Pharmacokinetics: Drug Action (ADME)

General Pharmacology: Pharmacokinetics

• Pharmacokinetics refers to what the body does to a drug
• Pharmacodynamics describes what the drug does to the body
• Four pharmacokinetic properties determine the onset, intensity, and duration of drug action: Absorption, Distribution, Metabolism, and Excretion (ADME)
• Absorption permits entry of the drug (either directly or indirectly) into plasma from the site of administration
• Next, the drug may reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids
• Third, the drug may be biotransformed through metabolism by the liver or other tissues
• Finally, the drug and its metabolites are eliminated from the body in urine, bile, or feces
• Clinicians can design optimal drug regimens, including the route of administration, dose, frequency, and duration of treatment with knowledge of pharmacokinetic parameters

Routes of Drug Administration

• Properties of the drug (for example, water or lipid solubility, ionization) determine the route of administration
• Therapeutic objectives (the need for a rapid onset, the need for long-term treatment, or restriction of delivery to a local site) determine the route of administration
• Major routes of drug administration include enteral, parenteral, and topical, among others

Enteral: Oral administration

• Easily self-administered
• Toxicities and/or overdose of oral drugs may be overcome with antidotes, such as activated charcoal
• Pathways of absorption are the most complicated
• Low gastric pH inactivates some drugs via oral administration

Enteral: Sublingual/buccal

• Sublingual route involves placement of drug under the tongue
• The buccal route involves placement of drug between the cheek and gum
• Advantages: ease of administration, rapid absorption, bypass of the harsh gastrointestinal (GI) environment, and avoidance of first-pass metabolism

Parenteral

• Introduces drugs directly into the systemic circulation
• Used for poorly absorbed drugs from the Gl tract (for example, heparin)
• Used for drugs unstable in the Gl tract (for example, insulin)
• Used for patients unable to take oral medications (unconscious patients)
• Used for circumstances that require a rapid onset of action
• Advantages: provides the most control over the dose of drug delivered to the body
• Disadvantages: irreversible and may cause pain, fear, local tissue damage, and infections
• The four major parenteral routes are intravascular (intravenous or intra arterial), intramuscular, subcutaneous, and intradermal

Parenteral Routes

• Intravenous (IV) is the most common parenteral route
• Useful for drugs that are not absorbed orally, such as the neuromuscular blocker rocuronium
• Permits a rapid effect and a maximum degree of control over the amount of drug delivered
• Injected as a bolus (immediate delivery of the full amount) or infused (over a longer period)
• Intramuscular (IM): can be in aqueous solutions, which are absorbed rapidly, or in specialized depot preparations, which are absorbed slowly
• Subcutaneous (SC) provides absorption via simple diffusion and is slower than the IV route
• Minimizes the risks of hemolysis or thrombosis associated with IV injection
• Should not be used with drugs that cause tissue irritation, because severe pain and necrosis may occur
• Intradermal (ID): injection into the dermis, the more vascular layer of skin under the epidermis

Other Routes

• Oral inhalation and nasal preparations provide rapid drug delivery(almost as rapid as that with IV bolus)
• Convenient for patients with respiratory disorders such as asthma, because drug is delivered directly to the site of action, minimizing systemic side effects
• Rectal route minimizes biotransformation by the liver and prevents destruction of the drug in the GI environment
• Useful if the drug induces vomiting when given orally, if the patient is already vomiting, or if the patient is unconscious
• Topical application is used when a local effect of the drug is desired
• Intrathecal/intraventricular route introduces the drug directly into cerebrospinal fluid; bypasses the blood-brain barrier, used when local or rapid treatment is required
• Transdermal route achieves systemic effects by application of drugs to the skin, usually via a transdermal patch

Absorption of Drugs

• Absorption is the transfer of a drug from the site of administration to the bloodstream
• The rate and extent of absorption depend on the environment where the drug is absorbed, chemical characteristics of the drug, and the route of administration (which influences bioavailability)
• Routes of administration other than intravenous may result in partial absorption and lower bioavailability

Mechanisms of absorption of drugs from the Gl tract

• Depending on their chemical properties, drugs may be absorbed from the Gl tract by passive diffusion, facilitated diffusion, active transport, or endocytosis
• Passive diffusion: the drug moves from an area of high concentration to one of lower concentration
• Passive diffusion does not involve a carrier, is not saturable, and shows low structural specificity
• The vast majority of drugs are absorbed by this mechanism
• Water-soluble drugs penetrate the cell membrane through aqueous channels or pores
• Lipid-soluble drugs cross membranes due to solubility in the membrane lipid bilayers
• Facilitated diffusion: large molecules enter the cell through specialized transmembrane carrier proteins
• Facilitated diffusion does not require energy, can be saturated, and may be inhibited by compounds that compete for the carrier
• Endocytosis: transports drugs of exceptionally large size and involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug-filled vesicle
• Vitamin B12 is transported across the gut wall by endocytosis
• Active transport: involves specific carrier proteins that span the membrane, is energy-dependent, and is driven by the hydrolysis of adenosine triphosphate (ATP)
• Active transport is capable of moving drugs against a concentration gradient (from a region of low drug concentration to one of higher concentration)
• Active transport is saturable, selective and may be competitively inhibited by other co-transported substances

Factors Influencing Absorption

• Most drugs are either weak acids or weak bases
• Acidic drugs (HA) release a proton (H+), causing a charged anion (A-) to form: HA ↔ H+ + A-
• Weak bases (BH+) can release an H+. The protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B): BH+ ↔ H+ + B
• A drug passes through membranes more readily if it is uncharged
• For a weak acid, protonated HA can permeate through membranes, and A- cannot
• For a weak base, the uncharged form B penetrates through the cell membrane, but the protonated form BH+ does not
• Ratio of charged and uncharged forms is determined by the pH at the site of absorption and by the strength of the weak acid or base (pKa)
• The lower the pKa of a drug, the more acidic it is.
• Intestines receive much more blood flow than the stomach, so absorption from the intestine is favored over the stomach
• Shock severely reduces blood flow to cutaneous tissues, thereby minimizing absorption from SC administration
• Intestine has a surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient
• Moving quickly through GI tract reduces absorption (severe diarrhea)
• Anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption
• Presence of food in the stomach slows gastric emptying. A drug taken with a meal is generally absorbed more slowly
• Expression of P-glycoprotein: A transmembrane transporter protein, expressed in tissues throughout the body, including the liver, kidneys, placenta, intestines, and brain capillaries
• P-glycoprotein "Pumps” drugs out of cells
• In areas of high expression, P-glycoprotein reduces drug absorption

Bioavailability

• Bioavailability is the rate and extent to which an administered drug reaches the systemic circulation
• If 100 mg of a drug is administered orally and 70 mg is absorbed unchanged, the bioavailability is 0.7 or 70%
• Determining bioavailability is important for calculating drug dosages for nonintravenous routes of administration
• Intravenous administration confers 100% bioavailability

Factors That Influence Bioavailability

• Extent to which the agent reaches the systemic circulation is affected by first-pass metabolism and the chemical and physical characteristics of the drug
• The first-pass effect is a pharmacological phenomenon in which a medication undergoes metabolism at a specific location in the body before entering the systemic circulation
• First-pass effect occurs in the liver (major site of drug metabolism), lungs, vasculature, and the gastrointestinal tract,
• First-pass hepatic metabolism: When a drug is absorbed from the Gl tract, it enters the portal circulation before entering the systemic circulation
• First-pass metabolism by the intestine or liver limits the efficacy of many oral medications.
• More than 90% of nitroglycerin, for example, is cleared during first-pass metabolism
• Nitroglycerin is primarily administered via the sublingual, transdermal, or intravenous route
• Drugs with high first-pass metabolism should be given in doses sufficient to ensure that enough active drug reaches the desired site of action

Bioavailability: Effects of drug properties

• Very hydrophilic drugs are poorly absorbed due to an inability to cross lipid-rich cell membranes
• Extremely lipophilic drugs are poorly absorbed because they are insoluble in aqueous parts, cannot gain access to the surface of cells
• For a drug to be readily absorbed, it must be largely lipophilic but have some solubility in aqueous solutions
• Chemical instability - Penicillin G, for example, is unstable in low pH or insulin is destroyed by Gl proteases
• Physical nature of drug (e.g, particle size, salt form, coating) of the drug formulation can affect the rate of absorption

Drug Distribution

• The process by which a drug reversibly leaves the bloodstream and enters the extracellular fluid and tissues
• For drugs administered IV, absorption is not a factor
• Distribution phase follows immediately, during which the drug rapidly leaves the circulation and enters the tissues
• The distribution of a drug from the plasma to the interstitium depends on local blood flow, capillary permeability, degree of binding of the drug to plasma and tissue proteins, and relative lipophilicity of the drug

Drug Distribution: Blood Flow

• The rate of blood flow to tissue varies widely
• Example: blood flow to brain, liver, and kidney is greater than that to the skeletal muscles
• Adipose tissue, skin, and viscera have still lower rates of blood flow

Drug Distribution: Blood Flow - Clinical Significance

• Clinical significance: Redistribution of propofol - variation in blood flow partly accounts for the short duration of hypnosis produced by a single IV bolus of propofol
• High blood flow, together with high lipophilicity of propofol, permits rapid distribution into the CNS and produces anesthesia
• A subsequent slower distribution to skeletal muscle and adipose tissue lowers the plasma concentration so that the drug diffuses out of the CNS, down the concentration gradient, and consciousness is regained

Drug Distribution: Capillary Permeability

• Capillary permeability is determined by capillary structure and the chemical nature of the drug
• In the liver and spleen, large proteins can pass due to discontinuous capillaries
• In the brain, the capillary structure is continuous, and there are no slit junctions
• To enter the brain, drugs must pass through the endothelial cells of the CNS capillaries or undergo active transport
• Lipid-soluble drugs readily penetrate the CNS while ionized or polar drugs generally fail to enter the CNS

Drug Distribution: Binding of drugs to plasma proteins and tissues

• Reversible binding to plasma proteins sequesters drugs in a non-diffusible form and slows transfer out of the vascular compartment
• Drugs have different affinity to plasma proteins
• Albumin is the major drug-binding protein, and it may act as a drug reservoir
• As the concentration of free drug decreases due to elimination, the bound drug dissociates from albumin to maintain the free-drug concentration
• Many drugs accumulate in tissues binding to lipids, proteins, or nucleic acids, minerals
• Tissue reservoirs may serve as a major source of the drug and prolong its actions (bisphosphonates accumulate in bones) or cause local drug toxicity (acrolein accumulates in the bladder causing hemorrhage)

Drug Distribution: Lipophilicity

• Lipophilic drugs dissolve in the lipid membranes and penetrate the entire cell surface
• The major factor influencing the distribution of lipophilic drugs is the blood flow to the area
• Hydrophilic drugs do not readily penetrate cell membranes and must pass through slit junctions

Drug Clearance

• Elimination is irreversible removal of drug from the body
• It involves biotransformation (drug metabolism) and excretion (removal of intact drug from the body)
• The three major routes of elimination are hepatic metabolism, biliary elimination, and urinary excretion
• Metabolism results in products with increased polarity, which allows the drug to be eliminated

Reactions of drug metabolism

• The kidney cannot efficiently excrete lipophilic substances because they are reabsorbed in the distal convoluted tubules
• Lipid-soluble agents are metabolized into more polar (hydrophilic) substances in the liver
• This is achieved via two general sets of reactions, called phase I and phase II

Phase I Rxns

• Phase I reactions convert lipophilic drugs into more polar molecules by introducing or unmasking a polar functional group, such as -OH or -NH2
• Reactions include oxidation, reduction and/or hydrolysis
• May increase, decrease, or have no effect on pharmacologic activity
• The phase I reactions most frequently involved in drug metabolism are catalyzed by the cytochrome P450 (CYP) system

Phase I metabolism: CYP450

• The P450 system is important for the metabolism of many endogenous compounds (such as steroids, lipids) and for the biotransformation of exogenous substances (drugs, carcinogens, and environmental pollutants)
• Cytochrome P450 (CYP) is a superfamily of heme-containing isozymes located in most cells, but primarily in the liver and Gl tract
• Certain drugs are capable of inducing CYP isozymes , called CYP inducers Examples: - phenobarbital, rifampin, and carbamazepine
• Stimulation of CYP isozymes results in increased biotransformation of drugs and leads to significant decreases in plasma concentrations of drugs metabolized by these CYP isozymes, often with concurrent loss of pharmacologic effect
• Rifampin (antituberculosis drug), for example, significantly decreases the plasma concentrations of HIV protease inhibitors, thereby diminishing the ability to suppress HIV replication

Phase I metabolism: CYP450 (continued)

• Inhibition of drug metabolism can lead to significant increases in plasma drug concentration and resultant adverse effects or drug toxicity
• Erythromycin, Ketoconazole, and Ritonavir, can inhibit several CYP isozymes
• For example, omeprazole is a potent inhibitor of three CYP isozymes involved in warfarin metabolism
• When taken with omeprazole, plasma concentrations of warfarin increase, which leads to greater anticoagulant effect and increased risk of bleeding

Phase II Rxns

• Phase II consists of conjugation reactions
• Many phase I metabolites are still too lipophilic to be excreted
• A subsequent conjugation reaction with an endogenous substrate, such as glucuronic acid, sulfuric acid, acetic acid, or an amino acid, results in polar, usually more water-soluble compounds that are often therapeutically inactive
• A notable exception is morphine-6-glucuronide, which is more potent than morphine
• Glucuronidation is the most common conjugation reaction
• Drugs already possessing an –OH, –NH2, or-COOH group may enter phase II directly and become conjugated without prior phase I metabolism
• The highly polar drug conjugates are then excreted by the kidney or in bile

Drug Clearance by the Kidney

• Renal excretion completes the process of elimination that begins in the liver
• Polar drugs or their metabolites get filtered in the kidneys and subsequently get excreted in the urine
• Reabsorption may occur in distal convoluted tubules
• Urinary pH has a significant impact on excretion, as drug ionization changes depending on urine pH
• Increased excretion occurs with weakly acidic drugs in basic urine and weakly basic drugs in acidic urine

Excretion by Other Routes

• Drug excretion may also occur via the intestines, bile, lungs, and breast milk, among others
• Drugs that are not absorbed after oral administration or drugs that are secreted directly into the intestines or into bile are excreted in the feces
• The lungs are primarily involved in the elimination of anesthetic gases (for example, desflurane)
• Elimination of drugs in breast milk may expose the breast-feeding infant to medications and/or metabolites being taken by the mother and is a potential source of undesirable side effects to the infant
• Excretion of most drugs into sweat, saliva, tears, hair, and skin occurs only to a small extent

Clinical Situations Resulting in Changes in Drug Half-Life

• When a patient has an abnormality that alters the half-life of a drug, adjustment in dosage is required
• Half-life defines the length of time required for the concentration of a drug to decrease to half of its starting dose in the body
• Patients who may have an increase in drug half-life include those with diminished renal or hepatic blood flow, for example, in cardiogenic shock, heart failure, or hemorrhage
• Patients who may have an increase in drug half-life include those with a decreased ability to extract drug from plasma, for example, in renal disease
• Patients who may have an increase in drug half-life include those with decreased metabolism, for example, when a concomitant drug inhibits metabolism or in hepatic insufficiency, as with cirrhosis
• These patients may require a decrease in dosage or less frequent dosing intervals
• The half-life of a drug may be decreased by increased hepatic blood flow, decreased protein binding, or increased metabolism
• This may necessitate higher doses or more frequent dosing intervals