Pharmacology I Notes PDF - Fall 2023

Pharmacology I Assoc. Prof. Mohamed Hamzawy Nature of the drug To interact chemically with its receptor, a drug molecule must have: Appropriate size, Electrical charge, Shape, Atomic composition. Drug….works, although distance A drug is often...

Pharmacology I Assoc. Prof. Mohamed Hamzawy Nature of the drug To interact chemically with its receptor, a drug molecule must have: Appropriate size, Electrical charge, Shape, Atomic composition. Drug….works, although distance A drug is often administered at a location distant from its intended site of action, eg, a pill given orally to relieve a headache. Therefore, a useful drug must have the necessary properties to be transported from its site of administration to its site of action. Drug….works, although distance Finally, a practical drug should be inactivated or excreted from the body at a reasonable rate so that its actions will be of appropriate duration. Two main division of pharmacology are: 1. Pharmacokinetic: what the body does to drug 2. Pharmacodynamic: what the drug does to body  Pharmacokinetic (ADME) Absorption How the drug is moved into blood stream from the site of administration ? Distribution How much drug is moved to various body tissues / organs ? Metabolism How the drug is altered – broken down ? Excretion How the drug is removed from the body ? Drug Excretion Administration Metabolism Blood Absorption Site of action Distribution Specific organs & tissues Enteral Other Oral Oral inhalation Sublingual/buccal Nasal inhalation Parenteral Intrathecal Intramuscular (IM) Topical Intravenous (IV) Transdermal Subcutaneous (SC) Rectal Oral route of administration  Oral Route Advantages Disadvantages Easy Slow effect Self use No complete absorption Safe (Low bioavailability). Convenient Destruction by GIT Cheap First pass effect No need for sterilization GIT irritation Food–Drug interactions Drug-Drug interactions Not suitable for vomiting, unconscious, emergency. First pass Metabolism Oral drugs are first taken to liver (via portal circulation) where they are metabolized. so the amount reaching circulation is less than the amount absorbed Where ? Liver - Gut wall - Gut Lumen Results ? Low bioavailability = low serum level of active drug that produce action Short duration of action (t ½). First pass Metabolism  Sublingual administration Advantages Disadvantages Rapid effect Not for (Emergency) Irritant drugs No first pass metabolism. High bioavailability No GIT destruction No food drug interaction Parental administration  Parental administration Advantages Disadvantages High bioavailability Infection Rapid action (emergency) Sterilization. No first pass metabolism Pain Suitable for Needs skill –Vomiting &unconsciousness Anaphylaxis – Irritant & Bad taste drugs. Expensive. – No gastric irritation – No food-drug interaction  Inhalation Advantages Disadvantages Rapid absorption (large surface Only few area) drugs can be Rapid effects as IV bolus. used Provide local action Minor systemic effect Low bioavailability Less side effects. No first pass effect Dosage form: Aerosol, Nebulizer  Rectal Administration Advantages Disadvantages Suitable for Not for Vomiting & children. Irregular &unconsciousness absorption & Irritant & Bad taste drugs. bioavailability Less first pass metabolism Irritation of rectal mucosa Dosage form: Not a well- accepted route suppository or enema  Transdermal administration Advantages Disadvantages Bypasses first-pass Allergy to patches, which effect cause irritation Convenient & painless Drug must be highly Ideal for drugs that are lipophilic lipophilic and have poor Delayed delivery of drug oral bioavailability Limited to drugs taken in small daily doses  Topical application Produce local effect to Skin e.g. topical local anesthesia The rate of absorption can vary markedly, depending on the physical characteristics of the skin at the site of application, as well as the lipid solubility of the drug.  Topical application Produce local effect to 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  Absorption Absorption is the transfer of a drug from the site of administration to the bloodstream. Cell membrane Sites of Bloodstream Administration Sites of action  Cell membrane Cell membrane is formed mainly of bimolecular LIPID sheet, interrupted by protein macromolecules (receptors, carriers, etc.), water-filled pores & ion channels.  Mechanisms of drug absorption 1. Simple diffusion = passive diffusion 2. Active transport 3. Facilitated diffusion 4. Pinocytosis (Endocytosis) Characters common. Occurs along concentration gradient. Non selective Not saturable low structural specificity. No energy No carrier is needed Depends on lipid solubility. Depends on pka of drug - pH of medium. High Conc. Low Conc. water soluble drug (ionized or polar) is readily absorbed via diffusion through aqueous channels or pores in cell membrane. Lipid soluble drug (nonionized or non polar) is readily absorbed via diffusion through lipid cell membrane itself.  Relatively unusual Occurs against concentration gradient. Requires specific carrier proteins that span the membrane Requires energy. Specific Saturable. Iron absorption. Uptake of levodopa by brain.  Occurs along concentration gradient. Requires carriers Selective. Saturable. No energy is required. Characteristics Simple Facilitated Active Diffusion Diffusion Transport Gradient Along Along Against Carrier NO Yes Yes Saturation NO Yes Yes & competition Energy NO NO Yes 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 e.g. Vitamin B12 e.g. norepinephrine Factors influencing absorption 1. Effect of pH on drug absorption 2. Blood flow to the absorption site 3. Total surface area available for absorption 4. Contact time at the absorption surface 5. Expression of P-glycoprotein  Factors influencing absorption 1. Effect of pH on drug absorption Drugs exist in two forms ionized (water soluble) nonionized forms (lipid soluble) in equilibrium. Drug ionized form + non ionized form A drug passes through membranes more readily if it is uncharged Non ionized / ionized fraction is determined by pH and pKa  Factors influencing absorption Drugs are either weak acids or weak bases Acidic drugs (HA) release a proton (H+), causing a charged anion (A−) to form: Weak bases (BH+) release an H+. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B):  Factors influencing absorption 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.  Factors influencing absorption PKa &pH –Weak acids → best absorbed in stomach. –Weak bases → best absorbed in intestine.  Factors influencing absorption 2.Blood flow to the absorption site The intestines receive much more blood flow than the stomach, so absorption from the intestine is favored over the stomach of the substance is ionized & half is unionized.  Factors influencing absorption 3.Total surface area available for absorption With a surface rich in brush borders containing microvilli, the intestine has a surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient.  Factors influencing absorption 4. Contact time at the absorption surface If a drug moves through the GI tract very quickly, as can happen with severe diarrhea, it is not well absorbed. Conversely, anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug.  Factors influencing absorption 5. Expression of P-glycoprotein P-glycoprotein is a transmembrane transporter protein responsible for transporting various molecules, e.g. drugs, across cell membranes. It is expressed in different tissues throughout the body e.g. liver, kidneys, placenta, intestines, and brain  Factors influencing absorption 5. Expression of P-glycoprotein P-glycoprotein is involved in transportation of drugs from tissues to blood. It “pumps” drugs out of the cells. Thus P-glycoprotein reduces drug absorption. P-glycoprotein associated with multidrug resistance.