Pharmacology Lecture 1 PDF

PPT301 Pharmacology General Principles: Pharmacokinetics Ahmed Fawzy El-Yazbi, Bharm, PhD, BCPS Faculty of Pharmacy Pharmacology: The Science of Drug Action Pharmacology is the systematic study of how drugs exert their effects on living systems. Pharmacologists...

PPT301 Pharmacology General Principles: Pharmacokinetics Ahmed Fawzy El-Yazbi, Bharm, PhD, BCPS Faculty of Pharmacy Pharmacology: The Science of Drug Action Pharmacology is the systematic study of how drugs exert their effects on living systems. Pharmacologists also study the ways in which drugs are modified within organisms. Drug Any agent that, by virtue of its chemical properties, alters the structure or function of biological systems (pharmacologist’s view). Any agent approved by the Food and Drug Administration (or Ministry of Health in a given country) for the treatment or prevention of disease (legal view). Pharmacokinetics is the study of the kinetics of drug absorption, distribution, and elimination (ie how the body affects the drug)  Why study PK? To produce a biological action the drug must reach its effector In order to achieve an effective concentration at the site of action, several processes need to occur Exceeding a certain drug concentration, the effects might switch towards a negative outcome (unwanted effects and toxicity) Knowledge of PK is required to understand and control the drug effect and design appropriate dosage regimens Source: Leon Shargel, Andrew B.C. Yu: Applied Biopharmaceutics & Pharmacokinetics  Routes of drug administration Enteral Oral Sublingual Rectal Parenteral Intravascular (IV) Intramuscular (IM) Subcutaneous (SC) Others Intranasal Topical (mucous membranes and ocular) Ocular Oral Advantages Disadvantages Safest Limited absorption Convenient Slow action Economical Irritable and unpalatable drugs Can be self-administered Some drugs destroyed by acidity of Painless stomach First-pass effect Uncooperative/unconscious patients Preparations for oral administration Tablets Drug plus binders and fillers (compressed together) Differ in their rate of dissolution/disintegration (based on manufacturing) Thus, two tablets containing the same amount of the same drug may differ in onset and intensity of effect Enteric-coated preparations Covered with material designed to dissolve in intestine, not stomach Protect drug from stomach and stomach from drug Disadvantage: depend on gastric emptying (which is variable) Sustained-release preparations Capsules filled tiny spheres that dissolve at various rates Thus, drug is released steadily (permits reduction in # of daily doses) Disadvantage: high cost and variable absorption Routes of drug administration Sublingual: Placement under the tongue allows a drug to diffuse into the capillary network This means it enters the systemic circulation directly Thus, it avoids first-pass effect (and also avoids acidity of stomach/intestinal enzymes)  Sublingual Advantages Disadvantages Economical Unpalatable/bitter drugs Absorption is quick Irritation of oral mucosa First-pass avoided Large quantities not given Quick termination (spit off) High Mwt. Drugs not absorbed Can be self-administered Routes of drug administration Rectal: 50% of the rectal drainage bypasses the first-pass metabolism Drugs avoids stomach/small intestine Useful if the drug induces vomiting when given orally (or if the patient is already vomiting)  Rectal Advantages Disadvantages Used in children Embarrassing Little or no first pass Inconvenient effect Absorption is not very Used in vomiting or fast unconscious Irritation or Higher concentration inflammation of rectal rapidly achieved mucosa can occur Can be used for drugs that irritate the stomach Parenteral routes Used for drugs that are poorly absorbed in the GI, or are affected by stomach acidity (insulin) Are useful in patients that are unconscious, or under conditions that require rapid onset of action Provides most control over the actual dose delivered Parenteral routes  Intravenous Advantages Disadvantages Avoids first-pass Antiseptic conditions Quick onset Painful Uncooperative/unconscious Risky (can’t be recalled) patients Embolism Nausea/vomiting Suspensions/oily drugs/depots Hypertonic solution/irritants cannot be given Large volumes Venous thrombosis and phlebitis Very good control of the amount Necrosis due to extravasation of drug Intramuscular Advantages Disadvantages Absorption reasonably uniform Only up to 10 ml drug given Rapid onset of action Local pain and abscess Mild irritants may be given Not economical First pass avoided Infection Gastric factors avoided Nerve damage (if injection is Suitable for poorly soluble drugs done improperly)  Subcutaneous (under skin) Advantages Disadvantages Smooth but slow absorption Small volume (1 ml) Depot injections/implants Irritant drugs-sloughing and necrosis not useful in shock Topical Mucous membranes of eye, ear, nose, throat, mouth, vagina, rectum Ointments, creams and lotions Example: clotrimazole as a cream on the skin in dermatophytosis, and atropine into the eye to dilate the pupil Factors governing drug absorption from extra-vascular sites Physicochemical properties of the drug and the surrounding environment (drug degradation?) The dosage form used The anatomy and physiology of the absorption site (surface area, motility, blood flow) Modes of transport across a membrane Source: Goodman & Gillman’s: The Pharmacological Basis of Therapeutics pH and pKa Source: Goodman & Gillman’s: The Pharmacological Basis of Therapeutics Distribution After absorption or intra-vascular administration, drug molecules are distributed in the body distribution depends on: physicochemical properties of the drug, tissue perfusion and regional blood flow, and capillary permeability First distribution phase: well-perfused organs, fast, liver, kidneys, and brain Second phase: slower, muscle, viscera, skin, and fat Penetration, accumulation, and protein binding pH differences between blood and interstitial fluid are too small to produce ion trapping For most organs (except brain), drug molecule transfer to interstitial fluid occurs fast Typically, this occurs by diffusion, so lipid solubility helps increase diffusion  Protein binding of drugs Typically drugs act through binding to macromolecules Binding can be reversible or irreversible through covalent bonding Reversible binding occur through hydrogen bonding and Van Der Waals forces Protein binding affect PK, the bound form is inactive, does not cross membranes, is not metabolized or cleared Source: Leon Shargel, Andrew B.C. Yu: Applied Biopharmaceutics & Pharmacokinetics Tissue accumulation Drugs accumulate passively in the tissues if they have a high affinity e.g. high partition coefficient, thiopental and chlorinated insecticides tend to accumulate in fat (termination of action by redistribution) Drugs can accumulate in the tissue if it binds macromolecules e.g. digoxin binding to proteins in the cardiac tissue Drug elimination (clearance) This process leads to the termination of the biological action of the drug It involves a decrease in the serum concentration Accomplished through metabolism and excretion The main excretory route occurs through the urine (aqueous medium) The main role of metabolism is to increase drug solubility in water to allow for urinary excretion Drug metabolism can lead to active or toxic products Drug metabolism (Biotransformation) Metabolic reactions are classified into two phases: Phase I: functionalization Phase II: conjugation Phase I involves the generation of a functional group, usually accomplished by hydrolysis of an ester or amide group, O- or N- delakylation, deamination, hydroxylation of an aromatic residue Phase I step typically involves the loss of drug activity, however, some metabolites retain activity Prodrugs are usually activated in this step Phase II reactions involve the formation of a covalent link between Phase I product and a highly polar residues Drug excretion The main route of excretion is the kidney, however, it can occur through bile, sweat, saliva, and tears Renal elimination involves three processes: Glomerular filtration Passive reabsorption Active secretion Renal function is not constant even in healthy individuals A decline in renal function is expected with age Glomerular filtration Drug excretion by this mechanism is determined by the GFR and extent of protein binding Small molecules (Mwt.