Drug Administration Routes

• Before drugs can be absorbed, they must be administered, and both drug-related factors and patient-related factors affect the selection of routes.
• Several determinants for selecting drug administration routes include drug characteristics, urgency, targeted site (local or systemic), patient condition, age, gastric pH influence, digestive enzymes, first-pass metabolism, and patient/doctor preferences.

Local Routes

• The simplest way of administering a drug where the action is required, and systemic side effects are minimal
• Topical: The drug is applied to the skin or mucous membrane for local action.
• Oral cavity examples: nystatin as a suspension, clotrimazole as a troche, acyclovir as a cream, and lignocaine hydrochloride as an ointment, jelly or spray
• GI tract example: neomycin as a tablet that's not absorbed
• Rectum and anal canal options: Enemas (evacuant or retention) and suppositories such as bisacodyl
• Eye, ear, and nose use drops, ointments, and sprays like gentamicin for infections or allergies
• Bronchi uses inhalation for conditions like asthma, using salbutamol or ipratropium bromide
• The skin uses ointments, creams, lotions, or powders like clotrimazole for cutaneous candidiasis.
• Intra-arterial route: rarely used, mainly for diagnostic studies like coronary angiography and some anticancer drugs for limb malignancies.
• Administration through injection into deep tissues, such as triamcinolone into the joint space for rheumatoid arthritis.

Systemic Routes

• Drugs enter the blood and produce systemic effects
• Enteral routes: include oral, sublingual, and rectal methods
• Oral route: safest, cheapest, painless, convenient, given repetitively or for long periods, and self-administered, the most common and acceptable
• Oral route dosage forms: tablets, capsules, syrups, mixtures
• Downsides to oral route: unsuitable in emergencies due to slow action, and cannot be used with unpalatable, highly irritant, unabsorbable, or digestive juices
• Oral route: should not be used with drugs that are destroyed by digestive juices (e.g., insulin), drugs with extensive first-pass metabolism (e.g., lignocaine), or in unconscious, uncooperative, unreliable patients with vomiting or diarrhea.
• Sublingual route: The preparation is kept under the tongue to absorb through the buccal mucous membrane and enter systemic circulation directly.
• Sublingual examples: Nitroglycerin for acute anginal attacks and buprenorphine for myocardial infarction
• Sublingual route: Rapid action, termination by spitting, bypasses first-pass metabolism, and capability of self-administration
• Sublingual route: Not suited for irritant or lipid-insoluble drugs, or drugs that are bad-tasting or smelling.
• Rectal Route: Drugs in solid or liquid form offer local or (mentioned above) systemic effects
• Rectal Route: Suppositories may have local (topical) effects or systemic effects (e.g., indomethacin for rheumatoid arthritis)
• Retention enemas can have local or systemic effects
• Enemas: Diazepam treats status epilepticus in children through drug absorption in the rectal mucous membrane, producing a systemic effect.

Parenteral Routes

• Routes of administration other than enteral
• Parenteral benefits: shorter action, suitable for emergency use, and usage for vomiting, or uncooperative patients
• Parenteral usage: drugs that irritate, undergo high first-pass metabolism, are poorly absorbed orally, or are degraded by digestive juices
• Parenteral disadvantages: require aseptic conditions, sterile preparations (expensive), invasive/painful, not usually self-administered, may cause tissue damage
• Inhalation: Quick action, low dose and toxicity, ability to regulate the quantity of drug administered
• Inhalation: may cause local irritation, elevated respiratory secretions, or bronchospasm
• Intradermal route: Injected into skin layers for BCG vaccinations and drug sensitivity tests
• Intradermal route: painful, accepts small volumes of drug
• Subcutaneous (s.c.) route: injection into subcutaneous tissues of the thigh, abdomen and arm
• Advantages: Self-administration (e.g. insulin)
• Depot preparations: can be used for contraception
• Subcutaneous route: slow absorption and unsuitability in emergencies
• Intramuscular (i.m.) route: injected into large muscle groups.
• Intramuscular route: More rapid absorption versus oral, can be used for mild irritants, depot injects and soluble substances with suspensions and injection volumes can be 5-10ml at a time
• Intramuscular route: requires precautions, painfulness, difficulty with self-administration, nerve injury risk
• Intravenous (i.v.) route: Drugs injected directly into the bloodstream through a vein
• Intravenous route: Drugs can be administered as bolus, slow injection, or intravenous infusion
• Bolus: The single, relatively high drug dose unit is injected at a fast and slow cadence into a vein
• Bioavailability is: 100%
• Quick onset of action: Primary emergency route, such as intravenous diazepam to control convulsions in status epilepticus
• Intravenous route: can infuse large fluids, or highly irritating anticancer drugs
• Hypertonic solutions and constant drug levels can be infused through injection
• Disadvantages: Once injected, stopping action is impossible, irritation may cause phlebitis, self-medication is difficult, and aseptic conditions are a must.

Absorption of Drugs

• Drug absorption is the movement of a drug into the bloodstream following administration
• Absorption: determined by the properties of the drug's physicochemical properties, formulation, plus route
• Drugs must be in solution to be absorbed, so tablets must disintegrate and deaggregate
• Absorption affects bioavailability, determining its rate and its magnitude is how quickly a drug reaches its point of contact
• Cell membranes selectively block passage of molecules
• Cell membranes: bimolecular lipid matrix influences permeability characteristics
• Drugs cross membranes through: passive diffusion, facilitated passive diffusion, active transport, or pinocytosis
• Membrane embedded proteins work as receptors to aid molecule transportation
• Passive mechanisms don't require energy use, but depend on membrane permeability
• Main types of passive transport: diffusion, osmosis, and facilitated diffusion
• Active mechanism: uses energy, frequently in ATP form, which creates charge gradient
• Active transport selectively requires transport for drugs similar to endogenous substances
• Active transport substances: ions, vitamins, sugars, and acids normally from the small intestine

Passive Diffusion

• Drugs diffuse membranes from high-concentration regions, which are usually (GI fluids), to low concentrations (blood)
• Diffusion rate is directly relative to the gradient, molecule's lipid solubility, dimension, degree of ionization, and absorptive surface area
• Lipophilic drugs diffuse faster, whereas smaller molecules move through membranes more rapidly than larger molecules
• Most drugs are weak organic acids/bases, in ionized/un-ionized forms in aqueous environments
• Lipid-soluble, un-ionized forms allow for rapid diffusion across cell membranes, whereas the ionized form has low lipid solubility
• Un-ionized form present, which determines ability to pass, is determined by environmental pH and drug's pKa
• pKa is when ionized and un-ionized form concentrations are the same
• Weak acid dominance: results on the un-ionized form when there is weak acid and the pH is low
• Reversed result: weak acids with a stronger base
• Absorption: Higher levels typically occur in the small intestine, regardless of drug type, due to larger surface area with more permeable membranes.
• Facilitated passive diffusion: Molecules with low lipid solubility can penetrate membranes more quicker than expected
• A carrier molecule within the membrane combines reversibly with a substrate molecule and diffuses across the membrane
• Membrane transports only substrates with particular molecular configuration, carrier availability limits process
• It doesn't require energy use, and transport can't occur with concentration gradients
• Active transport: Drug passage requiring energy-dependent membrane carrier mechanism, which is why it can occur without energy use and it can't occur with a concentration gradient
• Mechanisms include: ATP-dependent proteins
• Exhibits selectivity and saturability, it must also obey Michaelis-Menten kinetics
• Zero-order kinetics concentration is high (rate of transport is constant).

Exocytosis/Pinocytosis

• Types of active transport require energy use, and fluid or particles are engulfed by a cell
• The cell membrane invaginates to make a vesicle move around the cell interior
• Important factors for drug transfer across membranes are absorption, distribution, metabolism, and excretion
• Mechanisms by which drugs cross membranes and influence of physicochemical properties of molecules and membranes are important
• Characteristics that predict movement and activity of drug types depends on their molecular size and shape along with the degree of ionization and protein binding in the serum or tissues
• Barriers may involve a single layer of cells (intestine epithelium) or multiple layers with associated extracellular protein (skin) but the plasma membrane is a general barrier

Plasma

• Primarily amphipathic lipids, hydrocarbon chains oriented inward to form a hydrophobic phase with hydrophilic heads outward
• Lipid content: influenced by what membrane is involved, and can vary laterally organized by cholesterol and sphingolipids
• Membrane proteins embedded in the bilayer serve to transduce signals and enable targets for drugs
• Proteins may stay within caveolae
• Drugs use passive processes to cross membranes
• Passive transport: drug molecule penetrates via diffusion across a concentration gradient per the solubility in the lipid bilayer
• This transfer gradient is directly proportional to the magnitude and the partition coefficient
• Ionic compound balance depends on the electrochemical gradient differences in pH can affect ionization and result on the molecule.
• The lower soluble, non-ionized molecules diffuse easily
• Transmembrane distribution of weak electrolytes rely on pH and pKa as well per the formula: pKa is when half the electrolyte is ionized
• Factors that influence diffusion across cellular membranes, influenced by Fick's First Law of Diffusion
• Molar flux due to diffusion is proportional to the concentration gradient
• Distance variable: present in equations and influence the surface area
• Diffusion: Influenced by solution temperature, fluid viscosity, and size of molecules
• pKa and pH: can will influence the lipid-water partition with better partition rates result in increased capacity to cross.

This lesson explores various routes of drug administration, including oral, topical, rectal, inhalation, and intra-arterial. It also considers factors influencing route selection, such as drug properties and clinical urgency. Each method offers unique advantages and disadvantages depending on the drug and situation.