Pharmacokinetics

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Pharmaceutical phase

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i. Drug undergoes disintegration and dissolution
ii. Depends on dosage form and route of administration

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Pharmacokinetic phase

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i. Determines the concentration of a drug and its time course of action
ii. Adsorption
iii. Distribution
iv. Metabolism
v. Excretion

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Adsorption and distribution

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i. Determine how a drug is transported from its site of administration to its site of action

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Redistribution, metabolism, and excretion

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i. Terminate the effects of a drug and remove it from its site of action

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Pharmacodynamic phase

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i. Determines the intensity of a drug’s effect in relation to its concentration, usually at the site of action
ii. There is a defined relationship between administered dose, resulting concentrations in various tissues, and intensity of pharmacologic effects (dose-response relationships)

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Simple diffusion

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i. Passive
ii. No direct expenditure of energy for a substance to cross a biological barrier down its concentration gradient

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Nonelectrolytes

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1. Can diffuse passively across the lipid bilayer at varying rates
2. Very small water-soluble molecules or ions can diffuse through aqueous pores or channels
3. Large organic molecules are difficult to pass through membrane
4. Some water solubility for a drug molecule is essential for rapid diffusion across cell membranes

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Electrolytes

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1. Many drugs are either weak acids or weak bases→ tend to ionize in aqueous solutions
2. Degree of ionization based on Ka and pH of solution
3. Henderson-Hasselbalch used to determine fraction of molecules in ionized v. nonionized states at given pH

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pKa

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a. represents the pH at which there are equal proportions of ionized an dnonionized molecules

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Acid equation

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a. pKa-pH=Log [HA]/[A-]

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Base equation

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a. pKa-pH=Log [BH+]/[B]

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Ion trapping

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1. pH difference across a membrane, difference in ionized fraction
2. Rate of penetration of a weak electrolyte across a membrane is dependent upon pH gradient
3. At Eq, concentration of nonionized drug is equal on both sides of membrane, but total concentration of drug will be higher on side where degree of ionization is greater
4. Drugs may be trapped in body fluids whose pH differs from blood

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Ion trapping in what fluids?

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5. Breast milk, stomach contents, small intestinal contents, urine

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Acidic/basic drug accumulation

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a. Acidic→ more on basic side of membrane
b. Basic→ more on acidic side of membrane

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Aspirin

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a. Weak acid with pKa of 3.5
b. In acidic environment, weak acidic drugs are mainly in nonionized form (HA)
c. Aspiring can be readily absorbed from the stomach
d. In bloodstream (pH=7.4), aspirin is mainly A- which prevents it form diffusing back into the stomach

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Filtration

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1. Bulk flow of solvent and solute through pores in the membrane
2. Rate of movement depends on concentration gradient and molecular size of compound
3. Glomerular filtration is important for renal excretion of many drugs

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Ion-pair transport

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1. Highly ionized and lipophobic compounds combine with endogenous substances
2. Results in neutral ion-pair complex
3. Can penetrate the lipid membrane by passive diffusion
4. Quaternary ammonium and sulfonic acids reversibly combine with mucin in GI tract
5. Not common

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Carrier-mediated transport

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1. Special carrier molecules exist for many substances that are too large or lipid insoluble to diffuse passively through membranes
2. Binding sites are limited→ process is saturable

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Facilitated diffusion

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a. Driving force is concentration or EC gradient across membrane
b. Substrate forms complex with specific carrier protein that spans the membrane
c. Delivers molecule to other side of energy
d. No direct energy expenditure

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Active transport

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a. Energy-dependent

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Primary active transport

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i. Utilizes ATP

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Secondary active transport

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i. Utilizes EC energy to move another molecule against a concentration gradient
ii. Gradient created by primary active transporters

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ATP-binding cassette (ABC) superfamily

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a. P-gp→ pump substrates back into intestinal lumen from enterocytes, protect organs from drug accumulation
b. MDR1 transporter→ expressed in many tissues and can limit drug absorption or facilitate elimination

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Solute-linked carrier (SLC) superfamily of proteins

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a. Efflux transporters for organic anions, cations, amino acids, and neurotransmitters
b. Involved in intestinal absorption, hepatic uptake, and renal tubular secretion of many drugs

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Pinocytosis

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1. Invagination of a localized part of cell membrane to form a small vesicle
2. Transported across membrane and released in cytosol
3. Permits large or lipid-insoluble compounds (proteins) to cross membranes

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Transcytosis

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1. Receptor-mediated uptake and transport across cell
2. Endocytosis to exocytosis
3. Energy required
4. Selective

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Drug absorption

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a. Movement of a drug from its site of administration into the blood or lymph capillaries

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Drug solubility and dissolution rate

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i. Depends on form of the drug (salt)
ii. Particle size
iii. pH of environment relative to drug pKa

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Concentration (dose) of drug

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i. Increases in a linear fashion if the dose of drug is increased

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Circulation to the site of adsorption

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i. Rate of adsorption across any membrane is related to ability of vasculature to remove drug from local site of administration

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Absorbing surface area

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i. Rate of absorption increases with absorbing surface area increase
ii. Small intestine v. stomach

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Physiological characteristics

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i. Gastric emptying time
ii. GI motility
iii. Presence of food
iv. Presence of other drugs
v. Digestive disorders

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Enteral administration

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i. Drug placed directly into GI tract
ii. Drugs can be absorbed from oral cavity, stomach, intestines, or rectum

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Parenteral administration

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i. Any route of administration that bypasses the enteral route of administration
ii. IV, IM, SC
iii. Topically or transdermally
iv. Aerosol and volatile agents can be administered by inhalation

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First-pass effect

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i. Drugs absorbed from stomach or intestine first transported via portal vein to capillary bed of liver
ii. Effect occurs when drug is inactivated or eliminated prior to entry into systemic circulation
iii. w/in GI tract or during drug’s first pass through the liver

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First-pass effect and oral administration

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i. Drugs absorbed within oral cavity enter access to general circulation without first traversing the liver→ avoid first-pass effect
ii. Nitroglycerin

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First-pass and rectal administration

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i. 50% of a drug absorbed from rectum will also bypass the liver

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Area under concentration curve

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i. AUC
ii. Function of extent of absorption and represents overall systemic expore of drug
iii. Provides useful measure to compare relative bioavailability of different drug formulations

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Bioavailability

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i. Fraction (%) of unchanged drug reaching the systemic circulation following administration of any route

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IV bioavailability

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i. 100%

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Low bioavailability

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i. May result from failure of drug to disintegrate or dissolve iN GI tract
ii. Degradation in GI tract
iii. Poor mucosal permeability
iv. First-pass metabolism
v. Active efflux transport

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Bioequivalence

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i. Two drugs are considered bioequivalent if they contain the same active ingredients
ii. Rate and extent of absorption of active ingredients is not significantly different

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Capillary permeability

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i. Initial barrier to distribution of drugs outside the vascular compartment
ii. Transcapillary movement factors→ molecular size, lipid solubility, concentration gradient
iii. Renal and hepatic capillaries are especially permeable to movement of most molecules, especially large ones

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Tissue perfusion

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i. Greater blood flow leads to more rapid distribution of a drug to tissues and organs
ii. Well-perfused tissues achieve high tissue concentrations sooner than poorly perfused tissues

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Tissue mass

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i. Capacity of muscle and adipose tissue to remove drugs from blood tends to lower plasma concentration
ii. Lipid-soluble drugs may achieve high concentrations in adipose tissue

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Binding of drugs to plasma proteins

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i. Albumin (acidic) and α1-acid glycoprotein (basic) have a high affinity for drugs
ii. Some disease states are associated with changes in plasma protein binding of drugs
iii. Reversible binding

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Binding of a drug to plasma protein effect on concentration

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i. Effective concentration is decreased
ii. Slows rate of transfer across capillary
iii. As free drug leaves circulation, bound drug begins to dissociated and more free drug is available for diffusion
iv. Helps regulate concentration in tissues

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Volume of distribution

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a. Hypothetical concept that helps in quantifying the distribution of a drug
b. Assumes homogeneous distribution
c. Relates dose of drug to peak plasma concentration
d. Indicates relative size of body compartment containing the drug

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Blood-brain barrier

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a. Consists of capillary endothelium with tight junctions and astrocytic sheath
b. Limits passage of many drugs into the brain

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Permeability of blood-brain barrier

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a. Affected by age or inflammation
b. Bacterial meningitis or encephalitis, increased permeability allows entry of ionized lipid-insolube compounds (penicillins)

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Blood-CSF barrier

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a. Drugs can enter the CSF via the choroid plexus, which is line with fenestrated capillaries
b. Choroid epithelial cells have tight junctions and active transport processes