Drug Absorption and Bioavailability

• Pharmacology involves the study of drugs, including their origins, composition, pharmacokinetics, therapeutic uses, and toxicology.

General Principles of Pharmacology

• Pharmacodynamics characterizes the action of drugs on the body's biochemical and physiologic systems, identifying sites and modes of action.
• Pharmacokinetics describes the quantitative aspects of drug absorption, distribution, metabolism, and excretion, detailing the time course of drug and metabolite concentration at their site of action.

Drugs Acting Independently of Receptors

• Antacids neutralize stomach acids.
• Chelating drugs bind metallic ions.
• Osmotically active drugs include diuretics like mannitol, and cathartics like methylcellulose.
• Volatile general anesthetics cause reversible changes in the synaptic junction, with potency related to lipid solubility.

Drug Receptor Interactions

• Drugs combine with specific target molecules on cells to initiate a biochemical cascade, leading to an effect.
• Receptors may be proteins, carbohydrates, nucleic acids, or lipids.
• Binding may involve ionic, covalent, hydrogen, or van der Waals bonds.

Drug Receptor Interactions (cont.)

• Agonists bind to a receptor and stimulate it.
• Antagonists bind to a receptor and decrease or block the effect of an agonist.
• Competitive antagonists bind to the receptor and prevent agonist binding, can be overcome by high agonist concentrations, and produce a parallel right shift on the dose-response curve.
• Non-competitive antagonists bind to the receptor in an irreversible way, prevent any agonist action, cannot be reversed high [agonist], and decrease height of dose-response curve.

Summary of Antagonists

• Competitive Antagonists bind reversibly to an agonist and it can be overcome by a large amount of agonist
• Non-competitive Antagonists bind irreversibly and cannot be overcome by an agonist

Graded Dose-Response Curves

• The response of a system to increasing doses of a drug (agonist) can be analyzed.
• Agonists are drugs that bind to a receptor which results in stimulation.
• The effect is analyzed by plotting the response versus the log of drug concentration (dose).
• Efficacy is the maximum response by an agonist, which escalates as effect heightens (seen along the y-axis).

Graded Dose-Response Curves (cont.)

• Potency measures how much drug is needed to produce a given effect.
• Potency is expressed as the concentration that can give a 50% response (EC50).
• Less drug needed to produce an effect indicates a more potent drug.
• Potency increases as the curve shifts left on the x-axis.

Quantal Dose-Response Curves

• Demonstrates the minimum drug dose needed to produce a pre-determined response in a polulation.
• A percentage of the population is plotted against the Log (dose).
• ED50 (median effective dose) is the dose that will produce an effect in 50% of the population.
• TD50 is the minimum dose that produces a specific toxic effect in 50% of the population.
• LD50 is the minimum dose that will kill 50% of the population.

Quantal Dose-Response Curves (cont.)

• The therapeutic index (TI) is the ratio of the dose required to produce a toxic or lethal effect to the therapeutically effective dose.
• A TI greater than 4 is considered good.
• TI = TD50/ED50 or LD50/ED50.

Summary of Dose-Response Curves

• Drugs with high efficacy but low potency reach a high level of response with a greater dose.
• A low therapeutic index (TI) indicates a high incidence of side effects at usual doses.

Summary of High TI values

• A higher the therapeutic index is favorable and indicates a low incidence of side effects at usual doses.
• A high Therapeutic Index signifies a safer drug.
• Drug companies aim for a ratio of at least 4.
• Anything less than 2 requires close patient monitoring, such as with lithium for manic disorders.

Pharmacokinetics

• Factors that effect drug in the site of action include routes of administration. circulatroy systems, other copartments, distribution, metabolism and excretion.

Drug Absorption

• Permeability affects drug absorption because of a drugs ability to cross the cell wall, lipid solubility, aqueous solubility.
• Correlates to ability to cross cell wall
• Weak acids & bases more lipid soluble
• Charged (ions), water soluble molecules are excluded from crossing epithelial lining of skin & GIT (unless very small)

Factors affecting absorption (cont.)

• Bioavailability is the fraction of a drug that reaches systemic circulation.
• A bioavailability of "1" means 100% and indicates the drug was given intraveneously.
• <1 bioavailability, indicates permeability
• Oral administration could result in reduced bioavailability due to incomplete absorpition or the first-pass metabolism in the liver.

Routes of Administration

• An oral route of administration is most commun, safe, economical, and convenient
• Drugs must be lipid soluble and resistant to GI acid, GI digestive enzymes, and GI bacterial flora.
• Rate and degree of absorbtion can vary.

Routes of Administration (cont)

• Sublingual (buccal) administration enters venous drainage, leading to systemic circulation and bypassing the liver.
• It's good for self-administration and rapid onset, like nitroglycerin for angina pectoris.
• Suited for metabolized drugs in the liver.

Routes of Administration (cont.)

• The rectal route has less of a first-pass effect compared to oral routes.
• Rectal administration is useful in cases of vomiting or unconsciousness.
• Absorption is irregular.
• The intravenous (IV) route allows for rapid and complete delivery to target tissues.
• Useful in emergencies and for drugs highly metabolized by the liver or poorly absorbed from the GI tract.
• allows precise titration of dose levels.

Routes of Administration (cont.)

• Intramuscular (IM) administration is contraindicated for patients on anticoagulants.
• Aqueous solutions are absorbed rapidly and oil solutions are absorbed slowly.
• With Subcutaneous (SC) administration, small volumes are used and drugs are slowly absorbed

Routes of Administration (cont.)

• Topical administration is utilized on the skin, vagina, eyes, ear, nose, and throat.
• Transdermal administration is effective for the systemic delivery of drugs to the skin.
• Absorption is slow, such as with nicotine or nitroglycerin patches. Greater absorption occurs with topical lidocaine

Routes of Administration (cont)

• Intrathecal (IT) administration delivers the drug into subarachnoid space (lumbar puncture) or ventricular system (Ommaya reservoir).
• This route bypasses the blood-brain barrier and blood-CSF barrier.
• Useful for drugs with slow CNS penetration or rapid high CSF concentrations such as with meningitis and spinal anesthesia.

Routes of Administration (cont.)

• Intra-arterial (IA) administration allows for delivery of high concentrations to selective sites. • Used for X-ray contrast studies such as angiograms. • Inhalation can be used to administer gaseous and volatile drugs such as anesthetics and bronchodilators for asthma.

Drug Distribution

• Plasma protein binding is a key factor in drug distribution.
• It is determined by amount of tissue protein (albumin), the binding constant for the drug, and the fact that binding is non-specific, so several drugs may compete for the same binding site.

Drug Distribution (cont.)

• Volume of Distribution (Va) = Total drug in body(g) / Plasma [drug].
• Lipid-soluble drugs exhibit a Volume of Distribution greater than total body water.
• Drugs that bind strongly to proteins have a Volume of Distribution approaching plasma volume.
• Greater Volume of Distribution = slower excretion rate

Drug Distribution (cont)

• Unequal distribution of drugs occurs
• Tissue affinity involves binding to mucopolysaccharide, nucleoprotein & phospholipid reduces availability of drug
• Body fat acts as a reservoir for lipid-soluble drugs.
• Blood-Brain Barrier is highly selective for lipid-soluble, non-ionized drugs.
• High blood flow allows drugs to reach equilibrium quickly (e.g. brain).

Drug Distribution (cont.)

• Clinical Correlation drug competition can impact plasma protein binding and explain drug-drug interactions.
• Both fonamide & coumarin bind to proteins.
• Administration of fonamide to patient on chronic warfarin can displace it causing dangerously high levels of free warfarin in the blood, leading to severe bleeding

Drug Elimination

• Pharmacologic effects are terminated by transformation of drug to an inactive metabolite prior to excretion, excretion of unchanged drug, or active metabolite

Drug Elimination (cont.)

• Metabolism and transformation mainly occurs in the liver (most important site).
• Metabolic enzymes and hepatic microsomal enzymes are found in smooth endoplasmic reticulum (e.g. cytochrome P-450 system).
• Other enzymes are located in the mitochondria (e.g. monoamine oxidase), cytosol (e.g. alcohol dehydrogenase), or lysosomes.

Drug Elimination (cont.)

• Metabolism & Transformation occurs in two phases, Phase 1 & Phase 11
• Phase I reactions mostly encompass oxidations, reductions, or hydrolysis.
• Phase II reactions conjugate the drug or metabolite.
• Conjugations involve adding an endogenous substance (e.g. carbohydrate or sulfate).
• Phase two Inactivates drug or metabolite to hydrophilic form to facilitate excretion

Drug Elimination - Phase 11 (cont.)

• Conjugation occurs with glucuronic acid, sulfate, amino acid, or acetylation.
• Enterohepatic circulation involves:
  • conjugated drug being actively secreted in bile,
  • drugs being hydrolyzed in the small intestine,
  • most bile salts being reabsorbed in the terminal ileum,
  • drugs potentially being excreted in feces, urine, or saliva, or being reabsorbed.

Drug Elimination (cont)

• Factors that affect hepatic metabolism is age; very young or old are impaired.
• Genetics regulate activity of N-acetyltransferase
• Genetics influence metabolism of procainamide (Rx arrhythmia), dapsone (Rx autoimmune disease) and isoniazid (Rx TB)

Factors that affect Hepatic Metabolism (cont.)

• Hepatic insufficiency impairs metabolism such as with cimetidine to Rx peptic ulcer.
• Drug interactions may competitively inhibit the metabolism of microsomal enzymes leading to an increasing metabolism
• Reduced Hepatic Blood Flow can be caused by Congested Heart Failure (CHF) & drugs that reduce cardiac output (e.g. propanolol)

Metabolic Summary

• Drug interactions is an important interaction that is metabolized in the liver.

• There are inducers and inhibitors that affect metabolism.

• Inducers include Barbiturates, Phenyton (Rx epilepsy), Rifampin (Rx TB), and Carbamazepine

• Inhibitors include Cimetidine, Ketoconazole and Isoniazid

Drug Excretion

• The kidney is the primary site of the excretion process.
• Glomerular filtration occurs with protein binding
• Glomerular filtration is passive and non-saturable.
• Tubular secretion is active and saturable.
• Tubular secretion mainly happens in proximal convoluted tubules.
• Passive: neutral molecules enhance the secretion of toxic charged particles

Drug Excretion (cont.)

• Lungs excrete of gaseous anesthetics, paraldehyde (sedative & hypnotic), EtOH, and garlic

• GI tract drugs that are secreted into the liver biliary tract and are eliminated in the feces

Drug Excretion (cont.)

• Sweat, saliva, tears and breast milk are minimally involved in excretion.
• Lactating mothers require medical supervision to ensure drugs that excreted in breast milk not cause neonatal toxicity

Drug Decay Curves

• It's based on kinetic the model where the body is a single compartment
• Describes the time course of drug in the body
• Occurs when an elimination process is saturated
• Zero-order kinetics eliminates a constant amaount, not a fraction of drugs over a a given time(e.g., ETOH)

Drug Decay Curves (cont.)

• First-order kinetics are processes necessary for absorpiton or not saturable
• First-order kinetics are concentration dependent
• First-order kinetics shows a constant elimination per unit time
• First-order kinetics shows that the rate drug removal is proportional to concentration in the plasma
• First-order kinetics show a concentration of drug diminishes logarithmically with time

Drug Decay Curves (cont.)

• The rate of elimination can be desccribed in 2 ways:
  • Physiologic half-life is the time (t1/2) required for 50% of a drug to be eliminated.
  • Rate constant of elimination (ke) = percent change per unit time

Pharmaokinetics:Drug Decay Curves

• On a graph of plasma, a Plasma [drug] decreases to the with zero-order kinetics.
• An initial Plasma [drug]decreases over time with first order kinetics

Summary of Drug Decay Curves

• With Zero-order kinetics: drug decrease at a constant rate regardless of plasma drug concentration
• With First-order kinetics: drug elimination rate is proportional to plasma drug concentration

Drug Acculmulation

• Drug Clearance is the volume of blood that can completely cleared of a drug per unit time.

• Repeated doses may cause drug acculmulation

• Assuming First-Order kinetics is that if the administration is greater than the rate of elimination occurs

• Acculmulation stops when rate of elimination equals rate of administration to reach a steady state

Clinical Implications of Dose

• Determine dose interval necessary to obtain desired level of drug •Drug with short half-life: •Giving twice the dose does not double the duration of action • Drug with long half-life: • Larger loading dose, followed by smaller maintenance doses (e.g. penicillin)

Clinical Implications : Half-Life (cont)

• A drug accrues, therefore it takes approximately four half lives to reduce dosage.

Clinical Dose Implications (cont)

• Prolongation of Drug Action can be achieved by
  • Frequent doses,
  • Coating tablets (time release), -Depots, -Slow excreting and inhibiting the drug metabolism.

Clinical Dose Implications

• Loading dose is used to produce a therapeutic effect without delay of 4-5 half lives

Disease States Requiring Adjustment of Dose & Dosing Levels

• Renal Insufficiency requires the creatinine clearance to be high to eliminate the drug by kidney. The initial dose needs to be high, then decrease the intervals of the increased dose.
• With Hepatic Insufficiency the monitor of serum levels, or clinical signs of toxicity needs to be performed.

Explores drug absorption in the body, focusing on lipid solubility, aqueous solubility challenges, and bioavailability. Details intravenous administration benefits and oral route variability. Highlights first-pass metabolism effects and permeability factors.