Pharmacology Department General pharmacology (Pharmacokinetics) Grade I Prof. Hanan Hagar Pharmacology Department

Basic and Clinical Pharmacology by Katzung Recommended books Basic and Clinical Pharmacology by Katzung Pharmacology by Rang

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

Drug absorption Is the passage of drug through cell membranes to reach its site of action. Mechanisms of drug absorption Simple diffusion = passive diffusion. Active transport. Facilitated diffusion. Pinocytosis (Endocytosis).

Cell membrane

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

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

Simple diffusion Low conc High conc

pKa- pH= log protonated / non-protonated Simple diffusion Drugs exist in two forms ionized (water soluble & nonionized forms (lipid soluble) in equilibrium. Drug ionized + nonionized Only nonionized form is absorbable. Nonionized / ionized fraction is determined by pH and pKa according to Henderson- Hasselbach pKa- pH= log protonated / non-protonated

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

Which one of the following drugs will be best absorbed in stomach (pH=3)? Aspirin pka=3.0 warfarin pka=5.0 Arrange the following drugs in ascending order from least to greatest in rate of absorption in small intestine (pH=7.8)? 9.4 Propranolol pka=

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

Carrier-mediated Facilitated Diffusion Occurs along concentration gradient. Requires carriers Selective. Saturable. No energy is required.

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

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

Phagocytosis (Endocytosis & Exocytosis) Endocytosis: uptake of membrane-bound particles. Exocytosis: expulsion of membrane-bound particles. High molecular weight drugs or Highly lipid insoluble drugs

Routes of drug administration Enteral via gastrointestinal tract (GIT). Oral Sublingual Rectal Parenteral administration = injections. Topical application

Oral administration Disadvantages Advantages Slow effect No complete absorption (Low bioavailability). Destruction by GIT First pass effect GIT irritation Food–Drug interactions Drug-Drug interactions Not suitable for vomiting, unconscious, emergency. Easy Self use Safe Convenient cheap No need for sterilization

First pass Metabolism Metabolism of drug in the gut wall or portal circulation before reaching systemic circulation so the amount reaching system circulation is less than the amount absorbed Where ? Liver Gut wall Gut Lumen Result ? Low bioavailability. Short duration of action (t ½).

First pass effect

Dosage forms Capsules Tablets Syrup Suspension Hard- gelatin capsule Soft- gelatin capsule Tablets Spansule

Sublingual Disadvantages Advantages Not for irritant drugs Frequent use Rapid effect (Emergency) No first pass metabolism. High bioavailability No GIT destruction No food drug interaction Dosage form: friable tablet

Rectal administration Disadvantages Advantages Not for Irregular absorption & bioavailability. Irritation of rectal mucosa. Suitable for Vomiting & children. &unconsciousness Irritant & Bad taste drugs. less first pass metabolism (50%) Dosage form: suppository or enema

Parenteral administration Intradermal (I.D.) (into skin) Subcutaneous (S.C.) Intramuscular (I.M.) 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)

Parenteral administration Disadvantages Advantages Infection Sterilization. Pain Needs skill Anaphylaxis Expensive. high bioavailability Rapid action (emergency) No first pass metabolism Suitable for Vomiting &unconsciousness Irritant & Bad taste drugs. No gastric irritation No food-drug interaction Dosage form: Vial or ampoule

Ampoule Vial

Topical application Produce local effect to Skin (percutaneous) e.g. allergy testing, topical local anesthesia Mucous membrane of respiratory tract (Inhalation) e.g. asthma Eye drops e.g. conjunctivitis Ear drops e.g. otitis externa Intranasal, e.g. decongestant nasal spray Topical application

Only few drugs can be used Inhalation Disadvantages Advantages Only few drugs can be used Mucous membrane of respiratory system Rapid absorption (large surface area) Provide local action Minor systemic effect Low bioavailability Less side effects. No first pass effect Dosage form: aerosol, nebulizer

Nebulizer Atomizer

Transdermal patch a medicated adhesive patch applied to skin * Slow effect (prolonged drug action) * produce systemic effect e.g. the nicotine patches

Bioavailability Is the fraction of unchanged drug that enters systemic circulation after administration and becomes available to produce action I.V. provides 100% bioavailability. Oral usually has less than I.V. Bio = AUC oral / AUC IV X 100

Factors Affecting Bioavailability: Molecular weight of drug. Drug Formulation (ease of dissolution). (solution > suspension > capsule > tablet) Drug solubility of the drug Chemical instability in gastric pH (Penicillin & insulin ) First pass metabolism reduces bioavai

Greater blood flow increases bioavailability Factors Affecting Bioavailability (BAV): Blood flow to absorptive site Greater blood flow increases bioavailability Intestine has greater blood flow than stomach Surface area available for absorption. Intestinal microvilli increases it Rate of gastric emptying rapid gastric emptying fast transit to intestine pH of gut

Intestinal motility (Transit Time) Diarrhea reduce absorption Drug interactions Food slow gastric emptying generally slow absorption Tetracycline, aspirin, penicillin V