Pharmacology 1 - Dr Wai Ling Kok (2024-25) PDF

Pharmacology 1 - How do drugs enter the body? Absorption Dr Wai Ling Kok Acknowledgement: Dr Zoë Brookes  Learning objectives To define and understand the use of the terms pharmacokinetics and pharmacodynamics To have...

Pharmacology 1 - How do drugs enter the body? Absorption Dr Wai Ling Kok Acknowledgement: Dr Zoë Brookes  Learning objectives To define and understand the use of the terms pharmacokinetics and pharmacodynamics To have an understanding of different routes of drug administration (parental and enteral) and be able to give examples of drugs administered by each To be able to discuss specific issues relating to the different properties of skin and oral mucosa, in order to facilitate comparison of parental and enteral routes of administration To be aware of the concept of first pass metabolism  Pharmacology Y1 and Y2 spiral learning Year 1: Plenary 'Introduction to pharmacology, an overview’ Year 1: Plenary ‘Pharmacology of LA’ Year 2 : SFD Year 2 Plenary - Prescriptions and prescription writing Year 2 (2.5): SFD – Pharmacology 1 - How do drugs enter the body? Absorption Year 2 (2.6): SFD – Pharmacology 2 – How do drugs act? Pharmacokinetics Year 2 (2.6): SFD - Biological Effects of Alcohol Year 2 SFD/plenary (2.6) - Pharmacological and physiological steroids Year 2 (2.7): SFD - Pharmacology 3 - Drug distribution, metabolism and elimination and action at extremes of age Year 2 (2.7): SFD - Pharmacology 4 - Pharmacology of pain and inflammation Year 2 (2.10): SFD - Pharmacology 5 - Antimicrobials Year 2 (2.10): SFD Revision: Key Families of Drugs  Terminology Pharmacokinetics (what the body does to the drug) The way the body deals with the drug over time (Absorption, Distribution, Metabolism, Excretion) This session will focus on routes of administration and how drugs enter the body - absorption The next session will look at how drugs travel to their target cells (distribution) and exert their effects and a physiological response via interactions with receptors Pharmacodynamics (what the drug does to the body) The effects of drugs on the body, biochemical and physiological effects  Terminology Enteral Drugs administered via the oral, sublingual and rectal route Parenteral Drugs administered by a non-gastrointestinal route -Intravenous -Intramuscular -Subcutaneous -Topical -Inhalational -Nasal -Occular (eye) or otic (ear) -Transdermal (patches) -Intrathecal (space around the spinal cord) Each route has a specific purpose, advantages and disadvantages, but ‘pharmacodynamics’ is particularly relevant to the oral route Administration via oral route Most common route due to convenience "PO" from "per os", the Latin for "by mouth“ When given orally, the proportion of drug reaching the systemic circulation varies is termed bioavailability Some drugs destroyed by enzymes or acid in the gut Some drugs may become inactive due to first pass metabolism Bioavailability after administration via oral route You will learn more about this in Pharmacology 3  Administration via oral route Drugs given orally must pass through the gut wall, and enter the bloodstream to exert their therapeutic effect Factors affecting bioavailability, including dissolution and absorption, of drugs within the body: -Lipid solubility -Stability in acid -Formulation (coatings) -First pass metabolism -Motility of gut -Food in stomach Thus, not all of drug swallowed will enter the bloodstream…. Lipid solubility Molecules cross cell membranes by: - Diffusing through lipid (if lipid soluble) - Moving by solute or membrane carriers - Diffusing through aqueous pores (aquaporin channels) - Pinocytosis Non-polar or non-ionised molecules move freely across membrane liquid (lipophilic / hydrophobic) Polar molecules or ionised (acids or bases) molecules do not move across cellular membranes (lipophobic / hydrophilic) Lipid solubility Most drugs are weak acids or bases Exist in both ionised and un-ionised form (lipid soluble) Ratio depending on pH of environment & pKa of the drug Acidic drug being concentrated in high pH compartment and vice versa Ka BH+ B + H+ Remember LA in Year 1? BH+ is ionised base, low lipid solubility; B is un-ionised base, more lipid soluble, more readily absorbed B in the presence of acid (H +), equation shifts to left and becomes less soluble  Weakly acidic Alkaline environment, medication, weak acid more ionised, better absorbed in less likely to absorbed acidic environment Acidic environment, Weakly basic weak base more ionised, medication, less likely to absorbed better absorbed in alkaline environment Stability in the stomach Penicillin's have a pKa of approximately 3 Penicillin G (benzyl penicillin, intravenous use), penicillin V (phenoxymethylpenicillin, oral use) Penicillin G can react with water under acidic conditions (as found in the stomach), to break the β-lactam ring - hydrolysis reaction Nucleophilic acyl substitution reaction, forming a penicilloic acid, which does not have the desired antibiotic activity - penicillin no longer has a therapeutic effect Why can you not give insulin via the oral route? Hint: not just due to acidic conditions, what happens to proteins in the gut? Enteric coatings Prevent tablets dissolving in under acidic conditions of stomach, but allows them to be soluble at more basic conditions of the intestinal tract Prevent gastric distress/ulceration or nausea due to irritation caused by certain (often more acidic) drugs Provide a delayed-release component Early coatings involved gelatin capsules with formalin or shellac coatings Modern enteric coatings use synthetic polymeric materials or polyacids (many polymers insoluble at low pH but soluble at high pH) Give examples of the drugs in the Dental Practitioners Formulary (in BNF) that have an enteric coatings? Hint: an acid labile drug includes a dentally used antibiotic; acidic drugs include OTC drugs used for pain relief First pass metabolism Hepatic portal system Hepatic portal system Veins from intestines enter portal system and travel to liver Many drugs thus metabolised by the liver before reaching general circulation: first pass metabolism Liver Phase I (oxidation, reduction, hydrolysis) and Phase II (conjugation) enzymatic reactions for metabolism of drugs are covered later in this series Name 2 drugs used in dentistry that cannot be given orally due to first pass metabolism? (Hint: one as an LA; one used for immediate effect in medical emergencies) What advantage does sublingual administration have over oral administration? Mobility of gut, food in stomach Increased rate of gastric emptying and gastrointestinal motility increases the rate of absorption of a drug small intestine significantly larger surface area for drug absorption, less acidic Diseases, surgery and other drugs e.g. opioids alter gastric empty Food especially fatty foods may delay gastric emptying and thus slow drug absorption Oral mucosal permeability Effects of disease on drug absorption vary and still more research required GI disease may slow gastric emptying: - Emptying delay may lead to incomplete absorption of drugs, e.g. IBS, ulcerative colitis and Crohn’s disease GI disease may cause inflammation and dampen the ‘normal’ transmembrane transport systems GI disease may alter the integrity of cellular membranes - “Leaky gut syndrome" caused by the immune system reacting to germs or, toxins could increase intestinal permeability, but significance uncertain (bacteria may enter blood stream?) Increasing bioavailability Drugs administered by a non-gastrointestinal (parental) avoid the factors affecting oral administration, as drugs more readily enter into the bloodstream and avoid first pass metabolism: Other routes of administration are required for example: -When a person cannot take anything by mouth -When a drug must be given quickly or at a precise or high dose -When a drug has poor absorption from the GIT Consider some of the most common non-oral routes encountered during dentistry -Intravenous -Intramuscular -Subcutaneous -Sublingual -Topical -Inhalational Routes for parenteral administration of drugs Intravenous (i.v) route Drug ‘injected into a vein’ - needle, cannula (phlebotomy training required) Most common sites where veins close to the surface of the skin and visible - back of the hands, front and back of the lower arm, the antecubital fossa or elbow Used when a rapid effect is necessary, bolus dose Drugs can be delivered by continuous infusion pumps (general anaesthetics, e.g. propofol) Suitable for larger volumes Suitable for drugs that cause tissue damage if given by other routes (cytotoxic, such as general anaesthetic thiopental) What do you think this drug may be? Hint: commonly used general anaesthetic, given by an induction bolus, then continuous intravenous infusion What is the advantage of giving this type of drug by this route? Intramuscular (i.m) route Drugs will absorb fairly rapidly via this route, faster than oral administration, because of the dense vasculature The most common sites are the: deltoid muscle (arm) (vaccines), vastus lateralis (thigh), ventrogluteal muscle (hip) and dorsogluteal muscles (buttocks) The rate limiting steps for absorption are diffusion through the tissue; removal by local blood flow Absorption rate increased by increased blood flow, hyaluronase (enzyme that breaks down intracellular matrix) Absorption rate decreased by addition of adrenaline to formulation, circulatory shock (decreased blood flow peripheral organs), oily or pellet formulations Give an example of a drug that used in dentistry that may be administered by the intramuscular route? (Hint: used in a medical emergency) Subcutaneous route More superficial injection than i.m., short needle used to inject into subcutaneous tissue layer - between skin and muscle Slower, more sustained rate of absorption compared to i.m., but faster than intradermal Common sites of injection: arm, thigh, abdomen, buttocks What drug for diabetes may be administered s.c.? Why is it important to vary the injection site; what complications can occur if this is not done? Sublingual and buccal routes Useful when rapid absorption required, as mouth has thin highly vascularised tissues, drug passes straight into the systemic circulation Either under the tongue (sublingual) or against the cheek (buccal) Must dissolve in saliva and have high lipid solubility so it passes through the mucosa to the capillaries beneath the epithelium Formulations include tablets, lozenges, strips or sprays Give two examples drugs (and formulations) that are used in dentistry that may be administered by the sublingual or buccal route? (Hint: both used in medical emergencies) Topical and intradermal routes Most drug absorbed poorly through unbroken skin; a barrier of tight layers that keeps body water in and microorganisms and chemicals out. Lipophilic drugs can absorb transcellular, intracellular or follicular routes; via micro-needling and nanoparticle approaches Examples include topically applied steroids, oestrogen patches, fentanyl opioid (for pain) patches, nicotine patches What drug, including concentration, do we use topically in the mouth during dentistry? How long does it take to absorb across the skin versus the oral mucosa; why is the oral mucosa quicker? Inhalational route Inhaled medications absorbed quickly, as lungs have large surface and rich blood supply Also act both locally and be self-administered Patients can still breath in when unconscious Delivery devices: metered dose (propellant and drug both under pressure, use with spacer for best effect); dry power (uses patient inspiration to deliver); nebuliser (compressed gas or piezo electric crystals to vibrate into the air) Inhalational anaesthetics, e.g. sevoflurane, isoflurane, nitrous oxide, administered through a face mask, connected to an anaesthetic vaporiser and delivery system with carrier gases Name two common drugs delivered as aerosols to treat asthma? Name two common drugs administered inhalationally that are no longer used in dental practice? (Hint: one general anaesthesia and one for sedation) Summary You should now understand parental and several different enteral routes of administration, and be able to give examples of drugs administered by each You should now understand how drugs absorb and enter the body differently via different routes You should now understand why bioavailability is different following parental and enteral routes, in the context of the different properties of these tissues You should understand the mechanism of first pass metabolism why it effects drug bioavailability Reading list Rang and Dale’s Pharmacology, Elsevier M.J. Neal, Medical Pharmacology at a Glance, Wiley Blackwell