Kinetic%20

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Kinetic Dynamic in Poisoning

• YC Chan

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The Dose Makes The Poison

• What is there that is not poison? All things are
  poison and nothing is without poison. Solely
  the dose determines that a thing is not a poison

Philip Theophrastus Bombast von Hohenheim aka
PARACELSUS (1493-1541)
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Our Body Defines The Poison

• Things are poison
• if our body do something on it (kinetic)
• and the thing do something on us (dynamic)

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Why Do We Need To Know?

• Basic science principle
• Understanding why
• More easy to memorize stuffs
• Clinical application
• Guide our management decision
• From principle
• Help us to make tough call
• Especially in unstudied situation

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What Do We Need To Know?

• Everything , ideally but Impossible

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In Real Life

• We are clinicians, not scientists
• Just some basic
• Relevant to our clinical practice

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ToxicoKinetic

• 1st step of toxicity
• 4 basic steps
• Absorption
• Distribution
• Metabolism
• Elimination

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Compartments

• Our body
• Compartments
• Membrane
• Special barriers
• BBB
• Placenta

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Transfer Between Compartments

• Diffusion
• Size
• Lipophilic Vs Hydrophilic
• Charge or not/pH
• Protein bound
• Follow gradient

• Active Transport
• Can against gradient
• Used up energy
• More Specific
• NaK ATPase
• G-glycoprotein

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Disclaimer PK data

• From therapeutic range data
• Few from overdose
• PK is usually different in OD situation
• We are all different
• Pharmacogenetic

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Absorption

• Route of exposure
• Ingestion
• Inhalation
• Dermal
• Bioavailability (F)
• Absorption Vs Pre-systemic elimination
• Vmax/Cmax

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Delay Absorption

• Simply not dissolve
• Full stomach
• Enteric coated, SR preparation
• Stick together
• Aspirin, Fe
• Gut slow down
• Anticholinergic
• Opioids

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Distribution

• Compartments Model
• Volume of distribution
• Protein Bound
• Redistribution
• Therapeutic drug monitoring

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Compartment Model

• One Compartment
• Two Compartment
• Digoxin, Li
• Three Compartment
• Lead

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Volume Of Distribution (Vd)

• Concentration (mg/L)
• Dose (mg) X Bioavailability
• BW (kg) X Vd (L/kg)
• Cautious on units

• Expressed in L/kg
• Small lt 1L/kg
• Stay in blood mostly
• Large gt 1Lgtkg

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Protein Bound

• Albumin others
• Saturation in overdose situation
• Displacement
• Potential interaction
• Bound-toxicants
• NOT able to pass barrier
• NOT active
• Confused the level

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Redistribution

• Equilibrium shift
• Environment of different compartments change
• Rebound
• Li after HD
• Fat loss
• Superwarfarin toxicity

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Limitation Of Drug Level

• Measure one compartment only (plasma)
• Usually not well correlated to clinical toxicity
• Time of sampling is crucial
• Usually measure the total drug
• Bounded (inactive) and Unbounded (active)

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Metabolism

• Biotransformation
• Phase I
• Phase II
• Facilitate the elimination
• Result in
• More toxic Try to block it !
• Less toxic Try to enhance it !
• Inactive metabolites

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ADH
ALDH
Methanol
Formate
Formaldehyde
FOLATE

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Metabolism Kinetic

• Zero order kinetic
• Ethanol
• 15-20 mg/dl/hr
• 1st order kinetic
• Most drugs
• T1/2
• Michaelis-Menten Kinetic
• Phenytoin

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Elimination T1/2

• 1st kinetic order only
• Five T1/2 3.125 of the initial dose
• May be different in overdose situation
• Only measure the parent compound
• Not the metabolites
• Not necessarily Duration of action
• May have active metabolites
• Mellanby Effect
• Redistributed out of target organ

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Cytochrome P450

• Polymorphism
• Major risk area for ADR, Interaction
• Important Subtypes
• 1A2
• 2C9,2C19
• 2D6
• 2E1
• 3A4
• Cimitidine

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Metabolic Pathways of Codeine Biotransformation
Gasche, Y. et al. N Engl J Med 20043512827-2831
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Elimination

• Renal
• Hepatobiliary
• recirculation
• Lung
• Sweat/hair

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Enhanced Elimination

• Alkalinization of Urine
• Haemodialysis
• Charcoal Haemoperfusion
• Exchange Transfusion
• MDAC

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Alkalinization Of Urine

• Enhanced elimination by ion trapping
• Acid ONLY

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Considerations

• Haemodialysis
• Size lt 500 dalton
• Vd lt 1L/kg
• No/Low protein bound

• Charcoal HP
• Vd lt 1L/kg
• Affinity to Charcoal

• Exchange Transfusion
• Vd lt 1L/kg

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ToxicoDynamic
TD actions
Clinical effects

• Ultimate toxicants

Target Site
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Target site

• Specific
• Most therapeutic drug have a specific site
• Non specific

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Specific

• Receptors
• Agonist Vs Antagonist
• Competitive Vs Non-competitive
• Ion channels
• Na, K, Ca, Cl
• Open or Close
• Enzymes
• Inhibit or Enhance

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TD action

• Dysfunction or Destruction
• Common mechanism
• Over or under of existing regulatory systems
• (ANS, Inhibitory Vs Excitatory Neurotransmitter)
• Failure to maintain bio-environment
• Failure of energy supply
• Failure of gene regulation and expression

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Receptors Site (major) Agonist Antagonist
Adrenegic a1 Vascular smooth muscles Noradrenaline Indirect Cocaine, Ampethamine Phentolamine
Adrenegic ß1 Cardiac Adrenaline Indirect Cocaine, Ampethamine ß blocker
Dopamine CNS Vascular smooth muscles Bromocriptine Indirect Cocaine, Ampethamine Antipsychotic
Serotonin CNS, Peripheral Ergots, Methamphetamine Indirect SSRI Atypical antipsychotic
Ach muscarinic CNS, ANS Pilocarpine Indirect - Cholinesterase inhibitor Atropine
Ach nicotinic CNS, skeletal muscle Nicotine Indirect - Cholinesterase inhibitor Erabutoxin (Snake Venom)
Adenosine CNS, Cardiac Vascular smooth muscles ATP Methylxanthines
Opioid CNS, viseral neurons Morphine Naloxone
GABAA CNS Indirect - Ethanol, BZO Penicillin Indirect - Flumazenil
Glycine Spinal cord, CNS Taurine Strychnine
Glutamate CNS NMDA Ketamine, Mg, Propofol
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Ion Channels Site (major) Opener Blocker
Voltage-gated Na Channel Neurons Cardiac Muscle Aconitine Ciguatoxin Na channel blocking drugs Tetrodotoxin Saxitoxin
NaK ATPase Every cell Digitalis
Potassium Channel Ikr Cardiac Sotolal QTc prolonged drugs
Ca Channel (L type) CNS, Peripheral Ca Diltiazem Verapermil Nifidipine Pb
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Enzymes Enhancer Inhibitor
Glutamic acid decarboxylase (GAD) VPA Gabapentin INH
Pyridoxine Phosphokinase (PP) INH
Cytochrome C oxidase CN, CO, H2S, Formate
Pyruvate dehydrogenase complex (PD) Thiamine Ar
Cholinesterase OP
Vit K Reductase Warfarin
? Amniolevulinic acid dehydratase(ALA) Pb
Multiples Enzymes Heavy Metals
Angiotensin Converting Enzymes (ACE) ACE I
Monoamine Oxidase (MAO) MAO I
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Non-specific Site

• Harmful thru chemical and physical properties

Mechanism Example Toxicity
Physical Effect Dry Ice Hypoxia
Physical Effect Ca oxalate Renal tubules obstruction
Electrophilic NAPQI Cell necrosis
Free radical Paraquat Lipid perioxidation
Redox Reactant Dapsone Met-Hb
Redox Reactant Ethanol Impaired gluconeogenesis
Nucleophilic Fluoride Binds Ca
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Clinical Effects

• Acute toxicity
• lt24 hours
• Subsequent toxicity
• gt24hours
• subacute chronic

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Acute

• CNS
• Too high or too low
• Seizure coma death
• Cardiopulmonary
• Arrhythmias
• Hypo/Hypertension
• Hypoxia/Hypoventilaion
• Metabolic
• Failure of energy production
• pH, e-
• Falling Apart

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Subacute Chronic

• Organ Failure
• Liver
• Renal (Pre, ATN, Post)
• Marrow
• Carcinogenesis
• Terarogenicity

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Thank You