Tranylcypromine - Contraindications; - No data in pregnancy or breastfeeding, may just speak to a specialist - 14 day separation from any other antidepressants or serotonergics - Don't use in liver disease Pharmacology Adverse effects differ according to receptor affinity Cognitive therapy always first line If using meds, start low go slow - Always withdraw gradually - Can get relapse - Takes 2-3 weeks to see an effect and a 6 week wait for full effects - Do they have other disease states or medications to take - 1st lines and SSRIs and SNRIs Patients CANNOT stop after they feel better - Continue for 6-12 months after they start feeling better - Some patients on medication for life Bipolar disorder Mania is a hyperinflated mood; - Superman complex - Speak loudly and rapidly - Impulse behaviour or disinhibition - Excessive involvement in pleasurable activity - Can quickly lead to psychosis and suicide/death Epidemiology; Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Less than 1% of australians affected - Over 90% experience relapse - Can be idiotropic - Long term high dose corticosteroids Acute mania; - High risk emergency - Present w/ aggression, violence, imapired judgement Usually given; - Antipsychotics - Benzodiazepines - Lithium Treatment /prophylaxis - Antidepressants - Incorrect doses can cause a manic episode - CBT and ECT - Quetiapine - First line - Antipsychotic - Controls depression and mania Prophylaxis - Lithium - First line - Inhibits dopamine release - Stops impulsive behaviour - Enhances serotonin release - Narrow therapeutic window - Toxicity - vision changes, gastric upset, muscle rigidity - Lots of interactions; - Thyroid problems - Psoriasis - Renal impairment - Need to monitor sodium levels; - Dehydration - Use with caution in elderly - Hyponatremia risk - Try avoid in 1st trimester - Increased risk of congenital heart defects - Not used in renal impairment or thyroid issues, always monitor kidney function - Anti-epileptics - Often used for bipolar prophylaxis - Beyond the scope of the unit Anxiety and Sleep Disorders Comes in many forms & severities - Primary = no underlying cause - Secondary = caused by another condition First line therapy - Psychological therapy and support including; - Coping mechanisms - Stress reduction - Counselling Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Breathing control Goals of therapy; - Controls symptoms - Improve social functioning Types Panic attack - 15% of population worldwide Generalised anxiety disordered - 2-3% of population - 3:1 f t m PTSD - Females 2x more likely OCD - 2-2.5% of pop worldwide Specific phobias - Up to 12% of population Benzodiazepines Increase effects of GABA - GABA is an inhibitory neurotransmitter - When increase its effects, increase its ability to calm things down - Inhibits firing - Anxiolytic effects - Muscle relaxant - Hypnotic - Sedative Different classes - Different length of actions ADRs; - Dizziness - Vertigo - Retrograde amnesia - Slurred speech - Headache - Respiratory depression - Decreased libido and hypotension E.g midazolam w/ seizures Contraindications; - Caution in elderly - Respiratory depression - Short term - Avoid in children - Greater sensitivity - Low dose in pregnancy - Avoid in 3rd trimester - Contra in patients with history of alcohol or drug abuse - Effects increased in alcohol - Severe hepatic or renal impairment Start low go slow - Use for shortest amount of time - Slow withdrawal Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Inc tachycardia, insomnia, sweating Anxiety Generalised anxiety/panic disorder - Symptoms causing significant distress and disruption to daily life Start low go slow - Goal is long term control - Use antidepressants, in short term while we wait they may be given a benzodiazepine Take off benzos OCD Repetitive feelings of needing to do something to stop bad things are happening - Significant disruptions to daily routine Drugs that work best are serotonergic drugs - Most control - Doses higher for OCD than for typical depression SSRIs, TCAs Get cycles of; - Obsession - Anxiety - Compulsion - Relief Specific Phobias 5 subtypes; - Animals - Natural environments - blood/injury - Situational (airplanes, lifts) - Other (sounds, clowns) Cognitive therapy or diazepines 30 minutes prior to trigger Sleep disorders Lots of types, affects more than just a few nights 5 stages of sleep; - Non-rem (4) - How you fall asleep - Rem (5) - rapid eye movement Most adults get 4-6 cycles of non-rem rem Insomnia - Physiological and pathological mechanisms - Not just one neurotransmitter etc - When disrupted, get clinically significant effects on lifestyle 1st line therapy - Non-pharmacological - Removing drugs, alcohol or prescriptions - CBT or stress management - Sleep diaries and sleep hygiene - Good scheduling - Meditation or breathing beforehand Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - If they can't fall asleep for 20 minutes - Get out of bed, do something relaxing Pharmacotherapy - Benzodiazepine - Sedative effect - Zolpidem - Also the GABA inhibitory effect - Melatonin - Naturally occurring hormone in the body - Works with circadian rhythm - Resetting for jet lag and shift work - Prescription only Zolpidem (Stilnox) - Contraindications; - Risk in elderly - Avoid in pregnancy - Not rec in children - Contra w/ alcohol intake - Sleep related behaviours increased - Sleepwalking, eating etc Melatonin (Circadin) - Recommended in people over 55 years - Not rec in children - melatonin plays a role in sexual maturation - Category B3 in pregnancy, maybe preferred over benzos - Contra in hepatic impairment Dopamine - Increases alertness in hypothalamus - Any drug inhibiting dopamine will decrease alertness Narcolepsy - Dexamphetamine etc for stimulation - Amphetamines reverse all 3 MOA transporters - Promote wakefulness - Increase dopamine Restless leg syndrome - Product of reduced dopamine transmission in the substantia nigra - Treated with dopamine agonists - Increase DA transmissions and restore normal movement - Increase the amount of dopamine Schizophrenia Only affects 0.7% of population during their lifetime - 47% of patients with psychosis would be schizophrenic - 70% will have their first episode before the age of 35 American psycho & a beautiful mind - movies Symptoms and Presentation Usually experience; - Emotional disturbance - Distrubed volition Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Disturbed speech - Cognitive decline Years before clinical onset you usually see changes in; - Cognition, motor skills, language - Social skills - Behaviour Lots of different symptoms that can present Focus on positive; - Hallucinations - Delusions - Impaired insight - Disorganised thinking and speech Or negative (underfunctioning); - Lack of motivation - Poor self-care - Blunted affect (no facial expressions) - Social withdrawal Effects cognitive, excitement and mood too ⅓ progression happens quickly, but it usually takes years - Onset usually around 18-20 esp in males - Don't recover from subsequent episodes as well as earlier episodes - Longer recovery after each Reaches a plateau - Chronic or residual phase Pathophysiology Involves genetic factors - Multiple genes Environmental factors; - Exposures during pregnancy and birth being altered - Second trimester (any abnormal migration of fetal brain cells) - Infant hypoxia - Changes in size and activity of neurons Dopamine hypothesis - Excessive dopamine levels - Dopamine receptor defects Serotonin - Similar to dopamine neurons - Structurally similar - Tend to be in the same areas in the brain - Patients have high dopamine and serotonin levels - Effect of serotonin receptors on dopamine neuron depends on where in the brain we are Nigrostriatal pathway - Responsible for movement - Serotonin affects dopamine which can affect this pathway Treatment Non-pharmacological management - Family support - Counselling Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Psychosocial interventions Also use antipsychotics - Some are effective for controlling negative symptoms - Often see depression in this patients Newer generations control pos and neg - Older just pos symptoms Classifications - Generational - 1st gen = older, just act on dopamine - 2nd = dopamine and serotonin - Different times of discovery and the adverse effects we see - Typical - Typical = dopamine - Atypical = 5HT and dopamine - 2nd gen and atypical show lower incidence of extrapyramidal side effects Antipsychotics Block dopamine transmission in certain parts of the brain - Esp in limbic system All antipsychotics block the D2 receptor (dopamine 2) - If we antagonize 5HT receptors, also see antipsychotic effects Antagonists - Promazine (blocked D2) - Amphetamines (block dopamine reuptake) - More dopamine circulation - Increases symptoms of schizophrenia Dopamine receptor blockade - Variety of serious side effects - EPSE (extrapyramidal side effects) - Dopamine regulates voluntary movement - Low dopamine = trouble initiating movement and maintaining stillness - Block too much dopamine - Includes muscle spasms in head and neck (dystonia) - Akathisia - motor restlessness - Tardive dyskinesia - repetitive behavioural type movements, involuntary - Cardiovasc side effects - Orthostatic hypotension - Metabolic - Weight gain - Increased BGL - Dyslipidemia - Anticholinergic effects - Constipation - Dry mouth - Tachycardia problems Atypical - Lower risk of ESPE side effects - Different pharmacology than just blocking D2 - Also block certain 5HT (serotonin) receptors Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Don't completely block dopamine signalling - Allow a little to happen in movement areas of the brain - Block in emotional areas Dopamine stabilisation - Absolute blockade - reduces symptoms - Stimulants - result in psychosis - Reward balancing with side effects Older antipsychotic (1st gen) - Haloperidol - Contras; - Higher risk for ESPEs, stroke and death - Children higher risk for metabolic and learning difficulties - Pregnancy, metabolic and sedative in infant - Not for patients w/ CVD risk or acute glaucoma - Highest risk for ESPEs - Smoking can change the way the dose works in the body - Changes smoking habits might require dose change Atypical - Aripiprazole - 2nd gen - Partial dopamine and serotonin agonist - Fewer side effects, different pharmacology - Contras; - Caution in elderly, much lower risk - Children metabolic problems - hyperprolactinemia - Risk benefit calc in pregnancy - Cannot be given with CYP3A4 or 2D6 enzyme inhibitors - responsible for metabolism Lots of antipsychotics to choose from - Better side effects in 2nd gen - Usually start here - Also depends on symptoms - do they have positive or negative - How bad are psychotic effects Clozapine - One of the oldest - Also the most effective - Very serious side effects - agranulocytosis - Narrow therapeutic range - Need monthly blood drawn on clozapine levels to get next dose Only use antipsychotics for an adequate duration - Frequent relapses, may be medicated for life - Try to only use one antipsychotic at a time - eTg has a guide for dual use Always use a broadly based treatment program - Maintain physical health and monitor closely Common comorbidities Mental - Depression Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Anxiety - Substance abuse Physical - Risk of cardiovascular disease - Diabetes - Respiratory problems - Obesity Lifestyle - Smoking - Avoiding high alcohol intake - Make sure they are exercising and having a healthy diet Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 Week 9 Lectures - Gastrointestinal Constipation Normal stools - Type 1 through type 7 - 3-5 ideal and normal - 6-7 diarrhoea - 1-2 constipation Normal is individualised - 3 times a day to 3 times a week - Anything 24 hours apart - ONE unprovoked (or reflex) seizure and the risk of further seizures - Diagnosis of an epilepsy syndrome Cant have epilepsy without a seizure, but can have seizures without epilepsy - Seizures must be unprovoked or recurrent to be consistent with epilepsy Seizure following concussion or alcohol withdrawal - Provoked & isolated Seizure following a stroke - Unprovoked and high risk of recurrence Seizures; - Transient occurrence of signs/symptoms due to abnormally excessive or synchronous neuronal activity Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Caused by uncharacteristic excitation of neurons or clusters firing at the same time Seizure threshold (how susceptible to seizures) - Upper limit of neuronal activity your brain can handle - If it surpasses threshold, seizure will occur - Standard threshold - very unlikely to occur People with epilepsy have naturally lower thresholds Factors to lower threshold (in people with epilepsy and without); - Pharmacological substances - Sleep deprivation - fasting/malnutrition - Fever - Psychophysiological stress - Menstruation Also get factors to RAISE seizure threshold - This is how antiepileptics work - Reduce predisposition to seizure When seizing, start with classification which can be; - Focal - Specific group of neurons - Additional classifications include; - aware/impaired awareness - Motor onset/non-motor onset - Focal to bilateral tonic-clonic - Generalised - Affects both hemispheres - Generalised onset - Additional classifications; - motor/non-motor - Unknown onset - Additional classifications; - motor/non-motor - unclassified Epilepsy is an umbrella term for categorising different diseases or syndromes of the brain - Classification systems; - 1st step - classifying seizure types - 2nd - epilepsy type - 3rd - epilepsy syndrome - 4th - aetiology - 5th - comorbidities Pharmacological interventions Goals of therapy are; - Suppress seizures - Avoid adverse effects Fine line of risk vs benefit - Extremely complex area of medicine Very complex group of drugs; Downloaded by Danie Danie ([email protected])  lOMoARcPSD|48481542 - Barbiturates, benzos or other antiepileptics - Really drugs don't naturally fit into classes - Individual drugs with their own indications, mechanisms, interactions and effects 3 major pathways of drugs mechanisms; - BLOCK sodium voltage gated channels - BLOCK calcium voltage gated channels - Enhancing GABA inhibitory effects - Try REDUCE synchronous firing or excessive excitation by reducing neuron communication - We are increasing the seizure threshold Voltage-gated sodium channel blockers - Carbamazepine - Prevents excessive neuronal communication through inhibition of voltage gated sodium channels - ADRs; - LOTS of ADRs and some very serious - Need lots of monitoring - String CYP inducer - many interactions (drug-drug, drug-food, drug-herbal) - Not everyone that uses carbamazepine has epilepsy - Management of pain and bipolar disorder Voltage-g