6.3 Pharmacokinetics, Adverse Drug Reactions & Poison Management
Key Takeaways
- Pharmacokinetics describes drug movement through Absorption, Distribution, Metabolism, and Excretion (ADME), governing serum drug concentrations and half-life ($t_{1/2}$).
- Therapeutic Drug Monitoring (TDM) is essential for narrow therapeutic index drugs (e.g., Gentamicin, Vancomycin, Digoxin, Lithium, Phenytoin) to maintain serum levels within narrow safety windows.
- Adverse Drug Reactions (ADRs) are categorized into Type A (augmented, dose-dependent, predictable) and Type B (bizarre, idiosyncratic/allergic, dose-independent), requiring mandatory reporting to the Health Sciences Authority (HSA) via PRISM.
- In Singapore, pharmacogenomic screening for the **HLA-B*1502** allele is mandatory prior to initiating Carbamazepine in Han Chinese, Malay, and Asian populations to prevent Toxic Epidermal Necrolysis (TEN) and Stevens-Johnson Syndrome (SJS).
- Acute poisoning management follows the ABCDE stabilization approach combined with activated charcoal decontamination and targeted antidotes (e.g., N-acetylcysteine for paracetamol, Naloxone for opioids).
6.3 Pharmacokinetics, Adverse Drug Reactions & Poison Management
Clinical pharmacology forms the bedrock of safe medication administration. Understanding how the body processes drugs (pharmacokinetics) and how drugs affect the body (pharmacodynamics) enables registered nurses to monitor therapeutic efficacy, identify adverse drug reactions (ADRs), interpret drug blood levels, and execute emergency toxicology management under Health Sciences Authority (HSA) guidelines.
Pharmacokinetic Principles: The ADME Profile
Pharmacokinetics governs the time course of drug absorption, distribution, metabolism, and excretion:
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| THE ADME PHARMACOKINETIC CYCLE |
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| 1. ABSORPTION : Route, bioavailability (F), gastric pH & emptying |
| 2. DISTRIBUTION : Protein binding (albumin), Vd, blood-brain barrier |
| 3. METABOLISM : Hepatic CYP450 enzymes (inducers vs inhibitors) |
| 4. EXCRETION : Renal filtration/secretion, biliary, half-life (t1/2) |
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Key Concepts:
- Bioavailability ($F$): The fraction of administered active drug reaching systemic circulation intact ($100%$ for IV formulations; lower for oral due to first-pass hepatic metabolism).
- Volume of Distribution ($V_d$): The theoretical fluid volume required to contain the total drug mass at systemic plasma concentration.
- Elimination Half-Life ($t_{1/2}$): The time required for plasma drug concentration to decline by $50%$. Steady-state concentration is typically achieved after $4 \text{ to } 5 \text{ half-lives}$ of continuous or scheduled dosing.
- Cytochrome P450 System: Hepatic enzymes responsible for metabolizing most drugs.
- CYP Inducers (e.g., Rifampicin, Carbamazepine, Phenytoin): Accelerate drug metabolism, reducing therapeutic levels of co-administered drugs.
- CYP Inhibitors (e.g., Ketoconazole, Erythromycin, Grapefruit Juice, Cimetidine): Suppress metabolism, causing drug accumulation and toxicity.
Therapeutic Drug Monitoring (TDM) for Narrow Therapeutic Index Drugs
Drugs with a Narrow Therapeutic Index (NTI) have a small margin between therapeutic efficacy and lethal toxicity. Nurses must coordinate precise blood sampling times for TDM:
| Drug Name | Target Therapeutic Range | TDM Sampling Standard | Toxicity Clinical Manifestations |
|---|---|---|---|
| Gentamicin / Amikacin | Peak: $5\text{--}10\text{ mcg/mL}$<br/>Trough: $< 2\text{ mcg/mL}$ | Peak: 30 min post IV infusion.<br/>Trough: Within 30 min prior to next dose. | Nephrotoxicity (elevated creatinine), Ototoxicity (tinnitus, vestibular balance loss, irreversible deafness). |
| Vancomycin | Trough: $15\text{--}20\text{ mcg/mL}$ (severe infection/MRSA) | Draw trough level within 30 min immediately prior to 4th or 5th dose. | Red Man Syndrome (rapid infusion histamine release; flush, hypotension), Nephrotoxicity. |
| Digoxin | Range: $0.5\text{--}2.0\text{ ng/mL}$ | Draw sample at least 6--8 hours post-dose (ideally trough). | Anorexia, nausea, yellow-green visual halos, severe bradycardia, ventricular arrhythmias. |
| Phenytoin | Range: $10\text{--}20\text{ mcg/mL}$ | Trough level prior to next dose. Note non-linear saturation kinetics. | Nystagmus, ataxia, gingival hyperplasia, confusion, peripheral neuropathy. |
| Lithium | Range: $0.6\text{--}1.2\text{ mEq/L}$ | 12 hours post evening dose (trough). | Fine hand tremor, polyuria, hypothyroidism, coarse tremor, seizures, coma. |
Adverse Drug Reactions (ADRs) & HSA Pharmacovigilance
In Singapore, the Health Sciences Authority (HSA) oversees national pharmacovigilance. RNs are legally and professionally required to identify and report ADRs.
Classification of ADRs:
- Type A (Augmented / Predictable): Dose-dependent extensions of pharmacological action (e.g., hypoglycemia from insulin, bleeding from warfarin, bradycardia from beta-blockers). Management involves dose reduction.
- Type B (Bizarre / Unpredictable): Idiosyncratic or immunological reactions independent of dose (e.g., anaphylaxis from penicillin, SJS/TEN from allopurinol). Management mandates immediate drug discontinuation and lifelong allergy flagging.
Pharmacogenomic Safety: HLA-B*1502 Screening in Singapore
Singapore's multi-ethnic demographic presents specific genetic risks. HSA safety alerts mandate genetic testing for the HLA-B*1502 allele prior to starting Carbamazepine in Han Chinese, Malay, and Asian patients. Carrying HLA-B*1502 dramatically increases the risk of life-threatening Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN).
Acute Poison Management & Antidote Therapy
When managing acute drug overdose or chemical ingestion, the nurse follows the structured ABCDE emergency algorithm:
- Airway, Breathing, Circulation: Secure patent airway, provide supplemental $O_2$, establish IV access.
- Decontamination: Activated Charcoal ($1\text{ g/kg}$ PO/NGT) is most effective within 1 hour of oral toxin ingestion. Contraindicated in corrosive (acid/alkali) ingestion, petroleum distillates, heavy metals (lithium, iron), or impaired airway without intubation.
Key Clinical Antidotes:
| Toxic Agent / Overdose | First-Line Antidote | Mechanism / Clinical Key Points |
|---|---|---|
| Paracetamol (Acetaminophen) | N-Acetylcysteine (NAC) | Replenishes hepatic glutathione stores. Administer within 8 hours of ingestion based on Rumack-Matthew nomogram. |
| Opioids (Morphine, Fentanyl) | Naloxone | Competitive $mu$-opioid receptor antagonist. Monitor for resedation as Naloxone half-life ($30\text{--}90\text{ min}$) is shorter than morphine. |
| Benzodiazepines | Flumazenil | Competitive GABA receptor antagonist. Caution: can precipitate lethal withdrawal seizures in chronic users or co-ingestions. |
| Organophosphates / Pesticides | Atropine + Pralidoxime (2-PAM) | Atropine blocks muscarinic cholinergic excess (salivation, bronchospasm, bradycardia); Pralidoxime reactivates acetylcholinesterase. |
| Digoxin Toxicity | Digoxin Immune Fab (Digibind) | Antigen-binding Fab fragments bind free digoxin for renal elimination. |
| Beta-Blockers / CCBs | Glucagon / High-Dose Insulin | Glucagon increases intracellular cAMP; High-Dose Insulin Euglycemic Therapy (HIET) restores myocardial energy metabolism. |
A patient receiving IV Vancomycin for severe MRSA bacteremia is scheduled for a serum trough level check. When should the nurse schedule the blood specimen collection?
In Singapore, the Health Sciences Authority (HSA) mandates pharmacogenomic screening for the HLA-B*1502 allele prior to initiating which medication in Asian patients?
An emergency ward nurse receives an adolescent patient who ingested 20 tablets of Paracetamol 4 hours prior. What is the definitive antidote protocol indicated for this toxicity?