Principles of Pharmacokinetics

Principles of Pharmacokinetics and the ADME Framework

• Pharmacokinetics is defined as the time course and disposition of drugs in the body, essentially representing "what the body does to the drug."
• The pharmacokinetic profile of a drug varies based on the route of administration.
• Primary routes in psychiatric practice include oral, intramuscular (IM), intravenous (IV), and rectal.
• Less common routes include inhalation, topical, subcutaneous, sublingual, and intra-arterial.
• The four central processes of pharmacokinetics are abbreviated as ADME:
  • Absorption
  • Distribution
  • Metabolism
  • Elimination

Mechanisms and Factors of Drug Absorption

• Absorption is influenced by the route of administration and the chemical properties of the drug.
• General factors affecting the rate of absorption:
  • The form of the drug: For example, enteric coating of a tablet slows disintegration in the stomach.
  • Rate of blood flow: Higher blood flow at the site of administration increases the rate of absorption.
  • Solubility: This depends on the drug's pH, the size of formulation particles, and the $pKa$. $pKa$ is defined as the pH at which exactly half of the drug is in its ionized form.
• Oral Administration:
  • This is the most common route but leads to variable plasma concentrations due to erratic absorption.
  • Drugs are subject to the first-pass effect, where they undergo extensive metabolism by liver and gut mucosa before entering systemic circulation.
  • Main mechanisms of GI tract absorption: Active transport, Passive diffusion (the most common mechanism), and Pore filtration.
  • Factors influencing GI absorption: Intestinal motility, gastric emptying, gastric and intestinal pH, intestinal microflora, available surface area, blood flow integrity, and the presence or absence of food.
  • Food typically delays gastric emptying. Anticholinergic drugs (e.g., tricyclic antidepressants, opiates) also delay gastric emptying.
  • Site of absorption: Most absorption occurs in the small intestine due to its large surface area, long transit time, and less acidic environment compared to the stomach. Slow or sustained-release drugs may be absorbed in the large bowel.
• Special Preparations:
  • Tablets and capsules must undergo disintegration (breaking into smaller pieces) and dissolution (dissolving into fluid) to be absorbed. Hard compaction or wax matrices prolong disintegration to create modified-release effects (e.g., lithium, carbamazepine, sodium valproate, quetiapine XL).
  • Liquids and syrups are absorbed faster because they bypass disintegration and dissolution stages.
• P-GLYCOPROTEIN and the "Grapefruit Juice Effect":
  • P-glycoprotein is a reverse transporter that actively pumps drug molecules out of gut cells back into the gut lumen.
  • Grapefruit juice components (bergamottin, $6,7$-dihydroxybergamottin, and naringenin) inhibit P-glycoprotein and down-regulate intestinal (but not liver) $CYP3A4$ and $CYP1A2$.
  • This increases the oral bioavailability of drugs with high first-pass metabolism, such as felodipine, nimodipine, terfenadine, carbamazepine, triazolam, midazolam, diazepam, simvastatin, methylprednisone, buspirone, and pimozide.
• Intramuscular (IM) Administration:
  • Absorption occurs over $10-30$ minutes. It avoids most first-pass metabolism.
  • Used for emergencies (acute disturbance) or maintenance (depot injections).
  • Absorption rate depends on blood flow and aqueous solubility. Low molecular weight and lipid-soluble drugs are absorbed better.
  • Muscular exercise increases absorption rate by increasing blood flow.
• Intravenous (IV) Administration:
  • The most rapid method for achieving therapeutic concentrations.
  • Provides $100\%$ bioavailability with no first-pass metabolism.
  • Carries the highest risk for sudden, life-threatening adverse effects.

Permeation, Ionization, and Renal Clearance

• Permeation refers to the lipid membrane permeability of a drug molecule. Incomplete absorption (e.g., only $40\%$ for chlorpromazine) is often due to poor permeation.
• Lipophilicity Dynamics:
  • Highly hydrophilic drugs (e.g., atenolol) cannot easily cross lipid cell membranes.
  • Highly lipophilic drugs may struggle to cross the water layer in extracellular spaces.
• Forms of Permeation:
  • Simple diffusion: Along a concentration gradient without transport mechanisms.
  • Facilitated diffusion: Along a concentration gradient via carrier-specific mechanisms.
  • Active transport: Against a concentration gradient requiring ATP-dependent energy.
• Ionization Principles:
  • Only the nonionized form of a drug can cross lipid cell membranes.
  • Drugs exist in equilibrium between ionized and nonionized forms based on environmental pH and the drug's $pKa$.
  • Ionized forms are more water-soluble and are often trapped in glomerular filtrate, leading to higher renal clearance.
  • Clinical Application: To treat overdose, urine can be manipulated to trap drugs in ionized form. Alkalinizing urine helps eliminate weak acids like salicylate (aspirin) and barbiturates. Acidifying urine may theoretically help eliminate weak bases like amphetamines and phencyclidine.

Drug Distribution, Protein Binding, and Volumetric Analysis

• Distribution describes where in the body a drug is found and is rarely even across all tissues.
• Factors Influencing Distribution:
  • Hemodynamic factors (cardiac output, regional blood flow). The brain, kidneys, and liver receive the highest initial distribution.
  • Redistribution occurs in a second phase to skeletal muscles, adipose tissues, and skin.
  • Plasma protein binding and permeability (lipid solubility).
• Two-Compartment Model:
  • Central compartment: Plasma.
  • Peripheral compartment: Fat and other tissues (varies by age, sex, and weight).
• Protein Binding:
  • Drugs in the blood bound to plasma proteins are inactive. Only the unbound ("free") fraction can bind to receptors or cross the blood-brain barrier.
  • Acidic drugs primarily bind to albumin.
  • Alkaline (basic) drugs (most psychotropics) bind to $\alpha1$-acid glycoprotein and lipoproteins.
  • High protein binding (>90\%\%$): Diazepam (95-99\%\%$), chlorpromazine ($95-99\%\%$), amitriptyline ($95-99\%\%$), imipramine ($95-99\%\%$), phenytoin ($90-95\%\%$), valproate ($90-95\%\%).\n * Interactions: Diazepam can displace phenytoin from proteins, increasing free phenytoin levels and toxicity risks. However, increased metabolism of the free drug often restores steady state quickly.\n* Volume of Distribution (V_d):\n * Formula: V_d = \frac{Q}{C_{p}}$where$Q$is the quantity of drug and$C_{p} is plasma concentration at zero time.\n * V_d is an apparent volume, not a true physiological space.\n * High V_d$(e.g.,$500-1000 liters): Suggests the drug is concentrated in cells or fatty tissues outside the blood.\n * Low V_d$(e.g.,$10-20 liters): Suggests the drug is concentrated primarily in the blood.\n * High protein binding results in a low V_d$. High lipid solubility results in a high$V_d.\n\n# The Blood-Brain Barrier (BBB) and Blood-CSF Barrier\n\n* Distribution to the brain is governed by regional blood flow, the BBB, and the drug's receptor affinity.\n* Structure: Capillary endothelium with tight junctions acting as a single membrane sheet.\n* Function: Protects the brain from proteins (immunoglobulins), bacteria, and viruses; maintains an osmotic gradient and a distinct glucose compartment.\n* Permeability Factors: Fever, head injury, hypoxia, hypercapnia, retroviruses, inflammation, vasculitis, hypertension, cerebral irradiation, and aging.\n* Crossing the BBB:\n * Favored by small molecular size, high lipid solubility, and unionized status.\n * Specific carriers: Amino acid transport systems (stereospecific; L-amino acids cross easily, D-amino acids do not). Examples include L-dopa, L-tryptophan, and valproate.\n * Lithium ions diffuse readily into brain and CSF.\n* Circumventricular Organs: Areas lacking a BBB (e.g., subfornical organ, area postrema of the medulla, median eminence). The area postrema detects toxins and induces vomiting.\n* Nasal sprays may bypass the BBB via the olfactory epithelium. Inhaled medications and anesthetic agents do not generally bypass or increase BBB permeability.\n* Blood-Cerebrospinal Fluid Barrier: Located in the choroid plexus; tight junctions are between epithelial cells rather than endothelial cells.\n\n# Bioavailability, Bioequivalence, and First-Pass Metabolism\n\n* Bioavailability: The fraction of an administered dose that reaches systemic circulation. For IV administration, it is 100\%.\n* Determination: Calculated using the Area Under the Curve (AUC). Bioavailability = AUC_{oral} / AUC_{IV}.\n* First-Pass (Presystemic) Metabolism: Occurs in the gut mucosa, liver, and some muscle tissue. High first-pass examples: Imipramine (30-80\%$reaching circulation), fluphenazine ($10\% reaching circulation).\n* Bioequivalence: Compares plasma levels of two formulations of the same drug given at the same dose and route. Traces must be superimposable (same bioavailability and absorption rate).\n * Examples: Camcolit vs. Priadel (lithium); Clozaril vs. Zaponex (clozapine).\n\n# Metabolism: Phase 1/2 Reactions and the Cytochrome P450 System\n\n* Metabolism (biotransformation) renders drugs less lipid-soluble and more water-soluble for easier elimination.\n* Principal site: Liver (secondary sites: GI tract, lungs, kidneys, skin, etc.).\n* Phase 1 Metabolism: Includes oxidation, reduction, and hydrolysis. Often mediated by the CYP system.\n * Exceptions: Lorazepam, temazepam, and oxazepam bypass Phase 1 and undergo direct Phase 2 metabolism (beneficial in alcoholic liver disease).\n* Phase 2 Metabolism: Conjugation reactions (e.g., glucuronidation) creating polar, water-soluble compounds.\n * Excretion: Molecules < 300$mass units go to urine;$> 300 mass units go to bile.\n* Cytochrome P450 (CYP) Enzymes: Primarily in hepatocyte endoplasmic reticulum.\n * CYP2D6$and$CYP3A4$constitute nearly$90\% of psychotropic metabolism.\n * Genetic variations: 5-10\%$of Caucasians lack$CYP2D6$(poor metabolizers);$15-20\%$of East Asians are poor metabolizers of$CYP2C19.\n* Key CYP Interactions:\n * Inhibitors: SSRIs (fluvoxamine, fluoxetine), grapefruit juice, caffeine.\n * Inducers: Carbamazepine, phenobarbitone, smoking (induces CYP1A2 via Polyaromatic Hydrocarbons), brussel sprouts, alcohol.\n * Autoinduction: Carbamazepine induces its own metabolism (CYP2D6$and$CYP3A4$), requiring dose increases after$3-4 weeks.\n\n# Ethanol Degradation Pathways\n\n* Three Oxidative Pathways (producing acetaldehyde then acetate):\n 1. Cytoplasmic alcohol dehydrogenase: Accounts for >90\% of breakdown in Caucasians.\n 2. Microsomal Ethanol Oxidizing System (MEOS or CYP450\,2E1): Located in the endoplasmic reticulum.\n 3. Peroxisomal catalase.\n* One Non-oxidative Pathway: Produces fatty acid ethyl esters (FAEEs).\n\n# Excretion, Clearance, and Half-Life Dynamics\n\n* Major routes: Urine, feces, bile. Minor: Sweat, saliva, tears, breast milk.\n* Factors Influencing Renal Excretion: Age, renal blood flow (dehydration), renal impairment, and urine pH.\n * Lithium: Low sodium increases lithium reabsorption in proximal tubules, leading to toxicity.\n* Clearance (Cl): Volume of blood cleared of drug per unit time.\n * Formula: Cl = k \times V_{d}$, where$k is the elimination constant.\n * Clearance is constant in first-order kinetics regardless of plasma concentration.\n* Renal-only elimination (minimal liver involvement): Lithium, amisulpride, sulpiride, gabapentin, acamprosate, amantadine.\n* Half-life (t_{1/2}): Time for plasma concentration to halve.\n * Distribution half-life: Fall in concentration due to redistribution into tissues.\n * Elimination half-life: Fall in concentration due to removal from the body.\n\n# Elimination Kinetics: First-Order vs. Zero-Order Processes\n\n* First-Order Kinetics:\n * A constant fraction of the drug is cleared per unit time.\n * Rate is directly proportional to drug concentration (exponential decay).\n * Followed by most psychotropics.\n* Zero-Order Kinetics:\n * A constant amount of the drug is cleared per unit time because elimination systems (enzymes) are saturated.\n * The rate is independent of drug concentration.\n * Examples: Alcohol, phenytoin, and fluoxetine (at high supratherapeutic doses).\n * Half-life is not constant; it depends on the initial dose.\n* Steady State:\n * Reached when Rate In = Rate Out.\n * Takes 4-5\,t_{1/2} to achieve. Fluctuations persist, but average concentration remains stable.\n * Time to steady state depends on t_{1/2}; the level of steady state depends on the dose.\n\n# Safety Indices: Quantal Curves, Therapeutic Index, and Windows\n\n* Quantal Dose-Response Curves: Plot the percentage of a population showing a predefined effect against the dose.\n * Median Effective Dose (ED_{50}$): Dose where$50\% of patients show therapeutic effect.\n * Median Toxic Dose (TD_{50}$): Dose where$50\% of patients show toxic effect.\n* Therapeutic Index (TI): Ratio of median toxic dose to median effective dose (TD_{50} / ED_{50}).\n * Narrow TI drugs: Lithium, carbamazepine, phenytoin. These require plasma monitoring.\n* Therapeutic Window: A specific plasma concentration range required for efficacy (distinct from toxicity).\n * Examples: Imipramine, nortriptyline (curvilinear response; window for nortriptyline is 50-150\,ng/ml).\n\n# Pharmacokinetic Variables in Special Populations\n\n* Elderly:\n * Increased total body fat, decreased muscle mass, and decreased total body water. Leads to larger V_d$and longer$t_{1/2} for lipophilic drugs (e.g., benzodiazepines).\n * Plasma proteins: Albumin decreases, \alpha1-acid glycoprotein increases. Higher free drug concentrations.\n * Kidney: GFR and renal blood flow decline by 10\%$per decade after age 40.$40\% of renal function is lost by age 80.\n * Brain receptors: Decreased acetylcholine receptors, leading to higher delirium risk from anticholinergics.\n* Neonates:\n * Higher total body water, lower adipose tissue.\n * Lower GFR (until 3-5 months), lower liver microsomal enzyme activity (until 2 months).\n * More permeable BBB and lower albumin concentration.\n* Pregnancy:\n * Delayed gastric emptying and decreased GIT motility.\n * 5\%$increase in$V_d, decreased albumin, induced liver metabolic pathways, and increased GFR/renal clearance.\n\n# Renal Impairment and Psychiatric Medication Adjustments\n\n* Benzodiazepines: Use with caution. Diazepam's metabolite (desmethyldiazepam) accumulates. Lorazepam t_{1/2}$increases from$8-25$hours to$32-72 hours.\n* Antidepressants:\n * Imipramine/Amitriptyline: No dose reduction needed.\n * Citalopram: Reduce dose by half.\n * Paroxetine: Reduce dose in severe impairment.\n * Fluoxetine/Fluvoxamine: No reduction required.\n* Antipsychotics:\n * Haloperidol: No reduction unless sedation/hypotension occurs.\n * Amisulpride: Relative contraindication as it is almost exclusively renally excreted.\n * Risperidone: Clearance prolonged as it is substantially excreted in urine.\n* Lithium: Best avoided or given at very low dosages.\n\n# Clinical Kinetics of Specific Antidepressants\n\n* Tricyclic Antidepressants (TCAs):\n * Long t_{1/2} (~24 hours) allowing once-daily dosing.\n * Active metabolites: Imipramine \rightarrow$desipramine; Amitriptyline$\rightarrow nortriptyline.\n * Measured after 5-7 days for steady state.\n* SSRIs:\n * Selective and potent. Escitalopram is have low protein binding (56\%).\n * Fluoxetine: t_{1/2}$of$4-6$days; its metabolite norfluoxetine has$t_{1/2}$of$4-16 days.\n * Fluoxetine and paroxetine exhibit nonlinear kinetics due to autoinhibition.\n * Fluvoxamine inhibits CYP1A2, significantly increasing levels of theophylline and warfarin.\n* MAOIs:\n * Irreversible MAOIs require 5-7 days to synthesize new enzymes. Wait 2 weeks after stopping before starting interacting drugs.\n * Interaction with Pethidine: Fatal excitatory reaction (serotonin excess) or depressive reaction.\n* Other Antidepressants:\n * Venlafaxine: Low protein binding, short t_{1/2}$($3.5$hours). Metabolized to O-desmethyl venlafaxine ($t_{1/2} 9 hours).\n * Duloxetine: t_{1/2} 12 hours, highly protein bound.\n * Mirtazapine: Peak in 2 hours, t_{1/2}$of$20-40 hours. Linear kinetics.\n * Agomelatine: Bioavailability low due to high first-pass; mainly metabolized by CYP1A2.\n\n# Mood Stabilizers: Kinetic Profiles\n\n* Lithium:\n * Rapidly absorbed, not protein bound, not metabolized.\n * Steady state in 4-5$days.$t_{1/2} is 18 hours (rises to 36 hours after 1 year of use).\n * Agents increasing lithium: ACE inhibitors, loop diuretics, NSAIDs, thiazides.\n * Agents decreasing lithium: Caffeine, theophylline, osmotic diuretics.\n* Valproate:\n * 100\%$bioavailability,$t_{1/2}$of$9-16 hours.\n * 90\% protein bound; binding is saturable (leads to "sublinear" kinetics).\n* Carbamazepine:\n * erratic absorption, bioavailabilty 80\%.\n * t_{1/2}$falls from 24 hours to 8 hours after autoinduction (starts at$2-4 weeks).\n * Therapeutic range: 4-12\,ng/ml.\n* Gabapentin:\n * Bioavailability decreases as dose increases (60\%$at$900\,mg$vs$27\%$at$4800\,mg).\n * 100\%$excreted unchanged in urine;$t_{1/2} is 6 hours; not protein bound.\n* Lamotrigine:\n * Bioavailability 98\%$,$t_{1/2}$of$24-36 hours.\n * Valproate increases lamotrigine t_{1/2}; carbamazepine reduces it.\n\n# Kinetics and Interactions of Antipsychotics and Antidementia Agents\n\n* Antipsychotics:\n * Typical types: Steady state in 3-5$days,$t_{1/2}$of$10-30$hours. Chlorpromazine has$37\%$bioavailability and$100s of metabolites.\n * Atypical types:\n * Risperidone t_{1/2} 15 hours.\n * Quetiapine t_{1/2} 6 hours.\n * Olanzapine t_{1/2} 30 hours.\n * Aripiprazole t_{1/2} 75 hours (steady state at 14 days).\n * Depots:\n * Haloperidol/Fluphenazine decanoate: Peak at 7$and$1 days respectively. Smoking reduces levels.\n * Risperidone microspheres: Therapeutic release starts only after 3 weeks (requires 3-week oral supplement).\n * Paliperidone depot: No oral tapering needed; primarily renal excretion.\n* Antidementia Drugs:\n * Donepezil: t_{1/2}$70 hours (once daily),$100\% bioavailability.\n * Rivastigmine: t_{1/2} 1.5 hours, hydrolyzed by acetylcholinesterase itself.\n * Galantamine: 90\% bioavailability, low protein binding.\n * Memantine: Long t_{1/2}$($60-80 hours), reduced clearance if urine is alkalinized.\n* Benzodiazepines:\n * Long-acting: Diazepam (20-100\,hr\,t_{1/2}), chlordiazepoxide.\n * Short-acting: Lorazepam (15\,hr$), temazepam ($10\,hr).\n * "Z" Hypnotics: Zaleplon (t_{1/2}$$1-2$hrs), Zolpidem ($t_{1/2}$$1-4$hrs), Zopiclone ($t_{1/2}$$4-5$$ hrs).