15) Drug Monitoring In Clinical Toxicology (Bentur)

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Poison

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-any substance injurious to health/dangerous to life

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Toxin

Back 2

-a toxin whose origin is from cells, tissues or extracellular (i.e., from within the body)

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Poisoning

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-the health effects applied by a toxin/poison

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Antidote

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-an agent that counteracts or neutralizes a poison

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Toxicology

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-the science of poisons, their antidotes, and their effects

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How do patients get poisoned from medications?

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Most cases are UNINTENTIONAL (prescription error, dispensing error, administration error, misunderstanding/non-compliance, etc). Only 10-15% of poisonings are INTENTIONAL.

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Pharmacokinetics vs. Toxicokinetics

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PHARMACOKINETICS is the study of drug behavior, absorption, metabolism, and excretion. It involves the use of mathematical models.

TOXICOKINETICS is the study of absorption, distribution, and excretion of XENOBIOTICS (= foreign chemicals that can be natural or synthetic) under EXTREME CONDITIONS (overdose, toxicity)

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Pharmacodynamis vs. Toxicodynamics

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PHARMACODYNAMICS studies the relationship between drug level and the clinical effects that the drug produces.

TOXICODYNAMICS is the relationship between toxic levels of a drug/xenobiotic and the clinical effects associated with this toxicity.

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What is 1st pass metabolism?

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It's the metabolism that most drugs undergo in the liver.

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Bioavailability

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= the % of the drug that reaches its target site (e.g., a bioavailability of 0.7 means that 30% of the drug was lost to 1st pass metabolism and did not reach the target site)

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What happens to a drug after it's absorbed? (2)

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1) ELIMINATION

2) (RE)DISTRIBUTION. What affects the distribution of a drug? It's LIPOPHILICITY. The more lipophilic a drug is, the more it distributes to the peripheral compartments. Other things affecting distrubtion include: i) Charge; ii) Size of molecule; iii) Perfusion of tissue

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Which drug concentration correlates with the maximal effect of the drug: CMax (plasma concentration) or TMax (tissue concentration)?

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TMax--- TMax (tissue drug concentration) correlates with the maximal effect of the drug, NOT peak blood concentration.

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Drug Distribution Diagrams

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You will usually see 3 phases in these linear graphs: 1st phase) Absorption--- in this phase, the graph goes up (plasma [drug]= Y-axis= increases); Peak) CMax (you get a peak at CMax, which is the maximal [drug] in the plasma); 2nd phase) DISTRIBUTION--- this is seen as a sharp drop/decline in the group; 3rd phase) ELIMINATION--- this is seen as a second, less sharp drop/decline

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****What is the only phase/instance in which we assume that the blood [drug] correlates with the tissue [drug]?

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In the ELIMINATION PHASE, when the blood concentration is at equilibrium with the tissue concentration!!!!

We can't do this in the distribution phase, only in elimination!!! If you sample too early (i.e. you take blood [drug] before you reach the elimination phase, your values will be too high and will be practically meaningless!!!!

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Uses of Therapeutic Drug Monitoring (TDM)

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-Aid optimizing drug therapy (drug-dose regimen)

-If pharmacologic effect cannot be measured directly

-If small margin of safety - low therapeutic index  low toxic / therapeutic concentration ratio

-Unpredictable variable pharmacokinetics

-Check compliance of patient with prescribed therapy

-Examples: carbamazepine, phenobarbital, phenytoin, valproic acid, theophylline, methotrexate, cyclosporin, digoxin, lithium, salicylates, amitriptyline

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Drug Monitoring in the Poisoned Patient

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Confirm / exclude clinical diagnosis of poisoning

Guide the management of confirmed poisoning  estimate onset, duration and severity of toxicity  assess need for antidotes, interventions  monitor effectiveness and duration of treatment  anticipate possible withdrawal reaction (ethanol)

Exclude toxic reason to psychiatric disturbance

Provide medicolegal documentation  brain death, child abuse, substance abuse, forensic

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Benefits of TDM

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-Reassurance (patient, caregiver)

-Feedback: accuracy of clinical decisions, clarify unexpected findings / outcome

-Documentation facilitate case studies (improved knowledge) document toxicodynamics 

- toxic concentrations-effects relationships are often incompletely defined

-Hypothesis testing

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Challenges to mathematical precision of toxicokinetics and toxicodynamics

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-Unknown variables (dose, ingestion time, vomiting)

-Atypical solubilities (slow release tabs.  concretions)

-Enzyme saturation 1st pass effect  absorption;elimination

-Altered protein binding (free fraction; phenytoin)

-Patient characteristics (age, gender, obesity, genetics, diseases, interactions)

-Effect of critical illness (compromised organ perfusion)

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Factors altering concentration-effect relationship: measuring [Drug]serum in absorption phase

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Effect: Underestimation

Examples: SR drugs; theophyllineDecr. solubility; salicylates
Decr. gastric emptying; TCA

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Factors altering concentration-effect relationship: Measurement of [Drug]serum at distribution phase

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Effect: Overestimation

Examples: Li, Digoxin

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Factors altering concentration-effect relationship: decr. Protein binding

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Effect: Underestimation

Example: Phenytoin

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Factors altering concentration-effect relationship: saturation of protein binding

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Effect: Understimation

Example: Salicylates, valproic acid

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Binding by antidote

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Effect: Overestimation

Example: Digoxin/digoxin antibodies

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Qualitative analytical techniques (urine)

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IMMUNOASSAYS-- *main analytical technique--- Problems/limitations: i) Cross-reactivity; ii) Depends on # of sample; Pros: i) Rapid

SREENING-- Limitations: i) is only used for a limited # of substances; ii) Lots of False Positvies/False Negatives; Pros: i) used to confirm/exclude diagnosis

THIN LAYER CHROMATOGRAPHY: i) low sensitivity/specificity; ii) Slow

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Quantitative analytical techniques (serum, plasma)

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-indicate severity

-may affect treatment (antidote, interventions)

-Slow

-may require Expensive equipment

-examples of drugs for which we use this: acetaminophen, salicylates, Li, anticonvulsants, digoxin, theophylline

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Toxicological Treatment Principles (4)

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1) Support of Vital Functions

2) Prevention of absorption (e.g., activated charcoal)

3) Elimination enhancement

4) Antidotes

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Volume of Distribution (Vd)

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-tells us to what extent the drug is distributed to the periphery; the higher it (Vd) is, the greater the extent to which the drug is distributed

-when you OD on a drug, it takes about 4x longer to reach peak drug levels (b/c you have a slower rate of disintegration <???>---- Note: maybe it's like when you have a supersaturated solution, it takes longer for all of the solute to completely dissolve)

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What happens when we OD on acitominophen (paracetamol, tylenol)?

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Toxic dose in children= 200mg/kg; in adults= 10g/kg

TMax- doubles---> from 0.5-2h to 4h

T1/2- quadruples--> from 1-2h to >4hrs

Manifestations= DELAYED HEPATOTOXICITY (24-48h)--- Normally, acitominophen is broken down in the liver by Cytochrome P450. Some of the metabolites are removed by the kidney, while others are converted by Glutathione to the metabolites: Free NAPQI (toxic--> hepatocellular damage) and NAPQI Conjugate (non-toxic). In OD, renal excretion remains unchanged while Cyt P450 and Glutathione levels decrease --> ACCUMULATION OF TOXIC FREE NAPQI--> these toxic molecules bind to liver, kidney --> HEPATOTOXICITY

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Histologically, what do we see in acitominophen-induced hepatotoxicity?

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Central-vein necrosis in the liver (most of Cyt P450 is located in the Zone 3 hepatocytes surrounding the central vein)

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Clinical phases of APAP (acetominphen) toxicity?

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After 24-48h, AST begins to rise and after day 4, it either goes down (recovery) or it stays high (if pt. goes into acute liver failure).

INR is another substance that's released during hepatotoxicity. It increases in parallel to the extent of liver damage.

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How do we assess if a treatment level/dose of acitominophen is toxic?

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We use the RUMACK-MATTHEW APAP NOMOGRAM, which is a risk assessment tool that compares the relationship between drug level (quantity of drug); time after exposure and hepatic outcome (AST >1000). It is only used for SINGLE ACUTE EXPOSURE, NOT in chronic exposures.

It is a linear graph represented by two lines, that have the same slope. The slope represents the Half-life of the drug in the pt's. Sometimes we use two parallel lines--- the lower line represents pt.'s for whom we aren't sure about the time at which they ingested the drug, while the top line represents pt.'s for whom we know at which time they ingested the drug. So if we have a pt. for whom we know when they took the drug, we use the top line; and if we don't know when they took the drug, we use the bottom line.

If a pt. falls above the line, then the dose is considered to be potentially hepatotoxic, while if they fall below the line, then the dose is considered safe.

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When can't we use an acetominophen nomogram?

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When the pt. has had repeated exposures--> use clinical judgement and supporting data to decide whether a dose is toxic or not.

We can see how the elimination half life is affected by taking a particular dose of acetominophen by taking the [drug] at t=0 (ingestion) and then taking the [drug] a few hours later and calculating the Elimination half-life to see if it is increased (and by how much).

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Manifestations of Digoxin poisoning

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-GIT, cardiovascular, incr. K

Treatment= Digoxin Fab fragments (don't have allergic properties)

Therapeutic Dose= 0.5-2ng/ml

Toxic Dose= >2ng/ml

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Manifestations of Lithium poisoning

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-Lithium is used in depression/bipolar mood disorders.

-Toxic dose= acute toxicity >40mg/kg; chronic toxicity--- can happen at even therapeutic doses (e.g., during Gastroenteritis, renal impairment, NSAID's, ACE-I

-Toxic serum level= >1.5mEq/L

-toxicity at a given serum level is variable

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How can we calculate how much Digoxin Ab's we need?

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Step-by-step:

1) Calculate the Body Load of Digoxin in mg (Css*Vd*Weight= Body Load (BL)= the total mass of digoxin in our body--- divide by 1,000 to get units of mg)--- Css= steady state concentration

2) 40mg (1 vial) of Fab binds to 0.5mg digoxin so......Fab antibodies dose= BL*80= Fab dose needed

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What do we do once we give pt. digoxin Fab antibodies?

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After administering the Ab's, we don't measure digoxin blood levels, because we'll get a false positive result. For the next 48hrs, we treat pt's according to clinical judgement, NOT according to lab levels.