Pharmacology: Drug Interactions and Body Processes

• Pharmacology is the study of substances interacting with living systems through chemical processes.
• Interactions often involve binding to regulatory molecules.
• These interactions can activate or inhibit normal body processes.
• Drug interactions with the body are divided into pharmacodynamic and pharmacokinetic processes.
• Pharmacodynamic processes refer to a drug's actions on the body.
• These actions determine a drug's classification and suitability for treating specific symptoms or diseases.
• Pharmacokinetic processes refer to the body's actions on a drug
• These govern absorption, distribution, and elimination.
• These are important in choosing and administering drugs, especially for patients with impaired renal function.

Pharmacokinetics

• Absorption from the administration site allows the drug's entry into plasma.
• Distribution involves the drug reversibly leaving the bloodstream and entering interstitial and intracellular fluids.
• Metabolism involves the drug being biotransformed, primarily by the liver or other tissues.
• Elimination involves the drug and its metabolites being removed from the body via urine, bile, or feces.
• Clinicians use pharmacokinetic parameters to design optimal drug regimens.
• Regimens include administration route, dose, frequency, and treatment duration.

Routes of Drug Administration

• The route of administration depends on the drug's properties and therapeutic objectives.
• Objectives include rapid onset, long-term treatment, and local delivery.
• Major routes include enteral, parenteral, and topical.

Enteral Administration

• Enteral administration involves administering a drug by mouth.
• It is the safest, most common, convenient, and economical method.
• The drug can be swallowed for oral delivery.
• It can be placed under the tongue (sublingual) or between the gums and cheek (buccal)
• This facilitates direct bloodstream absorption.

Oral Administration

• Oral administration advantages include ease of self-administration.
• Overdoses may be overcome with antidotes like activated charcoal.
• Pathways are more complicated, and low gastric pH can inactivate some drugs.
• Preparations include enteric-coated and extended-release formulations.

Enteric-Coated Preparations

• Enteric coatings protect drugs from stomach acid.
• Coatings dissolve and release the drug in the less acidic intestine.
• These are useful for acid-labile drugs like omeprazole and drugs irritating to the stomach like aspirin.

Extended-Release Preparations

• Extended-release (ER, XR, XL, SR) medications have special coatings or ingredients.
• Coatings control drug release for slower absorption and prolonged action.
• ER formulations allow less frequent dosing
• This improves patient compliance.
• ER formulations maintain therapeutic concentrations longer than immediate-release forms.
• Oral morphine's half-life is 2-4 hours, requiring six daily doses.
• Only two doses are needed when using extended-release tablets.

Sublingual/Buccal Administration

• Sublingual route involves placing the drug under the tongue.
• Buccal route involves placing the drug between the cheek and gum.
• Advantages include ease of administration, rapid absorption.
• Bypasses the harsh gastrointestinal environment and avoids first-pass metabolism.

Parenteral Administration

• Parenteral route introduces drugs directly into the body by injection.
• It is used for drugs poorly absorbed or unstable in the GI tract, like heparin and insulin.
• Used when patients can't take oral medications and when rapid action is needed.
• Parenteral routes have the highest bioavailability
• Aren't subject to first-pass metabolism.
• Provides the best control over the dose delivered.
• Can cause pain, fear, tissue damage, and infections, and is irreversible.
• Intravascular (IV or intra-arterial), intramuscular, and subcutaneous are the three major parenteral routes.

Intravenous (IV) Injection

• IV injection is the most common parenteral route.
• It is useful for drugs not absorbed orally.
• IV delivery permits rapid effect and maximum control over the amount of drug.
• Bolus injection delivers the full amount immediately.
• IV infusion administers the drug over a longer period.
• Infusions result in lower peak plasma concentrations and increased duration.

Intramuscular (IM) Injection

• Drugs administered IM can be in aqueous solutions for rapid absorption.
• They can be in depot preparations for slow absorption.
• Depot preparations are suspensions in nonaqueous vehicles like polyethylene glycol which precipitates and dissolves slowly.

Subcutaneous (SC) Injection

• SC injection provides absorption via simple diffusion, slower than IV.
• It minimizes hemolysis or thrombosis risks.
• Creates constant, slow, and sustained effects.
• Avoid in drugs that cause tissue irritation, as severe pain and necrosis may occur.
• Insulin and heparin are commonly administered this way.

Intradermal Injection

• Intradermal (ID) route involves injecting into the dermis.
• It is used for diagnostic determination and desensitization.

Other Routes of Administration

• Oral inhalation and nasal preparations provide rapid drug delivery across mucous membranes and pulmonary epithelium.
• Effects can be as rapid as with IV bolus.
• Gases and aerosols can be administered via inhalation.
• Effective and convenient for respiratory disorders like asthma, minimizes systemic side effects.
• The nasal route involves topical administration for allergic rhinitis.

Intrathecal/Intraventricular Administration

• The blood-brain barrier delays or prevents drug absorption into the central nervous system (CNS).
• Direct introduction into cerebrospinal fluid is necessary when local, rapid effects are needed.

Topical Administration

• Topical application is used when a local effect is desired.

Transdermal Administration

• This route achieves systemic effects via transdermal patches.
• Absorption rate varies with skin characteristics and drug lipid solubility.

Rectal Administration

• It bypasses the portal circulation.
• Decreases biotransformation by the liver.
• Prevents drug destruction in the GI environment.
• Useful if the drug induces vomiting, or if the patient is vomiting or unconscious.
• Absorption is erratic and incomplete.
• Many drugs irritate the rectal mucosa.

Absorption Patterns and Advantages/Disadvantages of Different Administration Routes

• Oral route is affected by many factors.
• It's the safest, most common, convenient, and economical route.
• Limited absorption for some drugs, food affects absorption, drugs may be metabolized before systemic absorption.
• Sublingual route depends on the drug.
• It bypasses first-pass effect and destruction by stomach acid.
• Limited to certain drug types, drugs must be administered in small doses.
• Intravenous route requires no absorption.
• It can have immediate effects and it's valuable in emergencies.
• Unsuitable for oily substances, bolus injection may cause adverse effects, strict aseptic techniques are needed.
• Intramuscular route depends on drug diluents.
• It's suitable if drug volume is moderate, and for oily vehicles and irritants.
• Affects certain lab tests, can be painful, and can cause hemorrhage.
• Subcutaneous route depends on drug diluents.
• It's suitable for slow-release drugs and some poorly soluble suspensions.
• Pain or necrosis may occur if the drug is irritating.
• Inhalation may be rapid and immediate.
• It's effective for respiratory patients and has localized effects with fewer systemic side effects.
• It can be addictive, patients may have difficulty with dosage/using inhalers.
• Topical route is variable, affected by skin condition and other factors.
• It's suitable if a local drug effect is desired and minimizes systemic absorption.
• Some systemic absorption can occur, unsuitable for drugs with high molecular weight or poor lipid solubility.
• Transdermal route is slow and sustained.
• It bypasses the first-pass effect and is convenient and painless.
• Some patients are allergic to patches. Drug must be lipophilic.
• Rectal route is erratic and variable.
• It partially bypasses the first-pass effect and destruction by stomach acid.
• Irritates the rectal mucosa and is not widely accepted.

Absorption

• Absorption is the transfer of a drug from the administration site to the bloodstream.
• Rate and extent of absorption depend on the environment, drug's chemical characteristics, and administration route.
• Administration routes other than intravenous may result in partial absorption and lower bioavailability.
• Drugs may be absorbed from the GI tract by passive diffusion, facilitated diffusion, active transport, or endocytosis.

Passive Diffusion

• The driving force for passive diffusion is the concentration gradient across a membrane.
• The drug moves from high to lower concentration areas.
• It does not involve a carrier, is not saturable, and shows low structural specificity.
• The vast majority of drugs are absorbed this way.
• Water-soluble drugs penetrate the cell membrane through aqueous channels.
• Lipid-soluble drugs move across biologic membranes via solubility in the membrane lipid bilayers.

Facilitated Diffusion

• Other agents enter cells through transmembrane carrier proteins facilitating the passage of large molecules.
• Carrier proteins undergo conformational changes.
• Process does not require energy.
• Process can be saturated and inhibited.

Active Transport

• This mode involves specific carrier proteins that span the membrane.
• Active transport is energy-dependent due to ATP hydrolysis.
• It can move drugs against a concentration gradient.
• The process is saturable.
• Active transport systems are selective and may be competitively inhibited by other co-transported substances.

Endocytosis and Exocytosis

• Used to transport drugs exceptionally large across the cell membrane.
• Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug-filled vesicle.
• Exocytosis is the reverse of endocytosis.
• Vitamin B12 is transported via endocytosis
• Certain neurotransmitters are stored in intracellular vesicles and released by exocytosis.

Factors Influencing Absorption

• Most drugs are either weak acids or weak bases.
• Drugs pass through membranes more readily if uncharged.
• Uncharged, protonated HA can permeate for weak acids, and A- cannot.
• The uncharged form B penetrates for weak bases, but the protonated form BH+ does not.
• Effective concentration of the permeable form is determined by the relative concentrations of charged and uncharged forms.
• The ratio is determined by pH at the absorption site and by the strength of the weak acid or base, represented by pKa.
• The intestines receive much more blood flow than the stomach, so absorption from the intestine is favored.
• The intestine has a surface area about 1000-fold that of the stomach.
• Creates more efficient absorption.
• If a drug moves through the GI tract quickly, as with diarrhea, it isn't absorbed well.
• P-glycoprotein in tissues throughout the body transports molecules, including drugs, across cell membranes.
• It pumps drugs out of cells, reducing absorption in areas of high expression.
• Associated with multidrug resistance.

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 70mg is absorbed unchanged, the bioavailability is 0.7 or 70%.
• Determining bioavailability is important for calculating drug dosages for non-intravenous routes.
• Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (oral) with levels achieved by IV administration.
• IV administration ensures 100% of the drug rapidly enters circulation.
• By plotting plasma concentrations over time, the area under the curve (AUC) can be measured.
• IV administration confers 100% bioavailability, orally administered drugs undergo first-pass metabolism.
• Absorption depends on chemical and physical characteristics of the drug.

First-Pass Hepatic Metabolism

• A drug absorbed from the GI tract enters the portal circulation before systemic circulation.
• Drug metabolized in the liver or gut wall has decreased amount of unchanged drug entering systemic circulation.
• First-pass metabolism in the intestine or liver limits many oral medications' efficacy.
• More than 90% of nitroglycerin is cleared during first-pass metabolism, so it's administered sublingually, transdermally, or intravenously.
• Drugs with high first-pass metabolism should be given in sufficient doses.

Solubility of the Drug

• Hydrophilic drugs are poorly absorbed because of the inability to cross lipid-rich cell membranes.
• Lipophilic drugs are also poorly absorbed because they are insoluble in aqueous body fluids.
• Drugs must be largely lipophilic and have some solubility in aqueous solutions to be readily absorbed.
• In contrast to IV administration, orally administered drugs undergo first-pass metabolism.
• Factors such as particle size, salt form, crystal polymorphism, enteric coatings, and excipients alter drug absorption.

Drug Distribution

• Drug distribution is when a drug reversibly leaves the bloodstream and enters the interstitium and tissues.
• Absorption is not a factor for drugs administered IV.
• Initial phase (immediately after administration) represents the distribution phase.
• Transfer from the plasma to the interstitium depends on cardiac output and local blood flow, capillary permeability, tissue volume, and binding.

Blood Flow

• Blood flow varies with tissue capillaries.
• Blood flow to vessel-rich organs (brain, liver, kidney) is greater than to skeletal muscles, adipose tissue, skin, and viscera.
• Short duration of hypnosis with propofol is partly explained by high blood flow and lipophilicity.

Capillary Permeability

• Capillary permeability is determined by capillary structure and drug's chemical nature.
• Capillary structure varies in terms of the exposed basement membrane fraction.
• In the liver and spleen, there are discontinuous capillaries where large plasma proteins can pass.
• Capillary structure is continuous, without slit junctions in the brain.
• To enter the brain, drugs must pass through endothelial cells or undergo active transport.
• Lipid-soluble drugs penetrate due to dissolving in the endothelial cell membrane.
• Ionized or polar drugs generally fail due to no slit junctions.
• Closely juxtaposed cells form tight junctions that constitute the blood-brain barrier.

Binding of Drugs to Plasma Proteins and Tissues

• Reversible binding to plasma proteins sequesters drugs in a non-diffusible form.
• Albumin is the major drug-binding protein, acting as a drug reservoir.
• Bound drug dissociates to maintain a constant free-drug concentration.
• Many drugs accumulate in tissues, concentration is raised in tissues vs in interstitial fluid and blood.
• Accumulation occurs via binding to lipids, proteins, or nucleic acids/active transport into tissues.
• Tissue reservoirs are a drug source and cause drug toxicity.

Lipophilicity

• Drug transfer depends on its ability to cross cell membranes.
• Lipophilic drugs move across biologic membranes and dissolve in lipid membranes.
• Distribution is determined by blood flow to certain areas.
• Hydrophilic drugs do not readily penetrate and must pass through slit junctions.

Volume of Distribution

• The volume of distribution, Vd, is defined as the fluid volume required to contain the total drug at the same concentration in plasma.
• The calculation is dividing the dose by the plasma concentration at time zero (Co).
• Vd has no physiologic basis, it is useful to compare drug distribution with water compartment volumes.

Distribution into Water Compartments

• Once a drug enters the body, it distributes into one of the three body water compartments or becomes sequestered in a cellular site.
• Drugs with high molecular weight or extensive protein binding cannot pass through capillary slit junctions.
• Plasma compartment: Drugs trapped within the plasma have a low Vd (4 L in a 70-kg individual).
• Heparin demonstrates this distribution.
• Extracellular fluid: The drugs have a low molecular weight but is hydrophilic, it can pass through the endothelial slit junctions.
• In this state, hydrophilic drugs cannot move across the lipid membranes of cells to enter the intracellular fluid.
• With 20% of body weight or 14L in a 70-kg individual (includes plasma volume and interstitial fluid), aminoglycoside antibiotics exhibit this distribution.
• Total body water: Drugs with low molecular weight and lipophilicity can move into the interstitium and pass through the cell membranes into the intracellular fluid.
• Drugs can then distribute into 60% of body weight or 42 L in a 70-kg individual.
• A larger Va indicates greater distribution into tissues, a smaller Va suggests confinement to plasma or extracellular fluid.
• Drug clearance is usually a first-order process, allowing calculation of Va
• Constant fraction of drug is eliminated per unit of time.
• Analysis is plotting the log of plasma drug concentration vs time.
• Plasma is extrapolated to time zero (IV bolus) to determine C0
• Vd = Dose/C0

Drug Clearance by Metabolism

• Once a drug enters the body, three major routes of elimination begin: hepatic metabolism, biliary elimination, and urinary elimination.
• Elimination processes decrease plasma concentration exponentially.
• Constant fraction of drug is eliminated in a given unit of time.
• Drugs are eliminated according to first-order kinetics, although some, like aspirin at high doses, follow zero-order kinetics.
• Metabolism leads to products with increased polarity, allowing drug elimination.
• Clearance (CL) estimates the amount of drug cleared per unit of time.
• Kidneys cannot eliminate lipophilic drugs that cross cell membranes and are reabsorbed in the distal convoluted tubules.

Drug Metabolism

• Agents are metabolized into polar substances in the liver via two general sets of reactions: phase I and phase II.
• Phase I involves oxidation, reduction, or hydrolysis.
• Following phase I, the drug may be activated, unchanged, or inactivated.
• Phase II involves conjugation to produce water-soluble products which inactivates it.
• Some drugs directly enter phase II metabolism.

Drug Clearance Through the Kidney

• Drugs must be polar enough to be eliminated from the body.
• Removal occurs, primarily through elimination into the urine.
• Patients with renal dysfunction may be unable to excrete drugs.
• Accumulation and adverse effects may occur consequently.
• Processes involve in elimination is glomerular filtration, active tubular secretion, and passive tubular reabsorption.

Glomerular Filtration

• Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus.
• The drug (not bound to albumin) flows through capillary slits into the Bowman space as part of the glomerular filtrate.
• Glomerular filtration rate (GFR) is normally about 125 mL/min but may diminish in renal disease.
• Lipid solubility and pH does not influence drug passage into glomerular filtrate.
• GFR and protein binding of drugs affect the same filtration.

Proximal Tubular Secretion

• Drugs enter into the glomeruli through efferent arterioles, which divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule.
• Occurs through two energy-requiring active transport systems: one for anions (weak acids) and one for cations (weak bases).
• These transport systems show low specificity and transport many compounds, causing competition.

Distal Tubular Reabsorption

• A drug moves toward the distal convoluted tubule.
• Concentration increases and exceeds perivascular space.
• Drug may diffuse out of the nephric lumen back into the systemic circulation if uncharged.
• Increase of urine pH to increase the fraction of ionized drug in the lumen.
• In this state, it minimizes back diffusion and an undesirable drug clearance.
• Weak acids can be eliminated by alkalinization of urine and weak bases by acidification of the urine
• “Ion trapping:" a patient with phenobarbital (weak acid) overdose can be given bicarbonate to alkalize the urine.

Excretion by Other Routes

• Drug excretion, which may occur via the intestines, bile, lungs, and breast milk.
• Drugs not absorbed after oral administration or drugs secreted into the intestines/bile excrete into feces.
• Lungs primarily eliminate anesthetic gases (desflurane).
• Drugs in breast milk may expose breast-feeding infants.

Total Body Clearance

• The system eliminates drugs in sweat, saliva, tears, hair, and skin.
• Small extent.
• Total body clearance and drug half-life are important measures of drug clearance that optimize therapy and minimize toxicity.
• Total body (systemic) clearance, Cltotal, is the sum of all clearances from the drug-metabolizing and drug-eliminating organs.
• Kidneys are the major excretion organ.
• Liver contributes to metabolism and bile excretion.
• CLtotal = CLhepatic + CLrenal + CLpulmonary + CLother
• CLhepatic + CLrenal are typically the most important.

Clinical Situations

• Dosage adjustment is requires with changes in patients' half-life of a drug.
• May have increases in drug half-life include those with 1) diminished renal/hepatic blood flow 2) decrease from plasma 3) decrease metabolism/insufficiency.
• Require the decrease in dosage or less time of intervals.
• The half-life of a drug may be decreased by increased hepatic blood flow, decreased protein binding, or increased metabolism (higher doses).