32.1 Pharmacology Foundations: The Pharmacology TOS, Pharmacokinetics, Drug Metabolism and Interactions, Pharmacodynamics, Adverse Drug Reactions and Monitoring, Autonomic Pharmacology, and Philippine Prescribing Rules

Why this area matters

The Pharmacology and Therapeutics TOS lists seven organ-system areas:

For every drug, be ready to:

• explain its mechanism and link it to the disease;
• choose it rationally in a clinical scenario;
• predict adverse effects at usual and toxic doses;
• recognize interactions with drugs, food and laboratory tests;
• plan monitoring.

Quantitative Pharmacokinetics: Volume of Distribution, Clearance & Dosing Regimens

Pharmacokinetics describes what the human body does to an administered xenobiotic, fundamentally broken down into Absorption, Distribution, Metabolism, and Elimination (ADME).

Volume of Distribution ($V_d$)

The apparent Volume of Distribution ($V_d$) is a proportionality constant that relates the total amount of drug in the body to the plasma drug concentration ($C_0$) measured immediately after intravenous distribution:

$V_d = \frac{\text{Total amount of drug in body}}{C_0} = \frac{\text{Dose}}{C_0}$

$V_d$ does not represent a real anatomical volume; rather, it reflects the relative affinity of a drug for vascular versus extravascular tissue compartments:

• Low $V_d$ ($4\text{--}8\text{ L}$, approximately $0.05\text{--}0.1\text{ L/kg}$): Confined largely to the intravascular plasma volume ($3\text{--}4\text{ L}$). These drugs possess high molecular weights, strong negative charges, or extensive binding to circulating plasma albumin (e.g., Warfarin, Heparin). Because the drug remains in the vascular space, $C_0$ is high and calculated $V_d$ is low.
• Intermediate $V_d$ ($12\text{--}16\text{ L}$, approximately $0.2\text{ L/kg}$): Distributed throughout the extracellular fluid (ECF = plasma $+$ interstitial space). These are small, hydrophilic, polar molecules that cannot readily penetrate lipid cell membranes (e.g., Aminoglycosides, Beta-lactams).
• High $V_d$ ($> 40\text{ L}$, up to thousands of liters in lipophilic drugs): Distributed throughout total body water ($42\text{ L}$) and extensively sequestered within extravascular tissues (adipose tissue, liver, bone, skeletal muscle). Because plasma concentrations ($C_0$) are extremely low, calculated $V_d$ far exceeds total anatomical body volume (e.g., Digoxin $V_d \approx 500\text{ L}$, Chloroquine $V_d > 10,000\text{ L}$, Tricyclic Antidepressants). Drugs with very high $V_d$ cannot be cleared effectively by emergency hemodialysis during acute poisoning.

Clearance ($CL$) and Elimination Half-Life ($t_{1/2}$)

Clearance ($CL$) is the volume of plasma completely cleared of drug per unit time (expressed in $\text{mL/min}$ or $\text{L/hr}$):

$CL = \frac{\text{Rate of elimination}}{C_p} = k_e \times V_d$

Where $k_e$ is the first-order elimination rate constant (the fraction of drug eliminated per unit time). Clearance is additive across eliminating organs: $CL_{\text{total}} = CL_{\text{renal}} + CL_{\text{hepatic}} + CL_{\text{biliary/pulmonary}}$.

The Elimination Half-Life ($t_{1/2}$) is the time required for the plasma concentration to decrease by 50% under first-order conditions. It is governed entirely by $V_d$ and $CL$:

$t_{1/2} = \frac{\ln(2)}{k_e} = \frac{0.693 \times V_d}{CL}$

• Severe chronic kidney disease or cirrhosis reduces clearance ($CL$), prolonging $t_{1/2}$.
• Volume expansion (massive ascites, severe generalized anasarca, aggressive fluid resuscitation) increases $V_d$ of hydrophilic drugs, which also prolongs $t_{1/2}$ and lowers peak plasma levels.

Loading Dose ($LD$) vs. Maintenance Dose ($MD$)

When treating acute, life-threatening conditions (severe sepsis, status epilepticus, acute pulmonary edema), clinicians cannot wait for multiple half-lives to elapse before achieving therapeutic efficacy. A Loading Dose ($LD$) is administered to rapidly achieve the target plasma concentration ($C_{\text{target}}$):

$LD = \frac{C_{\text{target}} \times V_d}{F}$

Where $F$ represents bioavailability (the fraction of unchanged drug reaching systemic circulation; for intravenous administration, $F = 1.0$). Loading dose depends exclusively on Volume of Distribution ($V_d$) and is completely independent of clearance or organ function.

Once therapeutic concentrations are established, a Maintenance Dose ($MD$) is administered at scheduled dosing intervals ($\tau$) to replace the drug lost through ongoing elimination:

$MD = \frac{C_{ss} \times CL \times \tau}{F}$

Where $C_{ss}$ is the desired steady-state plasma concentration. Maintenance dose depends directly on Clearance ($CL$); in renal or hepatic failure, the maintenance dose must be adjusted downward by reducing the dose or extending the dosing interval ($\tau$).

Steady-State Kinetics

Under continuous infusion or regular repeated dosing, a drug reaches Steady State ($C_{ss}$) when the rate of drug input equals the rate of drug elimination. The time required to attain steady state depends solely on the drug's elimination half-life ($t_{1/2}$):

• $1\ t_{1/2} = 50.0\%$ of steady state
• $2\ t_{1/2} = 75.0\%$ of steady state
• $3\ t_{1/2} = 87.5\%$ of steady state
• $3.3\ t_{1/2} = 90.0\%$ of steady state
• $4\ t_{1/2} = 93.75\%$ of steady state
• $5\ t_{1/2} = 96.88\%$ of steady state

In clinical pharmacology, steady state is functionally achieved after 4 to 5 half-lives. Increasing the infusion rate or dose size increases the eventual steady-state concentration ($C_{ss}$), but does not shorten the time required to reach steady state.

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Elimination Kinetics: First-Order vs. Zero-Order

PLE High-Yield Point: In zero-order kinetics, metabolic elimination mechanisms (hepatic conjugating enzymes or active renal tubular transporters) become completely saturated at therapeutic or supratherapeutic concentrations. Consequently, a small incremental dose increase can lead to disproportionate, exponential surges in plasma drug concentration, precipitating catastrophic toxicity.

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Hepatic Biotransformation: Phase I vs. Phase II Metabolism & CYP450 Interactions

Most pharmacological agents are lipophilic molecules that would undergo continuous passive reabsorption across renal tubular epithelial membranes if excreted unchanged. The liver converts lipophilic xenobiotics into polar, water-soluble metabolites for excretion in urine or bile.

Phase I vs. Phase II Reactions

• Phase I Reactions (Functionalization):
  • Includes Oxidation, Reduction, and Hydrolysis.
  • Introduces or unmasks a polar functional group (such as $-\text{OH}$, $-\text{NH}_2$, or $-\text{SH}$).
  • Predominantly catalyzed by the microsomal Cytochrome P450 (CYP450) monooxygenase superfamily located in the smooth endoplasmic reticulum.
  • Phase I metabolites are often chemically active, sometimes possessing enhanced pharmacological activity (e.g., diazepam to oxazepam) or toxic potential.
  • Geriatric Vulnerability: Phase I hepatic enzymatic capacity declines significantly with advanced age. Elderly patients clear Phase I drugs more slowly.
• Phase II Reactions (Conjugation):
  • Includes Glucuronidation, Acetylation, Sulfation, Methylation, and Glutathione conjugation.
  • Covalently couples the polar functional group to an endogenous hydrophilic substrate (e.g., UDP-glucuronic acid, acetyl-CoA, sulfate, glutathione).
  • Yields biologically inactive, highly polar, water-soluble conjugates that are rapidly cleared by renal glomerular filtration and active tubular secretion.
  • Preserved in Geriatrics: Phase II conjugation mechanisms are well preserved in elderly individuals. Clinical mnemonic: Geriatric patients have More GAS (Glucuronidation, Acetylation, Sulfation). When prescribing benzodiazepines to geriatric patients or individuals with cirrhosis, agents that undergo direct Phase II metabolism without active Phase I intermediates are preferred: LOT (Lorazepam, Oxazepam, Temazepam).

Pharmacogenetic Acetylation: Slow vs. Fast Acetylators

Phase II acetylation is catalyzed by hepatic N-acetyltransferase-2 (NAT2). Genetically determined slow acetylators possess deficient NAT2 activity (autosomal recessive trait, found in roughly 50% of Caucasian and African populations, but $< 15\%$ of Asian populations). Slow acetylators accumulate parent drugs, predisposing them to dose-dependent toxicities and Drug-Induced Lupus Erythematosus (DILE). Classic offending agents include:

• Isoniazid (severe peripheral neuropathy due to pyridoxine deficiency, hepatotoxicity)
• Hydralazine (DILE with positive anti-histone antibodies)
• Procainamide (DILE with highest incidence)

Cytochrome P450 Modulators

Co-administration of drugs that induce or inhibit CYP450 enzymes represents a primary cause of adverse drug reactions and therapeutic failures.

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Pharmacodynamics: Potency, Efficacy, Antagonism & Therapeutic Index

Pharmacodynamics analyzes what a drug does to the body, exploring biochemical receptor interactions, dose-response relationships, and signal transduction cascades.

Potency vs. Efficacy

• Potency: The concentration or dose of a drug required to produce 50% of its maximal response ($EC_{50}$ or $ED_{50}$). On a semi-logarithmic concentration-effect curve, a drug with higher potency has a curve shifted to the left (lower $EC_{50}$). Potency is primarily determined by receptor affinity ($K_d$) and tissue receptor density.
• Efficacy: The maximal response achievable by a drug ($E_{\max}$), reflecting intrinsic activity once bound to the receptor. On a concentration-effect curve, efficacy is measured by the vertical height of the plateau. In clinical medicine, efficacy is far more important than potency; a drug that can completely suppress pain or control severe hypertension is clinically superior to a more potent drug that achieves only partial symptom control.

Receptor Antagonism Profiles

1. Competitive Antagonist:
   • Binds reversibly to the identical active orthosteric receptor site as the agonist.
   • Effect on Curve: Causes a parallel shift to the right of the agonist log concentration-response curve.
   • Kinetic Changes: Increases $EC_{50}$ (reduces apparent potency) while leaving $E_{\max}$ unchanged.
   • Can be completely surmounted and overcome by administering higher concentrations of the agonist.
   • Examples: Atropine competing with Acetylcholine; Phentolamine competing with Norepinephrine; Naloxone competing with Morphine; Flumazenil competing with benzodiazepines.
2. Non-Competitive Antagonist:
   • Binds irreversibly (covalently) to the orthosteric active site, or binds reversibly to a separate allosteric regulatory site.
   • Effect on Curve: Depresses the agonist concentration-response curve downward.
   • Kinetic Changes: Reduces $E_{\max}$ (reduces efficacy); the $EC_{50}$ may remain unchanged or shift slightly.
   • Cannot be surmounted, regardless of how much agonist is added, because available functional receptors are permanently inactivated or structurally modified.
   • Examples: Phenoxybenzamine covalently binding alpha-adrenergic receptors; Aspirin irreversibly acetylating cyclooxygenase.

Therapeutic Index ($TI$)

The Therapeutic Index ($TI$) quantifies drug safety by comparing the median toxic dose to the median effective dose:

$TI = \frac{TD_{50}}{ED_{50}} \quad \left(\text{or } \frac{LD_{50}}{ED_{50}} \text{ in preclinical animal lethality studies}\right)$

A high $TI$ indicates a wide margin of safety (e.g., penicillin). A low $TI$ indicates a narrow margin of safety requiring routine Therapeutic Drug Monitoring (TDM). Narrow therapeutic index drugs frequently tested on the PLE include:

• Warfarin (monitor PT/INR)
• Theophylline (monitor serum levels; toxicity causes refractory seizures and fatal arrhythmias)
• Digoxin (monitor serum levels, narrow window $0.5\text{--}0.9\text{ ng/mL}$)
• Lithium (monitor serum levels, target $0.6\text{--}1.2\text{ mEq/L}$)
• Carbamazepine & Phenytoin (monitor serum levels)
• Aminoglycosides (monitor peak and trough concentrations)

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Autonomic Pharmacology: Cholinergic System

The autonomic nervous system (ANS) maintains visceral homeostasis through opposing cholinergic (parasympathetic) and adrenergic (sympathetic) signaling branches.

Cholinergic Receptors & Second Messengers

• $M_1$ Receptors ($G_q \to \text{Phospholipase C} \to IP_3 / DAG \to \uparrow Ca^{2+}$): Expressed in central nervous system neurons and gastric parietal/enteric ganglia.
• $M_2$ Receptors ($G_i \to \downarrow \text{cAMP} \to \text{opens } K^+ \text{ channels}$): Expressed in cardiac nodal tissue (sinoatrial node, atrioventricular node). Stimulation hyperpolarizes nodal cells, slowing heart rate (negative chronotropy) and decreasing AV conduction velocity (negative dromotropy).
• $M_3$ Receptors ($G_q \to IP_3 / DAG \to \uparrow Ca^{2+}$): Expressed in exocrine glands (sweat, lacrimal, salivary, gastric glands $\to$ profuse secretion), visceral smooth muscle (bronchoconstriction, detrusor contraction, bladder emptying, hypermotility/cramping), and pupillary sphincter muscle (constriction $\to$ miosis and ciliary muscle spasm $\to$ accommodation for near vision). On vascular endothelium, $M_3$ stimulation drives endothelial nitric oxide synthase (eNOS) to release Nitric Oxide (NO), stimulating guanylyl cyclase to generate cyclic GMP, causing paradoxical vasodilation.
• Nicotinic Receptors ($N_N$ and $N_M$): Ligand-gated ion channels. $N_N$ is found on autonomic ganglia and the adrenal medulla; $N_M$ is located on the skeletal muscle motor end-plate. Binding of acetylcholine opens non-selective cation channels, driving massive inward $Na^+$ current and end-plate depolarization.

Cholinomimetic & Anticholinergic Agents

• Direct Muscarinic Agonists:
  • Bethanechol: Quaternary amine resistant to AChE; activates bowel and bladder smooth muscle. Used for non-obstructive postoperative urinary retention, neurogenic ileus, and diabetic gastroparesis.
  • Pilocarpine: Tertiary amine (penetrates cornea); causes rapid miosis and contracts the ciliary muscle, pulling open the trabecular meshwork to drain aqueous humor in acute angle-closure glaucoma; also stimulates salivation in Sjögren syndrome.
  • Methacholine: Inhaled muscarinic agonist used in bronchial challenge testing for diagnosing bronchial hyperreactivity in suspected asthma.
• Muscarinic Antagonists (Anticholinergics):
  • Atropine: Prototypic non-selective competitive muscarinic blocker. Reverses bradycardia, dries secretions, and causes mydriasis and cycloplegia.
  • Scopolamine: Crosses blood-brain barrier; transdermal patch used for motion sickness prophylaxis and end-of-life terminal respiratory secretions.
  • Ipratropium & Tiotropium: Inhaled quaternary ammonium derivatives; block $M_3$ receptors in bronchial smooth muscle without systemic anticholinergic absorption; first-line bronchodilators in COPD.
  • Oxybutynin & Tolterodine: Antagonize $M_3$ receptors on detrusor muscle, reducing bladder spasms in urge incontinence and overactive bladder.
  • Benztropine & Trihexyphenidyl: Central anticholinergics used to restore the dopaminergic-cholinergic balance in Parkinson disease and treat acute antipsychotic-induced extrapyramidal dystonias.

Anticholinergic Toxicity Syndrome

Excessive muscarinic blockade precipitates the classic clinical toxidrome:

• "Blind as a bat": Severe mydriasis, loss of accommodation (cycloplegia)
• "Mad as a hatter": Delirium, toxic psychosis, hallucinations, agitation
• "Red as a beet": Cutaneous vasodilation and flushing
• "Hot as a hare": Hyperthermia due to complete cessation of sweating (anhidrosis)
• "Dry as a bone": Severe xerostomia, parched mucous membranes, dry skin
• "Bowel and bladder lose their tone": Absent bowel sounds, paralytic ileus, acute urinary retention
• "Heart runs alone": Severe sinus tachycardia

Treatment of severe central anticholinergic toxicity is Physostigmine, a tertiary amine acetylcholinesterase inhibitor that readily crosses the blood-brain barrier to restore central and peripheral acetylcholine levels.

Acetylcholinesterase (AChE) Inhibitors & Organophosphate Toxicity

• Reversible AChE Inhibitors:
  • Neostigmine: Quaternary amine (does not cross BBB); reverses non-depolarizing neuromuscular blockade (rocuronium) and treats myasthenia gravis and acute colonic pseudo-obstruction (Ogilvie syndrome).
  • Pyridostigmine: Quaternary amine; long-acting maintenance therapy for Myasthenia Gravis.
  • Physostigmine: Tertiary amine (penetrates CNS); antidote for anticholinergic poisoning.
  • Donepezil, Rivastigmine, Galantamine: Lipid-soluble central AChE inhibitors; first-line symptomatic therapy for Alzheimer disease dementia.
  • Edrophonium: Ultra-short-acting inhibitor historically used in the Tensilon test to differentiate myasthenic crisis (improves with drug) from cholinergic crisis (worsens with drug).
• Irreversible AChE Inhibitors (Organophosphate Pesticides: Malathion, Parathion, Chlorpyrifos; Nerve Agents: Sarin, Soman):
  • Covalently phosphorylate the active catalytic serine residue of acetylcholinesterase, completely blocking acetylcholine degradation.
  • Clinical Manifestations: Muscarinic hyperstimulation produces the classic mnemonic SLUDGE (Salivation, Lacrimation, Urination, Defecation, Gastrointestinal cramping, Emesis) or DUMBBELLS (Diarrhea, Urination, Miosis, Bronchospasm, Bradycardia, Emesis, Lacrimation, Lethargy, Salivation). The life-threatening "Killer Bs"—Bronchorrhea, Bronchospasm, and Bradycardia—cause acute respiratory arrest.
  • Nicotinic hyperstimulation produces muscle fasciculations, cramping, followed rapidly by depolarizing flaccid paralysis of the diaphragm.
  • Emergency Antidote Protocol:
    1. Atropine: Competitive antagonist at muscarinic receptors. Administer immediate intravenous boluses (doubling the dose every 3 to 5 minutes) titrated aggressively until tracheobronchial secretions dry and bronchospasm clears. Atropine reverses muscarinic pulmonary collapse, but has zero effect on nicotinic neuromuscular paralysis.
    2. Pralidoxime (2-PAM): A nucleophilic oxime that chemically cleaves the covalent organophosphate bond from acetylcholinesterase, regenerating active functional enzyme at both muscarinic and nicotinic synapses. Must be administered promptly before chemical "aging" (dealkylation of the organophosphate-enzyme complex) permanently locks the enzyme in an irreversible inactivated state.

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Autonomic Pharmacology: Adrenergic System

Adrenergic Receptor Subtypes & Second Messengers

Sympathomimetic Agonists

• Epinephrine: Potent endogenous agonist across all alpha and beta receptors. At low therapeutic doses ($0.01\text{--}0.05\text{ mcg/kg/min}$), $\beta_1$ and $\beta_2$ effects predominate (bronchodilation, $\uparrow$ cardiac output, decreased peripheral resistance). At high doses ($> 0.1\text{ mcg/kg/min}$), $\alpha_1$ vasoconstrictor effects override $\beta_2$, driving marked systemic hypertension. Drug of choice for Anaphylaxis ($0.3\text{--}0.5\text{ mg}$ IM $1:1,000$ in anterolateral thigh) and cardiac arrest.
• Norepinephrine: Potent $\alpha_1$ and $\alpha_2$ agonist with moderate $\beta_1$ activity and negligible $\beta_2$ effect. Produces intense systemic vasoconstriction with elevated mean arterial pressure. First-line vasopressor for Septic Shock.
• Dopamine: Dose-dependent receptor activation:
  • Low dose ($1\text{--}2\text{ mcg/kg/min}$): $D_1$ receptors $\to$ renal and mesenteric vasodilation.
  • Intermediate dose ($2\text{--}10\text{ mcg/kg/min}$): $\beta_1$ receptors $\to$ positive inotropy.
  • High dose ($> 10\text{ mcg/kg/min}$): $\alpha_1$ receptors $\to$ generalized vasoconstriction.
• Dobutamine: Predominantly $\beta_1 > \beta_2$ selective inotrope; increases cardiac output with minimal change in heart rate and mild vasodilation. Drug of choice for acute cardiogenic shock without profound hypotension.
• Phenylephrine: Pure selective $\alpha_1$ agonist; induces intense vasoconstriction, increasing systolic and diastolic blood pressure with compensatory reflex vagal bradycardia.
• Clonidine & Methyldopa: Centrally acting selective $\alpha_2$ agonists. Stimulate presynaptic $\alpha_2$ receptors in the medullary vasomotor center, suppressing sympathetic outflow, reducing blood pressure and heart rate. Abrupt cessation of clonidine triggers severe rebound hypertensive crisis due to sympathetic surge. Methyldopa is a classic first-line agent for chronic hypertension in pregnancy; major adverse effect is a Coombs-positive autoimmune hemolytic anemia.

Sympatholytic Antagonists: Alpha- and Beta-Blockers

• Alpha-Adrenergic Blockers:
  • Phenoxybenzamine: Non-selective, irreversible covalent blocker of $\alpha_1$ and $\alpha_2$ receptors. Used preoperatively in pheochromocytoma to prevent catastrophic intraoperative hypertensive crises during surgical tumor manipulation.
  • Phentolamine: Non-selective, reversible alpha-blocker. Used for acute hypertensive crises associated with pheochromocytoma manipulation or MAO inhibitor-tyramine food interactions, and for local extravasation of norepinephrine infusions.
  • Prazosin, Doxazosin, Terazosin: Selective $\alpha_1$ antagonists; relax vascular arteriolar and venous smooth muscle and prostatic smooth muscle. Used for comorbid hypertension and Benign Prostatic Hyperplasia (BPH). Notable adverse effect: First-dose syncope and marked orthostatic hypotension (must be taken at bedtime).
  • Tamsulosin & Silodosin: Selective $\alpha_{1A}$ receptor blockers localized to the prostate and bladder neck; relieve urinary obstruction in BPH with minimal vascular hypotension. Can cause Intraoperative Floppy Iris Syndrome (IFIS) during cataract surgery.
• Beta-Adrenergic Blockers:
  • Cardioselective ($\beta_1$-Selective; "A to M"): Metoprolol, Atenolol, Bisoprolol, Esmolol, Nebivolol. Safer in patients with concomitant mild asthma, COPD, or peripheral artery disease. Esmolol is an ultra-short-acting agent ($t_{1/2} \approx 9\text{ minutes}$) metabolized by red blood cell esterases, ideal for acute aortic dissection and intraoperative arrhythmias. Nebivolol also stimulates endothelial nitric oxide release, providing direct vasodilatory action.
  • Non-Selective ($\beta_1 + \beta_2$; "N to Z"): Propranolol, Timolol, Nadolol. Strictly contraindicated in patients with active asthma or severe COPD due to life-threatening bronchospasm. Non-selective beta-blockers mask early warning signs of hypoglycemia (tachycardia, tremor, anxiety) in diabetic patients, though diaphoresis (sweating) is spared because it is mediated by cholinergic muscarinic innervation of eccrine glands.
  • Combined $\alpha_1$ and Beta-Blockers: Carvedilol, Labetalol. Labetalol is first-line for hypertensive emergencies, acute aortic dissection, and preeclampsia/severe gestational hypertension. Carvedilol reduces all-cause mortality in chronic heart failure.
  • Intrinsic Sympathomimetic Activity (ISA / Partial Agonists): Pindolol, Acebutolol. Act as weak partial agonists, causing less resting bradycardia; they are avoided after myocardial infarction because they lack the mortality benefit of other beta-blockers.

Adverse drug reactions and monitoring

• Type A (augmented): predictable from the drug's pharmacology and dose-related. Examples are bleeding with warfarin and hypoglycemia with insulin. These are the most common.
• Type B (bizarre): idiosyncratic or immunologic and not dose-related. Examples are anaphylaxis to penicillin, SJS with carbamazepine, and agranulocytosis with thionamides or clozapine.
• Other types:
  • chronic (adrenal suppression with steroids);
  • delayed (teratogenicity, carcinogenicity);
  • end-of-use (rebound hypertension after stopping clonidine, beta-blocker withdrawal);
  • failure of therapy (interactions that lower efficacy).
• Drug-food and drug-laboratory interactions:
  • grapefruit juice raises levels of some statins and calcium channel blockers;
  • tyramine-rich foods with MAO inhibitors cause hypertensive crisis;
  • vitamin K-rich foods reduce warfarin's effect;
  • dairy, antacids and iron chelate tetracyclines and fluoroquinolones;
  • biotin interferes with some immunoassays (thyroid tests, troponin).
• Pharmacovigilance: suspected adverse reactions are reported to the FDA Philippines.
• Monitoring plans combine:
  • therapeutic drug levels for narrow-therapeutic-index drugs;
  • safety laboratory tests, such as liver enzymes with statins and INH, creatinine and potassium with ACE inhibitors, CBC with clozapine and thionamides, and TSH with amiodarone and lithium;
  • clinical endpoints: BP, glucose, symptoms.
• Special populations:
  • older adults: lower renal function, more sensitivity, polypharmacy;
  • children: weight-based dosing;
  • pregnancy and lactation: weigh fetal risk against maternal benefit;
  • renal and hepatic impairment: adjust doses (for example, by creatinine clearance).

Philippine Prescribing Regulations & Medical Jurisprudence

Prescription writing in the Republic of the Philippines is governed by strict statutory frameworks designed to ensure generic accessibility and prevent the diversion of dangerous drugs.

The Generics Act of 1988 (Republic Act No. 6675)

Republic Act No. 6675 mandates all licensed medical practitioners to write prescriptions using the generic name of the drug. The statutory requirements are established in administrative regulations (DOH Administrative Order No. 62 s. 1989):

1. The generic name must be written in full and legibly.
2. The generic name must always precede the brand name.
3. If a brand name is written, it must be enclosed in parentheses immediately following the generic name (e.g., Amoxicillin 500 mg capsule (Amoxil)).

A later amendment (AO 90, s. 1990) allowed more than one drug product on one prescription form.

The Comprehensive Dangerous Drugs Act of 2002 (Republic Act No. 9165)

RA 9165 and Dangerous Drugs Board Regulation No. 1 (s. 2014) govern prescriptions for dangerous drugs such as morphine, fentanyl, oxycodone, pethidine and methylphenidate:

• Prescriber: a physician, dentist or veterinarian with a valid PDEA S-2 license.
• Form: the DOH Special Prescription Form for dangerous drugs (the "yellow prescription"), unless the drug is exempted; certain oral Schedule 4 and 5 preparations (and buprenorphine patches) are prescribed on an ordinary prescription in triplicate bearing the S-2 number.
• One dangerous drug per prescription, signed and dated on the day of issue.
• Triplicate copies: the original is surrendered to the dispensing pharmacy, the duplicate is the patient's copy, and the triplicate is retained by the prescriber.
• Contents: the prescriber's name, address, contact details, S-2 license number and validity, and PTR; the patient's name, age and address; the date; the generic and brand name, strength and form; the total quantity in words and figures; and directions.
• Quantity: up to a 30-day supply per prescription. In extraordinary circumstances the prescriber may issue multi-month prescriptions (each for no more than 30 days, numbered "1 of 3", etc.). Up to 60 days of certain Schedule 4 drugs may be prescribed for epilepsy and dystonia.
• Dispensing: the pharmacist stamps "USED IN FULL" or records partial dispensing, and must not dispense a prescription that is forged, altered, incomplete, or presented more than 60 days after issue.
• Special forms are non-transferable and used consecutively. Unused forms are surrendered when the prescriber stops practice or the S-2 license lapses.
• A temporary DDB regulation (BR 10, s. 2025) allowed ordinary triplicate prescriptions in place of yellow forms until June 30, 2026, for continuity of care during public health emergencies.