Pharmacokinetics 1

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  • Created by: LBCW0502
  • Created on: 16-01-18 16:14
What is pharmacokinetics (PK)?
The mathematical description, prediction and understanding, of the time-course of drugs (and their metabolites) in the body (study of what the body does to the drug)
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What is pharmacodynamics (PD)?
The study of the biochemical and physiological effects of drugs and the mechanism of their actions on body (study of what the drug does to the body)
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What is ADME?
Absorption, distribution, metabolism and excretion (describes the deposition of a pharmaceutical compound within the body)
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What is LADME?
Liberation, absorption, distribution, metabolism, excretion (determine factors which influence onset intensity and duration of action of a drug)
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What is clinical PK?
Use of PK principles to enhance safe and effective management of the patient
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What are the three terms in PK models?
Prediction, observation and simulation
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What are the three types of modelling?
Empirical (use of mathematical equations), physiological (major tool for prediction of in vivo PK from in vitro data) and compartmental (number of compartments defined by concentration over time data)
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What is the difference between one compartment and two compartment models?
One compartment assumes drug is distributed fully throughout body. Two compartment assumes simple model of drug absorption and elimination
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Describe features of one compartment IV bolus
Drugs initially distribute into a central compartment (Vc) before distributing into peripheral compartment (Vt). If drug rapidly equilibrates with the tissue compartment, then a one compartment model is used (one volume term/apparent Vd)
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Give an example of a drug in a one component model
Aminoglycosides (distribution phase 15-30 mins)
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Give an example of a drug in the two compartment model
Vancomycin (distribution phase of 1-2 hours with more accurate concentration-time curve in this model)
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Why is ADME and PK important (4)?
To prevent negative patient outcomes, ignorance leads to 'drug disasters' (e.g. Multaq dronedarone), primary cause of withdrawal of drugs, a prominent component of marketing strategy
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Give examples of preventable negative patient outcomes, PNPO (7)?
Unnecessary drug therapy (drug without indication), improper drug selection (wrong medication), sub-therapeutic dosage, over-dosage, adverse drug reaction, drug interactions, failure to take/receive drug (inappropriate compliance) - high cost
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Give an example of a drug on market with serious side effects
Zocor (simvastin) is a cholesterol lowering drug that has been linked to rhabdomyolysis and myopathy (muscle injuries). Other serious side effects include kidney failure, liver problems and interstitial lung disease, ILD
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What are the indications for Multaq?
Treats abnormal heart rhythm
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What are the side effects of Multaq?
Liver failure, stroke, heart failure, serious cardio vascular events (death), lung disease (pneumonitis and pulmonary fibrosis)
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Which questions can be answered with PK information about a drug?
Is the drug effect by mouth? Which organs is the drug exposed to? How long does it stay in the body? How is drug removed? What influences handling? Route of administration? Dose? Formulation? Drug interactions?
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Drugs act on which specific proteins at the cell membrane?
Receptors (enzymes, transporters, transmitters)
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Give an example of medicines which do not act on proteins
Anti cancer drugs act on DNA
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What is an agonist?
Direct receptor action. Stimulatory response is opening ion channel, activation G-protein, activation of an enzyme
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What is a partial agonist?
Drug binds to receptor but low efficacy (activity depends on dose and recipient)
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What is an inverse agonist?
Little receptor activation but not altogether absent activity is depressed
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What is an antagonist?
Drug binds to receptor but does not produce response. May be competitive reversible antagonist, competitive irreversible antagonist or non-competitive (ion channel blocker)
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Give examples of clinically useful agonists (3)
Salbutamol beta 2 adrenoreceptor agonist used to treat asthma. Morphine opioid Mu receptor agonist used to treat moderate/severe pain. Ropinirole D2 dopamine receptor agonist used to treat Parkinson's Disease
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Give examples of clinically useful antagonists (3)
Naloxone (reversible competitor/opioid receptor, reverses heroin overdose). Flumazenil (reversible competitor/benzodiazepine receptor, reverse effects anaesthesia/sedative effects of benzodiazepines). Ketamine (anesthesia, non-competitive, glutamate)
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Give an example of a drug that acts to inhibit enzymes
Disulfiram/antabuse. Aldehyde dehydrogenase is a polymorphic enzyme responsible for oxidation aldehydes to carboxylic acids, which leave the liver and metabolised bu muscle and heat (types of enzymes - ALDH1, 2 and 3)
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What is Asian flush/Oriental flushing syndrome?
ALDH2 maintains low blood levels of acetaldehyde during alcohol oxidation. Intermediate structures can be toxic/damage health. High blood levels of acetaldehyde can cause facial flushing, headaches, palpitations, light headedness/ hangover symptoms
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What is the disulfiram treatment?
ALDH2 inhibited by disulfiram. Prescribed to abstinent alcohol dependent people. High levels of acetaldehyde (drinking during treatment) leads to illness. Several drugs (antibiotic metronidazole) cause a similar disulfiram-like reaction
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Give the stimulating PD effects of psychoactive drugs (8)
Speed up body mechanisms, increase heart rate/blood flow, respiratory rate increased, BP raised, increase attention span, increase ability to focus, increase ability to concentrate, increase alertness
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Give the depressing PD effects of psychoactive drugs (7)
Slow down body, decreased heart rate/blood flow, respiratory rate depressed, analgesia, sedation, peacefulness, decrease alertness
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Why is PK and PD important in addiction (4)?
Addicts use drug doses much higher than safe recommended levels, no quality control of material (issue with purity), poly drug use and interactions, lack of adherence to any regimen
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What is therapeutic drug monitoring (1)?
The way in which we use PK and PD to optimise drug therapy for individuals
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What is therapeutic drug monitoring (2)?
The use of drug concentrations, PK principles and PD factors to optimise drug therapy in individual patients
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What shape is line on a concentration-time graph for IV administration?
A curve which slopes downwards
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What shape is line on a concentration-time graph for oral administration?
Curve moves upwards, reaches a peak then slopes downwards
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When the curve on a concentration-time graph is moving upwards, what does that mean?
Ka > Ke
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When the curve on a concentration-time graph reaches a peak, what does that mean?
Ka = Ke
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When the curve on a concentration-time graph slopes downwards, what does this mean?
Ka < Ke
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Which type of drugs require TDM?
Drugs which possess a narrow therapeutic index, poor correlation between dose and effect, good correlation between serum concentration and effect, wide inter-patient variation in clearance, influenced range of diseases, management
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What does Css mean?
Steady state plasma concentration
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Give examples of drugs requiring routine monitoring
Aminoglycosides (antibiotic/gentamicin), cardiac glycoside (atrial fibrillation/digoxin), phosphodiesterase inhibitor (asthma/threophylline), anticonvulsants (epilepsy/carbamazepine phenytoin), antipsychotics (mania, bipolar disorder/lithium)
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What is the toxicity profile for digoxin?
Nausea, vomiting, anorexia, bradycardia, ventricular arrhythmias
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What is the toxicity profile for theophylline?
Link to degree of accumulation
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What is the toxicity profile for phenytoin?
Nystagmus, ataxia, lethargy, gingival, hyperplasia, osteomalacia
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What is the toxicity profile for lithium (life threatening > 3.5 mmoles/L)
Vomiting, diarrohea, anorexia, muscle weakness, ataxia, drowsiness, tremor (extremities and jaw), seizures, renal failure, dehydration, circulatory failure, coma
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What is the toxicity profile for carbamazepine?
GI distress, hyponatremia, diplopia, dizziness, osteomalacia, hepatitis
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Describe the association between theophylline serum concentrations and toxicity
>10 (nausea, insomnia, headache, nervousness/minor, mainly transient), >20 (nausea vomiting diarrhoea, insomnia, irritability, headaches, tremor/potentially serious), >35 (cardiac arrhythmias, cardio-respiratory arrest, seizures, death/life threat-)
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