Pharmacology: Principles of Pharmacokinetics

Pharmacology: General Principles of Pharmacokinetics

• Pharmacology is the systematic study of how drugs affect living systems.
• Pharmacologists study drug modification within organisms.
• A drug, from a pharmacologist's perspective, is any agent that alters biological systems through its chemical properties.
• A drug, from a legal perspective, is any FDA-approved (or equivalent) agent for disease treatment or prevention.

Pharmacokinetics and Pharmacodynamics

• Pharmacokinetics describes processes affecting drug levels in the body. These include absorption, distribution, and elimination.
• Pharmacodynamics describes the relationship between drug concentration at the site of action and the resulting effect. This includes drug-receptor interaction and the target tissue response.

Pharmacokinetics Details

• Pharmacokinetics studies how the body affects the drug (absorption, distribution, elimination)
• Drug dose is the starting point for pharmacokinetics
• Drug dose --> Absorption --> Distribution --> Biotransformation --> Drug effect --> Elimination

Why Study Pharmacokinetics (PK)?

• Drugs must reach an effective concentration at the site of action to produce a biological effect
• Drug concentrations exceeding a certain level may lead to adverse outcomes (toxicity)
• Understanding PK is crucial to controlling drug effects and designing appropriate dosing regimens.

Routes of Drug Administration

• Enteral: Oral, sublingual, rectal
• Parenteral: Intravascular (IV), intramuscular (IM), subcutaneous (SC), intradermal (ID)
• Other: Intranasal, topical (including mucous membranes and eye)
• Different routes of administration affect drug absorption, bioavailability, and onset of action

Advantages and Disadvantages of Oral Administration

• Advantages:*
• Safest
• Convenient
• Economical
• Self-administered
• Painless
• Disadvantages:*
• Limited absorption
• Slow action
• Irritable or unpalatable
• Stomach acid degradation
• First-pass effect (drug metabolism in the liver before reaching systemic circulation)
• Variability in patient cooperation

Oral Drug Preparations

• Tablets: drug + binders/fillers; vary in dissolution/disintegration rates
• Enteric-coated: dissolves in the intestine, protects from stomach acid
• Sustained-release: drug in a capsule that dissolves slowly, controls release rate

Sublingual Administration

• Advantages:*
• Economical
• Quick absorption
• Avoids first-pass effect
• Quick termination
• Self-administered
• Disadvantages:*
• Unpalatable/bitter drugs
• Oral mucosa irritation
• Limited dosage form

Rectal Administration

• Advantages:*
• Bypasses first-pass metabolism (50% of rectal drainage)
• Useful for vomiting or unconscious patients
• High concentration can be achieved
• Suitable for drugs irritating the stomach
• Disadvantages:*
• Embarrassing
• Inconvenient
• Absorption can be slow
• Possible irritation of rectal mucosa

Parenteral Administration

• Advantages:*
• Useful for poorly absorbed drugs
• Useful for unconscious patients, emergencies
• Rapid onset of action
• High control over dose delivered
• Disadvantages:*
• Risk of infection, pain
• Risk of embolism, necrosis
• Potential for venous thrombosis and phlebitis

Intravenous (IV) Administration

• Advantages:*
• Rapid drug delivery and absorption (avoids first-pass)
• Ideal for emergencies and rapid onset of action
• Precise control over the dose
• Disadvantages:*
• Risk of serious complications (embolism, infection), cannot be recalled
• Requires sterility and trained personnel

Intramuscular (IM) Administration

• Advantages:*
• Relatively uniform absorption
• Rapid onset of action
• Suitable for drug irritants
• Avoids gastric absorption factors
• Disadvantages:*
• Limited volume
• Potential for pain, abscess, nerve damage
• Less control over the rate of absorption

Subcutaneous (SC) Administration

• Advantages:*
• Smooth but slow absorption
• Depot injections/implants
• Disadvantages:*
• Small volume capacity for administration
• Irritant drugs can cause necrosis
• Not suitable for emergencies

Topical Administration

• Delivery of drugs to mucous membranes (eye, ear, nose).
• Can also be creams and ointments on the skin.

Factors Affecting Drug Absorption

• Physiochemical properties of the drug.
• Properties of the environment (degradation).
• Dosage form used
• Anatomy & physiology of the absorption site (surface area, motility, blood flow)

Modes of Drug Transport

• Passive (diffusion)
• Active (transport mechanisms)

pH and pKa

• The pH difference between blood and interstitial fluid does affect drug ionization and penetration.
• However, these differences are typically not significant for most organs.

Drug Distribution

• Drug distribution is influenced by physicochemical characteristics, tissue perfusion, regional blood flow, and capillary permeability.
• First-pass distribution includes highly perfused organs. Second is muscle, viscera and skin.

Drug Accumulation

• Drugs can accumulate in tissues passively or by binding to macromolecules.
• High partition coefficients contribute to fat accumulation.

Drug Elimination (Clearance)

• Elimination of drugs from the body via metabolism and excretion.
• Metabolism transforms drugs into more water-soluble forms, helping with excretion.
• The main excretion route is through the kidneys (urine).

Drug Metabolism

• Phase I reactions involve functionalization, often creating active metabolites or converting inactive drugs into active ones
• Phase II reactions involve conjugation (combining a Phase I product with a highly polar residue), making drugs more hydrophilic and promoting renal excretion

Drug Excretion

• Renal elimination: glomerular filtration, passive reabsorption, active secretion
• Other routes: bile, sweat, saliva, tears

Glomerular Filtration

• Small molecules (Mwt <500) are filtered.
• Ionization status of the drug influences filtration rates.

Active Tubular Secretion

• Active (energy-requiring) process
• Affected by carrier proteins
• Protein binding does not hinder secretion

Passive Reabsorption

• Depends on ionization status, concentration gradient (water/sodium)
• Alkalization and acidification can affect the absorption of acidic/basic drugs.