Pathophysiology and Pharmacology Lecture 1

Patho & Pharmacotherapeutics lecture 1 - review Readings: see class schedule on eclass Associate Teaching Professor Helena Schaefer, MN H. Schaefer MN resources • Eclass • Announcements • Power Point is a guideline ONLY • • • • • Course outline • Lecture materials: • learning outcomes • power point presentation • • not my every word hand written note taking enhances learning and retention by intensifying the CNS synapse junctions add to your class notes during study time • • • Ask a question forum • helenas@ualberta.ca • Only if sharing confidential information • Allow 2 school days for e-mail response. • Subject line: N216A ….. (subject) • UofA email etiquette to be observed units/chapters resources are posted in the course outline add/write your own notes during lecture time E.g. diagrams, tables, charts, concept maps, … avoid rewriting the textbook, rather highlight key points and insert them into your existing notes on that topic you are responsible for your own work: self directed and independent • Recordings of class material are not permitted (as per University of Alberta St udent code of conduct) • Testable material: • • H. Schaefer MN Lecture depth Critical thinking – linking knowledge together How to use concepts, e.g.: main concept eg. in red – e.g. abdominal pain related concepts - e.g.in purple, a result of critical thinking (linking your knowledge) Patient Health/illness Health/illness Health/illness Health/illness Nursing/health care Development Fluid & Electrolyte Nutrition Mobility Mood & affect Professional identity Communication Functional ability Acid-base balance Perfusion Tissue integrity Anxiety Care HC coordination organizati on Collaboration Caregiving HC economics Family dynamics Thermoregulation Gas exchange Sensory perception Cognition Clinical judgement Culture Sleep Clotting Pain Psychosis Leadership Safety Spirituality Cellular regulation Reproduction Fatigue Addiction Palliative Care Health Policy Ethics Technology & informatics Health Disparities HC law Patient education Evidence Health promotion Health care quality Adherence Self Management Intracranial reg. Hormonal reg. Sexuality Immunity Glucose reg. Inflammation Elimination Infection Stress Coping Interpersonal violence Pharmacotherapeutics: 3 categories: 1) Drug/Medication = a chemical agent, synthetically produced 2) Biologic = a medication produced from living organisms or containing components of living organisms, like proteins, cells, or tissues e.g. antibodies (e.g. immunoglobulins), blood products (e.g. RBCs), hormones (e.g. Insulin) 3) Natural health product (NHP) = sourced/derived from nature (e.g. plants) e.g. vitamins, minerals (e.g. Calcium), dietary supplements (e.g. whey protein), dried herbs (e.g. echinacea) H. Schaefer MN Pharmacotherapeutics: each drug has a drug name: • 3 types of drug names: • Generic • • • • • describes the drug without a proprietary affiliation assigned (international non-propriatary name) same throughout the world 1 generic name per drug on NCLEX exam • Brand/trade • Named by the manufacturing company • Many trade names per one generic drug • Often the drug 1st to market, patent protected for 20 years prior to other manufactures • Chemical – the chemical composition is the drug name • Assigned by IUPAC (international union of pure and applied chemistry) • E.g. Potassium Chloride Drug Names: Ibuprofen & like What is the trade name? What is the generic name? H. Schaefer MN Drug schedules: who can dispense? Table 2.4 Schedule System for drugs Sold in Canada Schedule I Available only by prescription and provided by a pharmacist; includes all of the following •All prescription drugs •Drugs with no potential for abuse •Controlled drugs •Narcotics Schedule II Available only from a pharmacist (pharmacist Rx); must be retained in an area with no public access. Schedule III Available via open access in a pharmacy or pharmacy area (OTC) Unscheduled Can be sold in any store without professional supervision. H. Schaefer MN use the NURSING PROCESS • CHECK PATIENT, always: • • • • ASSESSMENT: health hx, chief concern assessment (S&S assess) PLANNING INTERVENTION: pharmacotherapeutics & patient education EVALUATION (includes assessment of drug action & drug effects + side effects) =NURSING PROCESS ! always include patient education in your nursing care H. Schaefer MN Drug formulations…. why so many & so many admin. routes? Factors: ▪ Clinical setting ▪ Medical situation ▪ Drug properties: stability of the drug & its metabolism drug needs to reach target tissues Clinical EXAMPLE: next slide H. Schaefer MN example • A 72 year old patient has been in pain due to an invasive malignancy. Takes Hydromorphone (Dilaudid), 4 mg PO, q4h. • With advancing disease, the patient is increasingly more somnolent. What change should be made to the above drug order, in regards to the formulation? Administration routes: e.g. • • • • • • • • • • • • • • Oral (PO) + via inserted tubes: NG, NJ, … Sublingual (SL) Intranasal (insufflation) Inhalation + via ET tube Topical Intravenous (IV) Intramuscular (IM) Subcutaneous (SC) Transdermal Rectal (PR) Implanted ports Vaginal Intraosseous Epidural + Spinal (intrathecal) • terminology: parenteral vs enteral H. Schaefer MN 11 activity • Turn to your classmate and review 2-3 main points regarding the various administration routes. • E.g. sublingual = SL • placement is sublingual (under the tongue) • capillary absorption directly into circulation (no GI, no 1st pass effect) • systemic effect achieved 10 rights of drug administration (Adam’s text: pg. 86-94) • RIGHT • • • • • • • • • • Drug Patient Dose Route Time (delivery & frequency) Documentation History & Assessment Informed consent (right to refuse) Interactions evaluation Education & Information PKPD • Pharmacokinetics ‘PK’ • ‘pharma’ = medicines & ‘kinetics’ = motion • movement across cell membranes via lipid bilayer • ADME: Absorption, Distribution, Metabolism, Excretion • Pharmacodynamics ‘PD’ • receptor binding & affinity (saturable, competitive) • E.g. G-protein receptor • increases OR suppresses existing processes • antagonist - only blocks the receptor, no efficacy H. Schaefer MN 14 Affected by: • molecular characteristics (mc) • Charge (ionization) • neutral atoms or molecules converted to electrically charged ones = “ionized” (polar): positive or negative • non-ionized = not charged (aka non-polar) • Lipophillicity vs hydrophilicity • Size • membrane transport • Passive = diffusion; osmosis; facilitated diffusion • Active H. Schaefer MN 15 H. Schaefer MN ADME general rule: • lipophilic, non-ionized, small = easy A&D hydrophilic, ionized = easy E • A=drug into circulation (bioavailable): route & mc • D= transport through the body to target tissues: blood flow, tissue size, mc, PPB • M=prepares drug for excretion/activates prodrugs; liver • E = excretion; CrCl; 1st order vs 0 order kinetics H. Schaefer MN 17 Metabolism: ‘First-Pass’ metabolism THERAPEUTIC RANGE graph e.g.: Single-dose drug administration: pharmacokinetic values for this drug are as follows: onset of action = 2 hours; duration of action = 6 hrs; termination of action= 8 hours after administration; peak plasma concentration = 10mcg/ml; time to peak drug effect = 5 hours H. Schaefer MN 19 TI: avoiding the Toxic range or a Toxic dose how safe is a drug? • ED 50 = median therapeutic dose • TD 50 = ‘median toxicity dose’ • 50% of pts - a toxic response • derived from LD 50 lab data (LD = lethal dose in lab trials) • the ratio between TD50 : ED50 = TI THERAPEUTIC INDEX • smaller number = higher risk • Narrow TI meds: • • • • Digoxin (Lanoxin) Warfarin (Coumadin) Phenytoin (Dilantin) Tacrolimus (Prograf, Astagraf) Helena Schaefer MN 20 Distribution: PPB explained • cohesion (‘binding’) with plasma protein molecules • drugs have varying ‘affinity’ for plasma carrier proteins • e.g. plasma proteins • Albumin = acidic drugs • Alpha-1-acid glycoprotein = basic drugs • binding decreases distribution rates • Competitive, Reversible, Saturable • Unbound drugs - effective • Bound drugs – NOT effective H. Schaefer MN 21 Recall the clinical example of PPB & 99% PPB drug Warfarin (Coumadin) - Warfarin: an anticoagulant drug which is highly effective in reducing blood coagulation - 99% PPB, means _____% free drug - why is PPB ‘beneficial’? - if PPB decreases by as little as 1%, how much more Warfarin is free? - is this technically an overdose? - what effect will this have on the patient? Metabolism (aka biotransformation) an enzymatic chemical conversion to prepare the drug/substance for excretion -termination of drug action (yields metabolites for excretion) -prodrugs require metabolism for activation LIVER – primary metabolizing organ (others: lungs, kidneys, …); ‘ionizes’ drugs (for better excretion) Phase I - via hepatic microsomal enzymes ‘CYP450 group’; saturable & dynamic (inducers & inhibitors) E.g. CYP3A4, CYP1A2 Phase II – only some drugs; e.g. conjugation E.g. glutathione conjugates Tylenol’s toxic metabolite (nacetyl-p-b) Biotransformation: active drug to inactive metabolite active drug to active metabolite (requires further metabolism to eliminate) inactive drug to active metabolite (‘prodrugs’) note: PO drugs -portion is ‘First pass’ metabolized (as per above) note: some drugs travel ‘unchanged’ (e.g. Amoxicillin) H. Schaefer MN 23 Recall the clinical example of Grapefruit juice & Lovastatin - Lovastatin: a cholesterol reducing drug - Lovastatin is CYP3A4 metabolized - Grapefruit juice is a CYP3A4 inhibitor - what does ‘inhibition’ of a metabolizing enzyme mean? - what will happen to the metabolism of Lovastatin, if its metabolizing enzyme is inhibited? - what will this cause in the patient? Factors Affecting Renal Excretion • Molecular characteristics: ionization, hydrophilicity, small size • PPB ? • Metabolized ? • Urinary pH ? • Medically altered to excrete specific drugs e.g. ASA excretion in OD • Cardiac Output • renal blood flow • Renal fx: • 1%/year decline in the elderly • neonates & young infants • integrity of the glomerulus – renal disease H. Schaefer MN 25 Clearance (Cl) ‘RATE OF ELIMINATION of drug in an hour’ • 1st order elimination kinetics • elimination proportionate to the drug serum concentration • Drug plasma concentration mg/dL or L • Calculated: • Cl = elimination/peak plasma concentration • (total amount of urine voided in an hour:peak plasma concentration of drug) • => mg/dL/hr or mg/L/hr • Zero order elimination kinetics • rate of elimination or ‘clearance’ is constant • E.g.: ethanol, aspirin (ASA), phenytoin (dilantin) • • H. Schaefer MN 26 Excretion: Renal function in clinical practice GFR calculation (normal >59 ml/min) • Creatinine – bloodwork lab results • Clearance – requires calculation a case • ETOH: why 10 shooters within 1 hour can cause ETOH poisoning? • CNS effects drug-dose dependent • GABA agonist & Glutamate inhibitor => calming • 1-2 drinks = 20-30 mg/dL (in serum) • Liver & GI metabolized by: alcohol dehydrogenase • Clearance rate = 20 mg/dL/hr • Inhibits ADH => diuresis (dehydration, electrolyte imbalances) • ETOH poisoning: ER admissions average = >295 mg/dL Note: Breathalyzer result x 1000 for mg/dl half-life (t ½) time required for a drug plasma concentration to decrease by one half (by `50%) • circulating drug is continuously biotransformed for excretion • if ‘unchanged’ => biotransformation not required • circulating biotransformed drug is continuously excreted with each CO • t1/2 is: • calculated & known per each drug • broad guideline to estimate frequency of administration • 4x t1/2 = 90% of the drug has cleared H. Schaefer MN 29 Pharmacodynamics: Terminology • Receptor Affinity • ‘strength’ of binding or ’length’ of binding • is: specific, saturable, reversible • Drug Efficacy • effectiveness • Degree to which a drug induces maximum therapeutic effect • E.g. Motion sickness nausea – Gravol; chemo tx nausea – Ondansetron • Note: antagonists have no efficacy (only block receptor) • Potency = strength • How much of the drug is required! Amount! • Eg. Drug A 20 mg & Drug B 10 mg = Drug B potency is higher! Helena Schaefer MN 30 Drug-receptor interactions: • Agonist: ‘primary’ or ‘full’ • binds readily & mimics an endogenous substance • Eg. Morphine • Partial Agonist • maximum response is smaller even if all receptors occupied = lower efficacy (note: can interfere with agonists’ binding) • E.g. Buprenorphine • Inverse agonist • induces the OPPOSITE effect of the naturally binding substance (adenosine) • E.g. caffeine • Antagonist • ‘blocks’ the receptor to prevent endogenous or endogenous-like substance’s binding; requires higher affinity than the agonist • No therapeutic effect other than to receptor block • E.g. Naloxone (Narcan) Helena Schaefer MN 31 pharmacotherapy effects on populations • E.g. older adult • • • • • Decreased peristalsis, acidity, elimination, GFR Decreased liver fx Lower albumin (affects PPB) Decreased CO (affects distribution) Polypharmacy • Eg. Pediatric • Dose per kg • More adipose tissue/kg – lipophilic drugs? • Immature liver fx until later teens • Pregnancy: most drug cross the placenta; maternal drug concentration determines degree of effect on fetus PD & drug tolerance • Tolerance (aka Down-regulation) • most common • receptor de-sensitization OR decreased number of viable receptors to a substance • => more drug required for same response • E.g. addictive substances (opioids, benzodiazepines, alcohol…) • Note: other kinetic alterations may develop forming a resistance • E.g. increased drug metabolism d/t increased demand for it => drug metabolized too fast & not effective Helena Schaefer MN 33 factors influencing patient response Helena Schaefer MN 34 H. Schaefer, MN Toxicity Drug effects undesirable Non-deleterious (side effects) therapeutic Deleterious TOXIC H. Schaefer MN Toxicities: most common • ASA (Aspirin) • Tylenol (Acetaminophen) • Opioids • Oxycodone, Fentanyl • Benzodiazepines • Xanax (alprazolam), Valium (diazepam) • Alcohol (ETOH) • THC • Cocaine • Medication errors ! H. Schaefer MN Clinical procedure in toxicity (overdose): ‘stabilize & analyze’ A & B assess patency, effort, rate, colour • ET tube insertion? • O2 ? C assess perfusion quality e.g. LOC, pulses, skin, BP • IV fluids? • Sympathomimetics ? D assess for dysfunctions & treat as needed • e.g. apnea, seizures, cardiac arrhythmias, hyperthermia E identify the drug/substance & initiate treatment H. Schaefer MN 1. Identify drug/substance patient’s Health History physical assessment of S&S, using a clinical tool: ‘toxidromes’ don’t make assumptions, assess the patient! Lab toxicology (urine, serum) • ASA • • • • • • • Acetaminophen Confusion Tachycardia Tachypnea Hyperthermia Diaphoresis Vomiting • • • • • H. Schaefer MN Abdominal pain Loss of appetite Nausea/vomiting Diaphoresis Somnolence Toxidromes cont. • Opioids (Fentanyl, Codeine, Morphine, Oxycodone, Heroin, ….) • • • • • Cocaine (& other stimulants) • • • • • • Bradypnea/Apnea Bradycardia Somnolence/Coma Pupils constricted H. Schaefer MN Agitation, tremors Tachycardia Tachypnea Hyperthermia Diaphoresis Pupils dilated Cannabis toxicity & toxidrome: • Neurocognitive effects, variable presentation: • • • • VS changes (tachycardia, hypertension) seizures nausea/vomiting acute psychosis • LOC changes: agitation; coma • Route of admin: • inhalation – 15-30 min onset, bioavailability 50% • PO - 1-2 hr onset (variable), bioavailability 20% • THC & CBD • THC causes CNS & VS instability • CBD modulates effect of THC at receptors • Tx: supportive review of ADME as tx of common toxicities: • stabilize patient with supportive tx • Adsorption: ‘binding of drug, to decrease its absorption’ • e.g. Tx of toxicities: Tylenol, ASA, Benzodiazepines • Tx drug: Activated Charcoal, enteral administration • Binds drug to surface carbons; elimination via stool • Metabolism: induction of metabolism • Tx of Tylenol toxicity: depleted liver enzyme Glutathione, causes low phase II metabolism thus accumulation of hepatotoxic phase I product: NAPB • Tx drug: NAC (n-acetylcysteine/acetylcysteine), IV, PO: Glutathione enzyme precursor • enhances phase II metabolism • Tx of ETOH intoxication: depleted alcohol dehydrogenase • Tx drug: Metadoxine, IV • induces alcohol dehydrogenase Algorithm e.g: Details are FYI, critical thinking is testable • https://emedicine.medscape.com/article/820200-treatment • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2637612/ H. Schaefer MN • Distribution: blocking the tissue receptor • Tx of opioid toxicity; antagonism at mu & kappa receptors • Tx drug: Naloxone (Narcan) • onset – 2-4 minutes • duration of action = 45 min • Tx: benzodiazepine toxicity; GABA receptor antagonist • Tx Drug: Flumazenil, IV • Elimination: stool, urine, blood • In the GI tract: Activated Charcoal increases GI elimination of charcoal-bound drug • In the kidneys: alkalization to induce acidic drug excretion • Tx drug: Sodium Bicarbonate • ionizes an acidic substance • E.g. Tx of ASA toxicity • In the blood: Hemodialysis • active removal from blood H. Schaefer MN Brainstorm: What would the effects of administering Narcan to a patient receiving opioids for therapeutic reasons be? Why is the duration of action of drugs so important? What could decrease the efficacy of Narcan? An apneic patient is given Narcan, IN (intranasal). Will it be effective? Homework, testable: • Review the main functions of the liver • List 5 major issues if the liver is compromised: • What would you note on patient assessment?