pharm quiz lecture 4

• Most drugs move from the administration site to their action site by permeating cell membranes that separate compartments.
• Transport across membranes affects drug absorption, distribution, metabolism, and excretion.
• Factors include molecular size, structural features, ionization degree, lipid solubility, and protein binding.

Passive Transport

• Passive transport is the most important type of transport.
• Cell membranes consist of amphipathic lipids, with both hydrophobic and hydrophilic parts.
• Membranes are permeable to water; bulk flow carries small water-soluble substances (100-200Da).
• Passive diffusion is generally limited to unbound drugs.
• Large lipophilic drugs typically pass through membranes easily.
• Passive diffusion dominates transport for most drugs.

Paracellular Transport

• Molecules can pass through intercellular gaps.
• Transfer in capillary endothelium is limited by blood flow.
• Capillaries can have tight junctions limiting paracellular flow.
• The liver has huge cellular gaps allowing protein passage.

Factors affecting passive flux

• Drug concentration gradient across the membrane.
• Lipid-water partition coefficient (higher = faster diffusion).
• Surface area of the membrane.
• Membrane thickness (thicker = slower diffusion).

Weak Acids & Bases

• Many drugs are weak acids or bases, present in solution as ionized and un-ionized species.
• Un-ionized species are more lipid-soluble and diffuse more easily.
• Ionized species are less lipid-soluble and cross membranes less easily.
• Ionizable groups include carboxylic acid (pKa 4.5) and primary amino groups (pKa 9.5).

Transmembrane Distribution

• Transmembrane distribution of a weak electrolyte is influenced by its pKa and the pH gradient.
• pKa is the pH at which 50% of the drug is ionized and 50% is un-ionized.
• pKa is usually between pH 3 and pH 11.

Drug Accumulation

• Drugs accumulate on the side of the membrane where ionization is highest (ion trapping).
• Basic drugs accumulate in acidic fluids.
• Acidic drugs accumulate in basic fluids.
• pH determines drug ionization degree on either side of cell membrane.

Carrier-Mediated Transport

• Used for molecules too large or not lipid-soluble for passive diffusion.
• Carriers are saturable, selective, and inhibitable.

Active Transporters

• Active transporters move molecules against their concentration and electrical gradient.
• Requires energy in the form of ATP.
• Example: Na+-K+-ATPase pumps in excitable cells.

Facilitated Transporters

• Facilitated transporters move large/lipid-insoluble molecules down their electrochemical gradient.
• No energy input required.
• Example: glucose via GLUT 4 transporter.

Pharmacokinetics

• Processes affecting drug movement through the body (ADME: absorption, distribution, metabolism, excretion).

Absorption

• Most drugs are absorbed into the systemic circulation from the administration site to reach target sites.
• Required for most routes except intravenous, intrathecal, and topical.
• Solid/semi-solid dosage forms require dissolution of the active drug before absorption.
• Absorption rate affects the onset, duration, and intensity of action.

Factors Affecting Absorption

• A large concentration gradient between the administration site and surrounding tissues drives drug uptake.
• Regional blood flow has the greatest effect on maintaining a large concentration gradient.
• The physical form and chemical ingredients of a medication (active drug and inactive chemicals).
• Modifications can slow or delay API release for absorption, which can be more convenient for drugs with short elimination half-lives.
• "Dose dumping" or erratic absorption are potential concerns with modified formulations.

Bioavailability

• Bioavailability is the fraction (%) of the administered dose that reaches the systemic circulation unchanged.
• Can be reduced by precipitation at the injection site, poor GI absorption (due to physicochemical properties or reverse transport proteins).
• First-pass effect is the elimination of a drug following oral administration, primarily due to liver metabolizing enzymes.
• Enzymes in the GI tract wall can also metabolize the and the drug can be excreted in bile.

Routes of Administration: Enteral (Oral)

• Most common
• Advantages: convenient, economical, safer, minimal infection risk, can induce vomiting.
• Disadvantages: erratic absorption, enteric coating issues, compliance problems, not for unconscious patients, emesis, first-pass effect.

Routes of Administration: Oral Transmucosal (Sublingual)

• Absorption from the oral mucosa.
• Can bypass the first-pass effect via venous drainage to the superior vena cava.
• Usually highly lipophilic drugs.

Routes of Administration: Rectal

• Estimated 50% of drug bypass "first-pass effect".
• Absorption can be erratic and incomplete.
• Potential irritation.
• Used in patients with GI motility disorders and near end of life.

Routes of Administration: Parenteral (Injectable)

• Drug availability is more rapid and predictable compared to oral routes.
• Bypasses the "first-pass effect".

Routes of Administration: Subcutaneous (SC or SQ)

• Injection into the tissues below the skin.
• Advantages: suitable for solid pellets and insoluble suspensions, easier than IV.
• Disadvantages: slower absorption than IM, can be erratic, not suitable for large volumes, pain and necrosis with irritating solutions.

Routes of Administration: Intramuscular (IM)

• Injection administered into the muscle.
• Advantages: rapid absorption for drugs in aqueous solution, oily suspensions form depot, safer than IV.
• Disadvantages: local pain and swelling with irritating solutions.

Routes of Administration: Intravenous (IV)

• Drug administered into an accessible vein (bolus vs. slow infusion).
• Advantages: choice for emergencies, large volumes can be given, complete bioavailability, controlled dose delivery, rapid onset.
• Disadvantages: solutions must be injected slowly, not for oily suspensions, adverse reactions.

Routes of Administration: Topical

• Drugs applied to the eye, skin, and mucus membranes.
• Advantages: drug delivered locally, can achieve high concentrations.
• Disadvantages: may be absorbed systemically causing adverse effects, may not remain at the desired site.

Routes of Administration: Transdermal

• Drugs applied to the skin and absorbed into systemic circulation.
• Advantages: absorption enhanced by damaged skin, controlled release (e.g., nicotine and fentanyl patches), prolonged duration, bypasses "first-pass" effect.
• Disadvantages: therapeutic blood levels are slow to achieve, delayed onset of action.

Explores how drugs move through the body, focusing on cell membrane permeation and its impact on drug action. Discusses passive transport, influenced by drug properties, and paracellular transport through intercellular gaps. Key factors include molecular size, lipid solubility and ionization.