Pharmacology Lecture Notes for Dentistry Students 2023-2024 PDF

0 Pharmacodynamics  Is the study of the effect of drugs on the body, contrasting with pharmacokinetics.  This effect can be either therapeutic or a side effect. Mechanisms of producing drug effects: 1. Changing enzymatic activity:  A common example is acetylcholinesterase inhibitors.  Acetylchol...

0 Pharmacodynamics  Is the study of the effect of drugs on the body, contrasting with pharmacokinetics.  This effect can be either therapeutic or a side effect. Mechanisms of producing drug effects: 1. Changing enzymatic activity:  A common example is acetylcholinesterase inhibitors.  Acetylcholinesterase is responsible for degrading acetylcholine into choline and acetate.  This enzyme is a target for many medications called acetylcholinesterase inhibitors.  When this enzyme is inhibited, acetylcholine will not be degraded, leading to an increased concentration of acetylcholine, which produces a greater effect than usual. 2. Change cell membrane permeability:  An example of this is local anesthetics.  They block voltage-gated Na+ channels, thereby blocking any action potential in the nerves, which changes the permeability of the membrane. 3. Combining with other Chemicals:  Some drugs are given to patients to neutralize or affect other chemicals.  For example, ⇒ antacids.  Antacids are given to patients suffering from a burning sensation in the stomach due to gastritis or peptic ulcers, neutralizing acidity in the stomach. 4. Inhibit physiological functions in the cell: Two example:  Inhibition of cell wall synthesis:  Antibiotics can target the cell wall of bacteria, inhibiting the formation of cell walls and inhibiting bacterial growth during infections.  Antibiotics can distinguish between mammalian cells and bacterial cells, as humans do not have a cell wall, making them safe for human cells.  Inhibition of nucleic acid synthesis:  Drugs that inhibit nucleic acid synthesis are used as anticancer medications (antineoplastic). 5. Replacement therapy:  Examples include hormones, vitamins, and supplements (such as iron) used to treat deficiencies. 1 6. Drug-receptor binding:  There are many types of receptors in our body, and drugs can bind to these receptors, either activating or inhibiting them.  This binding allows drugs to produce their effects. Two types of receptors:  Receptors (ionotropic and metabotropic) can be excitatory or inhibitory. 1. Ionotropic Receptors:  Allow the passage of ions in and out of the cell.  For example, ligand-gated ion channels (such as cholinergic nicotinic receptors).  When a ligand (such as acetylcholine) binds to this channel, it opens, allowing sodium ions to influx inside the cell, causing depolarization, or it closes, preventing ions from entering or leaving the cell. 2. Metabotropic Receptors:  These receptors do not have ion channels, so ions like sodium and calcium cannot pass through them.  They involve a series of reactions (via second and third messengers) that begin when a ligand binds to these receptors.  For example, G-protein coupled receptors (GPCRs).  Mechanism:  The drug attaches from outside (extracellular fluid side), causing conformational changes in the receptor.  This affects the receptor inside the cytoplasm, leading to interactions with G-proteins, which can result in the inhibition or activation of enzymes inside the cytoplasm.  We have many types of targets for these G-protein coupled receptors, depending on the:  Organ, Ligand, Subtype, Tissue.  Second messengers or third messengers may target other parts of the cell and may lead to the opening or closing of receptors. Type of ligands: 1. Agonist:  The drug exhibits a full effect.  When a drug binds to a receptor and produces a maximal biological response. 2. Partial agonist:  The drug exhibits a partial effect, which is between that of an antagonist and an agonist. 2 3. Antagonist:  The drug has no effect (there is no response), and the effect does not change with an increase in dose. Antagonists are also classified into:  Competitive antagonists:  They compete for the binding site with the agonist.  The binding site of a competitive antagonist is the same as that of the agonist.  Competitive antagonists prevent an agonist from binding to its receptor, maintaining the receptor in its inactive state.  They shift the agonist dose-response curve to the right (increased EC50) but do not affect Emax.  This shift to the right means a higher concentration of agonist is needed to reach the plateau Vmax. Kd, Km, Ed50  Non-competitive antagonists:  They irreversibly bind to the active site of the receptor, permanently reducing the number of available receptors to the agonist.  The agonist cannot reach the plateau because non-competitive antagonists bind permanently.  There is no competition between the agonist and the antagonist.  They move the curve to the right and downward.  Unlike competitive antagonists, adding more agonist does not overcome the effect of irreversible antagonists.  EC50 (KM) is the dose of the agonist that produces 50% of the full effect.  Emax is the maximal efficacy. Potency and Efficacy Potency:  It is the effect of a drug per unit of weight.  It refers to the amount of drug needed to produce an effect.  EC50 (Kd): The concentration of drug producing 50% of the maximum effect, which is usually an indication of potency:  If Kd is high, then the potency is low.  If Kd is low, then the potency is high.  Conclusion:  To produce a specific effect, if the dose needed for drug X is smaller than the dose needed for drug Y, then drug X will be more potent. 3  For example, consider two over-the-counter medications: ibuprofen and diclofenac sodium (Voltaren).  The regular dose of ibuprofen is 400 mg.  The regular dose of Voltaren is 50 mg.  If a patient takes 400 mg of ibuprofen or 50 mg of Voltaren, they will experience the same effect.  In this case, Voltaren is more potent than ibuprofen because a lower dose is needed to achieve the same effect. Efficacy:  Efficacy is the maximal "ceiling" of a drug (Emax), beyond which there is no increase in response even with an increase in dose.  It refers to the magnitude of response produced by a drug. 1  Emax is the maximum effect of a drug.  A drug with a higher Emax is more efficacious. In the picture (1):  Both drugs have the same Emax, indicating that they have the same efficacy (same ceiling).  Drug A is more potent than B, because it has a lower EC50 compared to drug B. 2 In the picture (2):  Drug A is more potent and more efficacious than Drug B. In the picture (3):  We can observe differences in both potencies and efficacies among different drugs:  Drug A is the most potent.  Drug B and Drug A are the most effective compared to Drug C. Notes:(from book and doctor)  A fundamental difference between competitive and noncompetitive antagonists: Competitive antagonists:  Shift the agonist dose-response curve to the right, reducing agonist potency (increasing EC50).  Do not change the curve downward, so they do not affect Emax. 4 Noncompetitive antagonists:  Move the curve to the right, reducing agonist potency (increasing EC50).  Move the curve downward, reducing agonist efficacy (preventing it from reaching Emax, decreasing Emax) Therapeutic Index  The therapeutic index is a measurement of drug safety.  It is calculated as TI = TD50 / ED50.  TD50 ⇒is the dose that produces toxicity in 50% of individuals.  ED50 ⇒is the dose that produces a therapeutic effect in 50% of individuals.  A higher therapeutic index indicates a higher TD50 or a lower ED50.  A lower therapeutic index indicates a small gap between TD50 and ED50, which is not favourable for medications in humans.  LD50 ⇒is the dose that produces death in half of the population.  Is measured in rats and mice, not in humans.  Increasing the dose beyond the therapeutic effect may lead to toxicity and eventually death. This graph:  Shows how the drug can behave, these three curves represent different effects of the same drug at different doses.  The ED50 is measured from the therapeutic dose.  For example, if we consider a drug that relieves fever like Paracetamol:  If the drug reaches Emax, it may produce toxicity, and the patient may experience vomiting, nausea, or constipation (toxic side effects).  Further increasing the dose can lead to reaching TDmax, where the patient may be at a higher risk of death, initiating the lethal phase (LD50 can be measured). Therapeutic Range:  The therapeutic range is the range within which a patient feels the therapeutic effect of the drug with minimal side effects.  In the diagram:  The x-axis represents time, while the y-axis represents the concentration of the drug in the body.  Our goal is to maintain the drug concentration between these two lines to avoid toxicity while providing a therapeutic effect for the patient. 5 Terminology  Half-life: The time required to eliminate 50% of a drug from the body, associated with the drug's clearance.  EC50 (effective concentration): The concentration of the drug that produces 50% of the maximal effect.  Kd: The concentration of the drug that occupies 50% of the receptors.  In general, the more receptors that are occupied, the greater the effect we'll observe. Therefore,Kd = EC50 Tolerance  Tolerance is the decrease in the intensity of the response after repeated use of a drug.  When a patient takes the drug for the first time, they will experience the full effect.  However, after repeated administration over many days, the drug starts to lose its efficacy.  This means that the effect will be less for the same dose that the patient took initially.  We need a higher dose to produce the same effect of the original dose.  Pharmacokinetics tolerance:  The drug starts to lose its effectiveness over time.  Metabolic enzymes in the liver start to mature and grow, leading to higher rates of metabolism.  Pharmacodynamics tolerance:  The receptors will not respond to the drug as they did initially.  After repeated administration, the receptors will not behave or respond similarly to the first time the patient took the medication Explanations why could this happened: 1. Receptor Down-regulation:  Less receptors are available to bind to the drug and produce the effect, leading to a decrease in the effect.  Cells adapt to the presence of the drug by downregulating (decreasing the number of) receptors present in the plasma membrane.  The drug loses its effectiveness because there are fewer receptors available for binding. 2. Receptor Up-Regulation:  If the patient takes X drug and in his body, there are 100 receptors of X drug.  After many administrations, the cell will decrease the receptors and become 70.  But if the patient stopped taking X drug the body realizes upthat there is a shortage of activation of the receptors. Regulatio  which causes the cells to start to resynthesize the receptors. n Downregulation 6 Onset of action:  Is the time needed from the intake of the drug until it starts to produce its effect, and it is related to the route of administration.  For example, the oral route has a prolonged onset of action compared to intravenous (IV) administration. Duration of action:  The time during which the drug continues to produce its therapeutic effect before it is eliminated.  It is determined by the concentration of the drug in the blood and the duration it remains unchanged.  Some drugs have a long duration of action, while others have a short duration of action. ‫أبصرتَنا‬ ‫لو‬ ْ ‫مين‬ ْ ِ ‫يا عاب َد ال َح َر‬ ‫علمتَ أنّك في العباد ِة ت َ ْلعب‬ ْ َ‫ل‬ ‫َم ْن كان يَ ْخ ِضب خدَّه بدمو ِع ِه‬ َّ ‫فَنحورنا بِ ِد َمائِنا تَت َ َخ‬ ‫ضب‬ ‫ال تنسوا إخواننا في غزة من الدعاء‬ Best wishes 7