Table of Contents
1. Pharmacokinetics (ADME)
Absorption
Factors Affecting Absorption
- • Route of administration: IV (100% bioavailable) > IM > SC > Oral
- • Drug properties: Lipophilicity, ionization state, molecular size
- • Formulation: Solution > Suspension > Capsule > Tablet
- • GI factors: pH, motility, food, blood flow, first-pass metabolism
Bioavailability (F)
- • Definition: Fraction of administered dose reaching systemic circulation
- • Formula: F = (AUC oral / AUC IV) × (Dose IV / Dose oral)
- • IV administration: F = 1 (100%)
- • First-pass effect: Drug metabolism in gut wall and liver before reaching systemic circulation
Distribution
Volume of Distribution (Vd)
- • Formula: Vd = Amount of drug in body / Plasma concentration
- • Low Vd (3-5 L): Drug confined to plasma (highly protein-bound)
- • High Vd (>40 L): Drug distributed to tissues (lipophilic)
- • Clinical significance: Affects loading dose calculation
Protein Binding
- • Albumin: Acidic drugs (warfarin, phenytoin)
- • α1-acid glycoprotein: Basic drugs (lidocaine)
- • Only free drug is pharmacologically active
- • Displacement interactions possible
Special Barriers
- • Blood-brain barrier: Lipophilic drugs cross
- • Placental barrier: Most drugs cross
- • P-glycoprotein: Efflux transporter
Metabolism
| Phase | Reactions | Enzymes | Result |
|---|---|---|---|
| Phase I | Oxidation, Reduction, Hydrolysis | CYP450 (CYP3A4, 2D6, 2C9) | Expose/add functional groups |
| Phase II | Conjugation | Transferases (UGT, SULT, GST) | Increase water solubility |
CYP450 Interactions
- • Inducers (increase metabolism): Rifampin, Phenytoin, Carbamazepine, St. John's Wort
- • Inhibitors (decrease metabolism): Ketoconazole, Erythromycin, Grapefruit juice, Cimetidine
- • CYP3A4: Most abundant, metabolizes ~50% of drugs
Excretion
Renal Excretion
- • Glomerular filtration: Free drug filtered (protein-bound not filtered)
- • Tubular secretion: Active transport (OAT, OCT transporters)
- • Tubular reabsorption: Lipophilic drugs reabsorbed
- • Urine pH manipulation: Ion trapping for overdose treatment
Half-Life (t½)
- • Time for plasma concentration to decrease by 50%
- • t½ = 0.693 × Vd / CL
- • Steady state: 4-5 half-lives
- • Drug eliminated: 4-5 half-lives
Clearance (CL)
- • Volume cleared of drug per unit time
- • CL = Dose / AUC
- • Determines maintenance dose
- • Affected by organ function
2. Pharmacodynamics
Drug-Receptor Interactions
Agonists
- • Full agonist: Maximal response (e.g., morphine)
- • Partial agonist: Submaximal response (e.g., buprenorphine)
- • Inverse agonist: Opposite effect (e.g., some benzodiazepines)
- • Have both affinity AND efficacy
Antagonists
- • Competitive: Reversible, surmountable (e.g., naloxone)
- • Non-competitive: Irreversible or allosteric (e.g., phenoxybenzamine)
- • Have affinity but NO efficacy
- • Block agonist effects
Dose-Response Relationships
- • Potency (EC50/ED50): Amount of drug needed for 50% effect - relates to position of curve
- • Efficacy (Emax): Maximum effect achievable - relates to height of curve
- • Therapeutic Index (TI): TD50/ED50 - margin of safety
- • Therapeutic Window: Range between minimum effective and toxic concentrations
Receptor Types
| Type | Mechanism | Speed | Examples |
|---|---|---|---|
| Ion Channels | Direct ion flux | Milliseconds | GABA-A, nAChR, Glutamate |
| G-Protein Coupled | Second messengers (cAMP, IP3) | Seconds | Adrenergic, Muscarinic, Opioid |
| Enzyme-Linked | Kinase activity | Minutes | Insulin, Growth factors |
| Nuclear/Intracellular | Gene transcription | Hours | Steroids, Thyroid hormone |
Signal Transduction
Gs (Stimulatory)
- • Activates adenylyl cyclase
- • Increases cAMP
- • β1, β2 receptors
- • Glucagon, Histamine H2
Gi (Inhibitory)
- • Inhibits adenylyl cyclase
- • Decreases cAMP
- • α2 receptors
- • Muscarinic M2, Opioid
Gq
- • Activates phospholipase C
- • Increases IP3 and DAG
- • α1 receptors
- • Muscarinic M1, M3
3. Autonomic Nervous System Drugs
Cholinergic System
Cholinergic Agonists
- Direct-acting:
- • Bethanechol: Urinary retention, GI atony
- • Pilocarpine: Glaucoma, xerostomia
- • Carbachol: Glaucoma
- Indirect-acting (AChE inhibitors):
- • Neostigmine: Myasthenia gravis
- • Physostigmine: Anticholinergic poisoning
- • Donepezil: Alzheimer's disease
Anticholinergics (Muscarinic blockers)
- • Atropine: Bradycardia, organophosphate poisoning
- • Scopolamine: Motion sickness
- • Ipratropium: COPD, asthma (inhaled)
- • Oxybutynin: Overactive bladder
- • Benztropine: Parkinson's, EPS
- Side effects: Dry mouth, constipation, urinary retention, blurred vision, tachycardia
Adrenergic System
| Receptor | Location | Effect | Agonists |
|---|---|---|---|
| α1 | Blood vessels, eye, bladder | Vasoconstriction, mydriasis | Phenylephrine |
| α2 | Presynaptic, CNS | Inhibit NE release | Clonidine |
| β1 | Heart | ↑HR, ↑contractility | Dobutamine |
| β2 | Bronchi, blood vessels | Bronchodilation, vasodilation | Albuterol, Terbutaline |
α-Blockers
- Non-selective: Phentolamine, Phenoxybenzamine
- α1-selective: Prazosin, Doxazosin, Tamsulosin
- Uses: BPH, hypertension, pheochromocytoma
- Side effect: First-dose orthostatic hypotension
β-Blockers
- Non-selective: Propranolol, Nadolol
- β1-selective: Metoprolol, Atenolol, Bisoprolol
- α+β: Carvedilol, Labetalol
- Uses: HTN, angina, arrhythmias, HF, migraine
4. Central Nervous System Drugs
Sedative-Hypnotics
Benzodiazepines
- • Mechanism: Enhance GABA-A (increase frequency of Cl- channel opening)
- • Uses: Anxiety, insomnia, seizures, alcohol withdrawal
- • Short-acting: Triazolam, Midazolam
- • Intermediate: Lorazepam, Alprazolam
- • Long-acting: Diazepam, Clonazepam
- • Antidote: Flumazenil
Non-Benzodiazepines
- • Z-drugs: Zolpidem, Zaleplon, Eszopiclone
- • Bind GABA-A at different site
- • Less muscle relaxation, less dependence
- • Buspirone: 5-HT1A agonist, anxiolytic, no sedation
Antidepressants
| Class | Mechanism | Examples | Side Effects |
|---|---|---|---|
| SSRIs | Block serotonin reuptake | Fluoxetine, Sertraline, Paroxetine | Sexual dysfunction, GI upset, serotonin syndrome |
| SNRIs | Block 5-HT and NE reuptake | Venlafaxine, Duloxetine | Hypertension, sexual dysfunction |
| TCAs | Block 5-HT, NE reuptake + others | Amitriptyline, Nortriptyline | Anticholinergic, sedation, cardiac (QT) |
| MAOIs | Inhibit monoamine oxidase | Phenelzine, Tranylcypromine | Tyramine crisis (cheese reaction) |
Antipsychotics
Typical (1st Generation)
- • Block D2 receptors
- • High-potency: Haloperidol, Fluphenazine
- • Low-potency: Chlorpromazine
- • EPS: Acute dystonia, akathisia, parkinsonism, tardive dyskinesia
- • Neuroleptic malignant syndrome
Atypical (2nd Generation)
- • Block D2 and 5-HT2A
- • Risperidone, Olanzapine, Quetiapine
- • Clozapine: Treatment-resistant schizophrenia
- • Less EPS, more metabolic effects
- • Weight gain, diabetes, dyslipidemia
- • Clozapine: Agranulocytosis (monitor WBC)
Anticonvulsants
- • Phenytoin: Na+ channel blocker, zero-order kinetics, gingival hyperplasia
- • Carbamazepine: Na+ channel, trigeminal neuralgia, SIADH
- • Valproic acid: Multiple mechanisms, broad spectrum, hepatotoxic, teratogenic
- • Lamotrigine: Na+ channel, bipolar, Stevens-Johnson syndrome risk
- • Levetiracetam: SV2A modulator, minimal interactions
- • Gabapentin/Pregabalin: Ca2+ channel, neuropathic pain
Opioid Analgesics
- • Mechanism: Activate μ, κ, δ opioid receptors (Gi-coupled)
- • Full agonists: Morphine, Fentanyl, Oxycodone, Hydromorphone
- • Partial agonist: Buprenorphine (ceiling effect for respiratory depression)
- • Mixed agonist-antagonist: Pentazocine, Butorphanol
- • Side effects: Respiratory depression, constipation, miosis, sedation, tolerance
- • Antidote: Naloxone (short-acting), Naltrexone (long-acting)
5. Cardiovascular Drugs
Antihypertensives
| Class | Mechanism | Examples | Side Effects |
|---|---|---|---|
| ACE Inhibitors | Block ACE, ↓angiotensin II | Lisinopril, Enalapril, Captopril | Dry cough, hyperkalemia, angioedema |
| ARBs | Block AT1 receptor | Losartan, Valsartan, Irbesartan | Hyperkalemia (no cough) |
| CCBs (Dihydropyridines) | Block L-type Ca2+ channels (vasculature) | Amlodipine, Nifedipine | Peripheral edema, reflex tachycardia |
| CCBs (Non-DHP) | Block Ca2+ channels (heart) | Verapamil, Diltiazem | Bradycardia, heart block, constipation |
| Thiazide Diuretics | Block Na-Cl cotransporter (DCT) | HCTZ, Chlorthalidone | Hypokalemia, hyperuricemia, hyperglycemia |
Diuretics
Loop Diuretics
- • Furosemide, Bumetanide, Torsemide
- • Block NKCC2 (TAL)
- • Most potent diuresis
- • Side effects: Hypokalemia, ototoxicity
Thiazides
- • HCTZ, Chlorthalidone
- • Block NCC (DCT)
- • Moderate diuresis
- • Hypercalcemia (useful in stones)
K+-Sparing
- • Spironolactone (aldosterone antagonist)
- • Eplerenone (selective)
- • Amiloride, Triamterene (ENaC blockers)
- • Risk: Hyperkalemia
Antiarrhythmics (Vaughan-Williams)
- • Class I (Na+ blockers): IA (Quinidine), IB (Lidocaine), IC (Flecainide)
- • Class II (β-blockers): Propranolol, Metoprolol
- • Class III (K+ blockers): Amiodarone (multiple effects), Sotalol
- • Class IV (CCBs): Verapamil, Diltiazem
- • Other: Adenosine (SVT), Digoxin (rate control)
Anticoagulants & Antiplatelets
Anticoagulants
- • Heparin: Activates antithrombin III, monitor aPTT
- • LMWH (Enoxaparin): Factor Xa, no monitoring needed
- • Warfarin: Vitamin K antagonist, monitor INR
- • DOACs: Rivaroxaban, Apixaban (Xa); Dabigatran (thrombin)
Antiplatelets
- • Aspirin: Irreversible COX inhibitor
- • Clopidogrel: P2Y12 inhibitor (prodrug)
- • Ticagrelor: P2Y12 inhibitor (reversible)
- • GPIIb/IIIa inhibitors: Abciximab, Eptifibatide
6. Anti-Infective Agents
Antibacterials by Mechanism
| Target | Class | Examples |
|---|---|---|
| Cell Wall | β-Lactams | Penicillins, Cephalosporins, Carbapenems |
| Cell Wall | Glycopeptides | Vancomycin (MRSA) |
| Protein Synthesis (30S) | Aminoglycosides | Gentamicin, Amikacin, Streptomycin |
| Protein Synthesis (30S) | Tetracyclines | Doxycycline, Minocycline |
| Protein Synthesis (50S) | Macrolides | Azithromycin, Clarithromycin, Erythromycin |
| DNA Gyrase | Fluoroquinolones | Ciprofloxacin, Levofloxacin, Moxifloxacin |
| Folate Synthesis | Sulfonamides | TMP-SMX (Bactrim) |
Antifungals
- • Polyenes (Amphotericin B): Bind ergosterol, nephrotoxic
- • Azoles: Inhibit ergosterol synthesis (CYP inhibitors)
- - Fluconazole, Itraconazole, Voriconazole, Ketoconazole
- • Echinocandins: Block β-glucan synthesis (cell wall)
- - Caspofungin, Micafungin, Anidulafungin
- • Terbinafine: Block squalene epoxidase (dermatophytes)
Antivirals
Anti-Herpes
- • Acyclovir: HSV, VZV (requires viral TK)
- • Valacyclovir: Prodrug of acyclovir
- • Ganciclovir: CMV (bone marrow suppression)
- • Foscarnet: CMV resistance, nephrotoxic
Anti-HIV
- • NRTIs: Tenofovir, Emtricitabine, Zidovudine
- • NNRTIs: Efavirenz, Nevirapine
- • Protease inhibitors: Ritonavir, Darunavir
- • Integrase inhibitors: Dolutegravir, Raltegravir
7. Endocrine & Metabolic Drugs
Diabetes Medications
| Class | Mechanism | Examples | Key Points |
|---|---|---|---|
| Biguanides | ↓Hepatic glucose output | Metformin | First-line T2DM, lactic acidosis risk |
| Sulfonylureas | Stimulate insulin release | Glipizide, Glyburide, Glimepiride | Hypoglycemia, weight gain |
| DPP-4 Inhibitors | ↑Incretin levels | Sitagliptin, Linagliptin | Weight neutral |
| GLP-1 Agonists | Incretin mimetic | Liraglutide, Semaglutide | Weight loss, injectable |
| SGLT2 Inhibitors | Block glucose reabsorption (kidney) | Empagliflozin, Dapagliflozin | CV/renal benefits, UTI, DKA risk |
Thyroid Medications
Hypothyroidism
- • Levothyroxine (T4): Drug of choice
- • Long half-life (~7 days)
- • Take on empty stomach
- • Monitor TSH
Hyperthyroidism
- • Thioamides: PTU, Methimazole (block TPO)
- • Methimazole preferred; PTU in pregnancy (1st trimester)
- • Radioactive iodine (I-131)
- • β-blockers for symptom control
Corticosteroids
- • Hydrocortisone: Short-acting, mineralocorticoid activity
- • Prednisone/Prednisolone: Intermediate, most common
- • Dexamethasone: Long-acting, high potency, no mineralocorticoid
- • Side effects: Hyperglycemia, osteoporosis, immunosuppression, adrenal suppression, Cushing's
- • Never stop abruptly: Taper to avoid adrenal crisis
8. Toxicology & Adverse Effects
Common Antidotes
| Toxin/Drug | Antidote | Mechanism |
|---|---|---|
| Acetaminophen | N-Acetylcysteine (NAC) | Replenishes glutathione |
| Opioids | Naloxone | Opioid receptor antagonist |
| Benzodiazepines | Flumazenil | GABA-A antagonist |
| Warfarin | Vitamin K, FFP | Restore clotting factors |
| Heparin | Protamine sulfate | Binds heparin |
| Organophosphates | Atropine + Pralidoxime | Muscarinic block + reactivate AChE |
| Iron | Deferoxamine | Chelation |
| Lead | EDTA, Dimercaprol, Succimer | Chelation |
| Methanol/Ethylene glycol | Fomepizole, Ethanol | Block alcohol dehydrogenase |
| Digoxin | Digoxin immune Fab | Binds digoxin |
Drug-Induced Conditions
- • Serotonin syndrome: SSRIs + MAOIs (hyperthermia, rigidity, autonomic instability)
- • Neuroleptic malignant syndrome: Antipsychotics (high fever, rigidity, altered mental status)
- • QT prolongation: Antipsychotics, macrolides, fluoroquinolones, antiarrhythmics
- • Drug-induced lupus: Hydralazine, Procainamide, Isoniazid (anti-histone antibodies)
- • Stevens-Johnson syndrome: Sulfonamides, Phenytoin, Carbamazepine, Allopurinol, Lamotrigine
Teratogenic Drugs
- • Isotretinoin: Severe birth defects (iPLEDGE program)
- • Thalidomide: Limb defects (phocomelia)
- • Warfarin: Fetal warfarin syndrome
- • Valproic acid: Neural tube defects
- • ACE inhibitors/ARBs: Renal dysgenesis
- • Methotrexate: Fetal aminopterin syndrome
- • Tetracyclines: Teeth/bone discoloration
Key Takeaways
- ✓CYP3A4 metabolizes ~50% of drugs; watch for interactions
- ✓Steady state reached in 4-5 half-lives
- ✓ACE inhibitors: Dry cough; ARBs: No cough
- ✓Metformin is first-line for T2DM
- ✓Naloxone for opioid overdose; Flumazenil for benzodiazepines
- ✓NAC is the antidote for acetaminophen toxicity
- ✓Clozapine requires WBC monitoring (agranulocytosis)
- ✓Never stop corticosteroids abruptly - taper!