Lecture 2 CSB601 2021 QUT Brisbane, Semester 2 PDF

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Health practitioners play a variety of roles in relation to drug therapy for improved health outcomes in patients. Depending on your scope of practice with patients you care for, you might prescribe, dispense, administer or review and evaluate the effects of medicines. In order to assume these roles...

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Lecture 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 recipients) - 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 implicated - E.g warfarin - 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 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) - 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 -

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 - 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 Clearance =

Cu x Vu

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 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 -

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 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...