II. Definitions
- Pharmacokinetics (or kinetics)
- Absorption, Distribution, Metabolism and Excretion (ADME)
- Biological Availability (Bioavailability)
- Rate and amount of drug absorption into the bloodstream and distribution to tissues
- Measured by serum concentrations or by pharmacologic or therapeutic response
- Metabolic Clearance Rate
- Rate that a drug and its metabolites are cleared from tissue and body fluids
- Drug elimination is chiefly via renal and Hepatic Clearance
- Renal Elimination
- Drug clearance via the Kidney and urine
- Hepatic Elimination
- Drug clearance via the liver, biliary tract and intestinal tract
- First Pass Effect (First Pass Metabolism)
- Drugs taken orally must first pass through the liver where they may be metabolized to inactive forms (reducing their Bioavailability)
- Half-Life (T1/2)
- Time required for a drug's plasma concentration to drop 50% after discontinuation
- Distribution Half Life (T1/2a)
- Time required for a drug's plasma concentration to drop 50% as it distributes to body tissues (typically rapid over minutes)
- Elimination Half-Life (T1/2b)
- Time required for half of a drug to be metabolized and excreted (typically slow over hours)
- Steady State
- Plasma concentration that is consistent (continuous IV infusion) or fluctuating in a consistent range (intermittent dosing)
- Drugs reach their steady state (plasma concentration, peak or trough) typically after 4-5 drug half-lives
III. Types: Proteins that increase drug water solubility and in turn aid elimination
- Cytochrome P450
- Uridine Diphosphate-glucuronosyltransferase (UGT) Conjugating Enzyme
- Glucuronosyltransferases perform Glucuronidation primarily in the liver and aid drug excretion
IV. Types: Transport Proteins move drugs and metabolites from one body compartment to another
-
Adenosine Triphosphate binding casette (ABC) drug uptake/efflux transporters
- Enzymes: Efflux pump P-Glycoprotein (P-gp)
- Organic anion-transporting polypeptide (OATP) drug transporters
- Enzymes: OATP1A1, OATP1A2, OATP2B1
V. Dosing
- Single dose
- Drug reaches a peak plasma concentration after full absorption or infusion
- Plasma levels typically fall at a consistent linear rate as tissue distribution, metabolism and excretion occur
- Continuous IV infusion
- Drugs reach their steady state plasma concentration after 4-5 drug half-lives
- Increased infusion rate raises the plasma concentration but does not decrease the time to steady state
- Intermittent dosing
- Drugs reach their steady state (fluctuation between consistent peak or trough) typically after 4-5 drug half-lives
- Peak
- High point of drug plasma concentration
- Drug toxicity is more likely to occur at peak drug concentration
- Trough
- Low point of drug plasma concentration
- Inadequate drug effect is more likely to occur at trough concentration
- Loading dose
- Drug loading doses (higher initial dose or doses) may be given to reach higher early therapeutic peak plasma concentrations
- Subsequent maintenance doses follow loading doses
- Time to steady state is not affected by the loading dose, and still depends solely on drug Half-Life
- Onset of Drug Activity
- Onset of therapeutic drug effect
- Primarily affected by Drug Administration Route (e.g. slow via oral route, rapid via IV)
- Duration of Drug Activity
- Duration of therapeutic drug effect
- Most influenced by a drug's Half-Life, although other factors (e.g. prolonged receptor binding) may extend activity duration
VI. Physiology: Pharmacokinetics
- Absorption
- Bioavailability of a drug is dependent on absorption of that drug across multiple membrane surfaces
- Passive diffusion allows for small, lipophilic, nonionic molecules to rapidly cross membranes, following a concentration gradient
- Facilitated diffusion relies on carrier molecules to cross membranes
- Aqueous channels allow small (MW <200), hydrophilic molecules to cross membranes, following a concentration gradient
- Active transport requires both a carrier molecule (facilitated) and ATP for specific drugs to cross membranes, against a gradient
- Absorption is dependent on multiple drug characteristics (polarity, size, solubility, formulation)
- Small, nonionized, lipid soluble drugs have the highest absorption (most membrane permeable)
- Patient factors impact absorption (e.g. GI Tract perfusion, Stomach acidity, interacting ingested substances including food)
- Bioavailability of a drug is dependent on absorption of that drug across multiple membrane surfaces
- Distribution
- Apparent Volume of Distribution (Vd)
- Calculated volume needed to contain the total administered drug at the same measured plasma concentration
- Vd indicates the degree of tissue distribution of a drug compared with its plasma distribution (volume of plasma in adults)
- Drugs limited to plasma distribution would have a Vd = 3 Liters
- Drugs limited to extracellular compartment would have a Vd = 16 Liters (plasma and interstitial fluid)
- Drugs with very large Vd (e.g. >46 liters, greater than Total Body Water) suggest a drug depot effect
- Membrane permeability
- Small, lipophilic drugs may rapidly cross intestinal lining, capillary walls and the blood brain barrier
- Other drugs may fail to cross key membranes
- Blood brain Barrier (differentiates drugs with CNS effects)
- Blood-placenta Barrier (differentiates drugs considered safe in pregnancy)
- Blood to Breast Milk Barrier (differentiates drugs considered safe in Lactation)
- Blood-Testes Barrier
- Plasma Protein binding
- Protein-bound drugs (e.g. albumin bound) are typically inactive and not distributed to organs and tissue
- Free drug concentrations are key to the drugs distribution and activity
- Depot Storage
- Lipophilic drugs may accumulate in fat and result in prolonged effects
- Drugs that bind Calcium may accuulate in bone and teeth
- Apparent Volume of Distribution (Vd)
- Metabolism
- Drug Metabolism typically results in a more polar (and more water soluble) drug
- Prodrugs (inactive or less active) must be metabolized to their active drug forms
- Prodrug examples include Clopidogrel, Prednisone, valacylovir
- Many, less polar drugs require metabolism before they are able to be excreted
- Polar drugs (e.g. Gentamicin, Digoxin) do not require metabolism before excretion
- Reaction Phases
- Phase 1 Reaction (non-synthetic)
- See Redox Reaction
- Oxidation or reduction of a drug into a more polar form
- Phase 2 Reaction (synthetic)
- Polar group is conjugated to the drug, resulting in a highly polar agent
- Phase 1 Reaction (non-synthetic)
- Cytochrome P450 System
- Hepatocytes in the liver contain a P450 family of microsomal enzymes on the endoplasmic reticulum
- P450 Enzymes facilitate drug oxidation and reduction, utilizing NADPH donated electrons (Phase 1 Reaction)
- Excretion
- Most drugs (90%) require metabolism to more polar and water soluble agents before excretion
- Majority of drugs are excreted in the urine
- Renal dysfunction may be associated with drug accumulation
- Urine excretion depends on glomerular filtration, tubular secretion and tubular reabsorption
- Glomerular Filtration allows easy passage of small non-ionic drugs, but typically blocks Protein-bound drugs
- Tubular secretion requires active transport of specific drugs competing for carrier binding sites
- Tubular reabsorption is typically of small nonionic drugs, which may result in their lower excretion rates
- Ionic drugs are poorly reabsorbed and typically have higher excretion rates
- Some drugs are excreted in stool (may be concentrated in bile)
- Enterohepatic circulation may result in prolonged drug effects after a drug is reabsorbed after excretion
- Clearance
- Clculated rate that a drug and its metabolites are cleared from tissue and body fluids
- Drug Clearance (L/h) = ElimRate / DrugConc
- Where ElimRate = Elimination Rate (mg/h)
- Where DrugConc = Drug Concentration (mg/L)
- Drug Clearance is measured in L/h (contrast with Rate of Elimination, measured in mg/h)
VII. Physiology: Drug Dependency
- Drug Tolerance
- Drug dosing needs to be increased to maintain the same prior effect
- Mechanisms
- Metabolic (Drug Metabolism is upregulated as dosing is increased)
- Cellular (drug receptors are down regulated)
- Examples: Alcohol Tolerance
- Blood Alcohol Level falls 0.03/h in Alcoholics compared with 0.02/h in others
-
Drug Dependence
- See Chemical Dependence
- Drug is required by patient to maintain normalcy (often with withdrawal symptoms when that drug is stopped)
- Examples: Alcohol Dependence, Benzodiazepine Dependence
-
Drug Withdrawal
- Drug stoppage results in exaggerated symptoms
- Examples: Alcohol Withdrawal, Opioid Withdrawal, Antidepressant Withdrawal
VIII. Physiology: Patient Factors
IX. References
- Olson (2020) Pharmacology, Medmaster, Miami, p. 1-12
- Asher (2017) Am Fam Physician 96(2): 101-7 [PubMed]
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