General pharmacology Pharmacokinetics Prof Hanan Hagar Dr Abdul

General pharmacology (Pharmacokinetics) Prof. Hanan Hagar Dr. Abdul latif Mahesar Pharmacology Department

Pharmacokinetics By the end of this lecture, the student should be able to n Discuss the different routes of drug administration n Identify the advantages and disadvantages of various routes of drug administration n Know the various mechanisms of drug absorption n List different factors affecting drug absorption n Define bioavailability

Recommended books n Lippincott’s illustrated reviews (Pharmacology) by Howland Mycek n Basic and Clinical Pharmacology by Katzung

q q Pharmacokinetics of drugs (ADME) Are studies of Absorption Distribution Metabolism Excretion of drugs

Drug Excretion Metabolism Administration Blood Absorption Site of action Distribution Different organs & tissues

Sites of Administration Absorption & distribution Elimination

n Enteral via gastrointestinal tract (GIT). q q q n n n Oral Sublingual Rectal Parenteral administration = injections. Topical application Inhalation

Advantages - Easy - Self use - Safe - Convenient - cheap - No need for sterilization Disadvantages - Slow effect -No complete absorption - Destruction by p. H and enzymes - GIT irritation - Food - Drug interactions -Drug interactions - First pass effect - (low bioavailability). Not suitable for q vomiting & unconscious patient q emergency q bad taste drugs

First pass Metabolism § Drugs taken orally are first taken to liver (via portal circulation) where they are metabolized before reaching to rest of body. § so the amount reaching system circulation is less than the amount absorbed Results ? Low bioavailability = low serum level of active drug that can produce action

First pass effect

Oral Dosage Forms (oral formulations) n n n Tablets (enteric coated tablets) Capsules (hard and soft gelatin capsules) Syrup Suspension Emulsion

Tablets Hard- gelatin capsule Spansule Soft- gelatin capsule Suspension Emulsion

Advantages Rapid effect q can be used in emergency q High bioavailability q No first pass effect. q No GIT irritation q No food drug - interaction q Dosage form: friable tablet Disadvantages Not for - irritant drugs - Frequent use

Advantages Suitable for q children q Vomiting or unconscious patients q Irritant & Bad taste drugs. q less first pass metabolism (50%) Dosage form: suppository or enema Disadvantages Irregular absorption & bioavailability. q Irritation of rectal mucosa. q

Intradermal (I. D. ) (into skin) Subcutaneous (S. C. ) (under skin) Intramuscular (I. M. ) (into muscles) Intravenous (I. V. ) (into veins) Intra-arterial (I. A. ) (into arteries) Intrathecal (I. T. ) (cerebrospinal fluids ) Intraperitoneal (I. P. ) (peritoneal cavity) Intra - articular (Synovial fluids)

Advantages Rapid action (emergency) q High bioavailability q No food-drug interaction q No first pass metabolism q No gastric irritation Suitable for q Vomiting &unconscious q Irritant & Bad taste drugs. Dosage form: Vial or ampoule q Disadvantages Only for water soluble drugs q Infection q Sterilization. q Pain q Needs skill q Anaphylaxis q Expensive Not suitable for oily solutions or poorly soluble substance q

Ampoule Single use Vial Repeated use

Injection Special Utility Limitations I. D. minute volume (0. 1 ml) suitable for vaccinations & sensitivity test not suitable for large volumes S. C. 0. 1 ml – 1 ml suitable for poorly soluble suspensions and for instillation of slow-release implants e. g. insulin zinc preparation not suitable for large volumes I. M. larger volume 3 -5 ml Suitable not suitable for irritant drugs for moderate volumes, for oily Abscess- necrosis may happen solutions or poorly soluble substances I. V. suitable for large volumes and not suitable for oily solutions for irritating substances or poorly soluble substances Must inject solutions slowly as a rule

Ø Ø Drugs are applied to skin, ear, eye, nose, vagina, respiratory tract Usually used to provide local action. No first pass metabolism. Used for lipid soluble drugs

Advantages mucous membrane of respiratory system q rapid absorption (large surface area) q provide local action in q limited systemic effect q less side effects. q no first pass effect q Dosage form: aerosol, nebulizer Disadvantages Not suitable for irritant drugs Only for some drugs as inhalation anesthetics & bronchodilators

Nebulizer Atomizer

Is the passage of drug from its site of administration to its site of action through cell membranes. Cell membrane Sites of Administration Sites of action

1. 2. 3. 4. Simple diffusion = passive diffusion. Active transport. Facilitated diffusion. Pinocytosis (Endocytosis).

Ø water soluble drug (ionized or polar) is readily absorbed via diffusion through aqueous channels or pores in cell membrane. Ø Lipid soluble drug (nonionized or non polar) is readily absorbed via diffusion through lipid cell membrane itself.

Characters Ø Ø Ø Ø common. Occurs along concentration gradient. Non selective Not saturable Requires no energy No carrier is needed Depends on lipid solubility. Depends on pka of drug - p. H of medium.

Drugs exist in two forms ionized (water soluble) nonionized forms (lipid soluble) in equilibrium. Drug ionized form + nonionized form n Only nonionized form is absorbable. n Nonionized / ionized fraction is determined by p. H and p. Ka

PKa of the drug (Dissociation or ionization constant): p. H at which half of the substance is ionized & half is unionized. p. H of the medium Affects ionization of drugs. q q Weak acids best absorbed in stomach. Weak bases best absorbed in intestine.

Ø Ø Ø Ø Relatively unusual. Occurs against concentration gradient. Requires carrier and energy. Specific Saturable. Iron absorption. Uptake of levodopa by brain.

Ø Ø Ø Occurs along concentration gradient. Requires carriers Selective. Saturable. No energy is required.

Passive transport along concentration gradient (From high to low) Active transport against concentration gradient (From low to high) No carriers Needs carriers Not saturable Not selective Selective No energy is required

Active transport Against concentration gradient (From low to high) Needs carriers Carrier-mediated facilitated diffusion along concentration gradient (From high to low) Needs carriers saturable Selective Energy is required No energy is required

Endocytosis: uptake of membrane-bound particles. Exocytosis: expulsion of membrane-bound particles. Phagocytosis occurs for high molecular weight Drugs or highly lipid insoluble drugs.

OUT IN IN OUT

Is the fraction of unchanged drug that enters systemic circulation after administration and becomes available to produce an action n I. V. provides 100% bioavailability. n Oral usually has less than I. V. n

Summary n n n Different routes of administration are available Parenteral administration is the suitable route to provide rapid effect IV is used in emergency and provide high availability Oral administration is best avoided during emergency or when severe first pass metabolism may occur Drugs may cross any cell membrane by simple diffusion, active transport, facilitated diffusion, Pinocytosis

Questions?