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PHARMACODYNAMICS Edited By: Dr. Mohammed Samir Hussein BCs of Pharmaceutical Science, MD of Clinical Pharmacology
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PHARMACODYNAMICS PHL-315 (423-2020) Reference: Basic & Clinical Pharmacology Bertram G. Katzung, MD, PhD 14th edition
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PHARMACODYNAMICS Pharmacodynamics describes the actions of a drug the actions of a drug on the body and the influence of drug concentrations on the magnitude of the response. Types of Drug Action: Stimulation 2. Inhibition 3. Replacement 4. Cytotoxic
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Non-Receptor Mediated Mechanisms
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Drugs Act by Chemical Action: Antacids neutralize gastric acid secretion. Protamine (alkaline & +ve charge) antagonizes heparin (acid & -ve charge). Non-Receptor Mediated Mechanisms 2. Drugs Act by Physical Means: Osmosis e.g. mannitol Adsorbent e.g. kaolin and charcoal
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Non receptor mediated actions - Sulphonamides – interfere with bacterial folic acid synthesis by inhibiting bacterial folate synthases enzyme 3. Alteration of Metabolism 4 - Enzymatic Action Stimulation: Pyridoxine acts as co factor for dopa decarboxylase activity. Inhibition: Aspirin inhibits Cyclooxygenase
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Drug Actions Receptor Mediated Mechanisms Ligand : any molecule attaches selectively to particular receptor.
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it’s a specialized Protein or glycoprotein Macromolecule (Present on cell surface, on an organelle within the cell, or in the cytoplasm) act as Target site at which Drug binds to form a Drug-Receptor complex (selectively recognizing and binding a drug) which followed by Sequence Of biological events (Initiate biochemical reactions, Signal Transduction) which leads to the response (alteration of an intrinsic physiologic Activity). Most receptors are proteins that have undergone various post-translational modifications such as covalent attachments of carbohydrate, lipid and phosphate. Receptor
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Receptors have mainly two functions: 1- Recognition of specific ligands. 2- Transduction of signal into response Drug-receptor relation looks like key and lock relation, that is means each drug designed to bind to a specific receptor only. Receptor the magnitude of the response is directly proportion to the number of Drug-Receptor complexes formed.
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Major Receptor families
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A receptor that is embedded in the cell membrane and functions to receive chemical information from the extracellular compartment and to transmit that information to the intracellular compartment. Cell Surface Receptors
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A. Ion gated receptors They are localized on cell membrane. They bind to a ligand and open a channel through the membrane that allows specific ions ( sodium, calcium, magnesium, and hydrogen) to pass through. They regulate the flow of ions across the cell membranes. Response to these receptors are rapid (milliseconds). They mediate diverse functions: neurotransmission, cardiac conduction, and muscle contraction. This group includes : the nicotinic cholinergic receptor, Aminobutyric acid A (GABAA) receptor, and receptors for glutamate, aspartate, and glycine.
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B. G-protein-coupled receptors The receptor composed of 7 spans helix with tail and loop One part is extracellular where the drug binds, And the other intracellular binds to G-protein G-Protein composed of 3 subunits α (20 different types), β, γ The different types of α unite explain the different Response of the same receptor The reaction is fast (seconds to minutes) E.g.: Muscarinic Receptors Dopaminergic Receptors Adrenergic Receptors (α and β receptors) :
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B. G-protein-coupled receptors Before ligand binds, inactive G-protein (GDP) bind to a site on a specific receptor. They bind to a ligand and activate a membrane protein called a G-protein (GTP). Once the G-protein binds to the receptor, the G-protein changes shape, becomes active, and splits into two different subunits. One or both of these subunits may be able to activate other proteins as a result. The activated G-protein then interacts with either an ion channel or an enzyme in the membrane resulting in a new intracellular molecule (Second Messenger). They mediate diverse functions: neurotransmission, olfaction, and vision. :
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Second Messengers Second messenger, molecule inside cells that acts to transmit signals from a receptor to a target. Examples: Activation of adenylyl cyclase results in the production of cyclic adenosine monophosphate cAMP Activation of phospholipase C results in the production of inositol 1,4,5-triphosphate (IP3), diacyl-glycerol (DAG) and release of Calcium.
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Different Types of G-protein and Second messenger
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C. Enzyme-linked receptors They are cell-surface receptors with intracellular domains that are associated with an enzyme. When a ligand binds to the extracellular domain, a signal is transferred through the membrane, activating the enzyme. Activation of the enzyme starts a chain of events within the cell that eventually leads to a response Examples : Tyrosine kinase receptors and Guanylate cyclase receptor.
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D. Intracellular receptors They are different than other receptors because they are entirely intercellular (either in the cytosol or nucleus of the cells). Ligand must diffuse into cell to interact with receptors. Therefor, the ligand must be lipophilic This process takes long time Hours to Days Examples of ligands are hormones or steroids: Thyroxin Receptors, Vit. A, Vit. D Receptor 3. Corticosteroids Receptors 4. Estrogen, Progesterone, and Testosterone R. :
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Comparison of receptor families
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Signal Transduction Ion channel receptors G-protein coupled receptors Enzyme-linked receptors Intracellular receptors
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Signal Transduction Signal amplification is defined as the ability of receptors to amplify signal duration and intensity. The most common receptor that is known for amplifying the signal is G protein-coupled receptors. Two reasons counts for this amplification 1- a single ligand can bind to many receptors, 2- the activated G protein persist for a longer duration (hundreds of milliseconds). A. Signal amplification
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Signal Transduction Downregulation of receptors happens when receptors have been chronically exposed to an excessive amount of a ligand. This results in ligand-induced desensitization or internalization of that receptor. Example: Insulin receptor downregulation. Upregulation of receptors results in super-sensitized cells especially after repeated exposure to an antagonistic drug or prolonged absence of the ligand. B. Desensitization, down-regulation and upregulation of receptors
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Drug-Receptor Interaction The drug binds with the receptor with a permanent attachment, this attachment may be: A- Irreversible attachment: Which is a strong bond, cannot be broken easily E.g. Covalent Bond (the strongest) B- Reversible attachment: Which is a very weak bond, can be broken easily even by body temperature. Ionic , Electrostatic Bond H Bond, Vander Walls Bond (dipole-dipole) Hydrophobic Bond (very weak between highly lipid-soluble drugs with the lipids of cell membranes)
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Drug-Receptor Interaction There are many drugs with the same mechanism or the same drug gives a different response, why? There are many different ways of drug binding, with different Affinities AFFINITY : It is the ability of a drug to bind a receptor a measure of the tightness that a drug binds to the receptor Refers to the strength of binding between a drug and receptor Number of occupied receptors is a function of a balance between bound and free drug More Affinity = More Force = More Binding ►► Higher Response
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Drug-Receptor Interaction
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Drug-Receptor Interaction Agonists: Ligands that bind to a receptor and produce an appropriate response are called agonists (affinity and high efficiency). For example, adrenaline is an agonist at β-adrenoceptors. When it binds to β-adrenoceptors in the heart, it increases the heart rate. Partial agonists: A drug which does not produce maximal effect even when all of the receptors are occupied (affinity and partial efficiency). For example: Buprenorphine is a partial agonist at opioid receptors produce less effect than the full agonist morphine.
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Inverse agonists: An inverse agonist is a compound that binds to a receptor and produces a pharmacological response that is opposite to that of the corresponding agonist. In the presence of the agonist the inverse agonist acts as an antagonist. Antagonists: Ligands that bind to a receptor, compete with and prevent binding of agonist and it does not activate the receptor. For example, acetylcholine receptor blockers such as atropine are antagonists because they prevent access of acetylcholine and similar agonist drugs to the acetylcholine receptor site and they stabilize the receptor in its inactive state. Drug-Receptor Interaction
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Antagonism It is the decrease or the complete abolishment of the effect of one drug in the presence of another.
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Two drugs act on different receptors to produce different physiological effects. Example: Histamine & Adrenaline effects on the Bronchi. A. Physiological antagonism
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- Simple chemical reaction and loss of activity. - No receptor is needed. - Example: Heparin (acidic) can be inactivated with protamine sulfate (base). Antacids (alkalis) as Sodium bicarbonate neutralize the gastric acid secretion. B. Chemical antagonism
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The antagonist effectively reduces the concentration of the active drug at the site of action. Examples, Phenobarbital accelerates hepatic metabolism of warfarin. C. Pharmacokinetic antagonism
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Pharmacodynamic antagonism (Receptor-blockade antagonism). D. Pharmacodynamic antagonism
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D. Pharmacodynamic antagonism A-Competitive (reversible): The antagonist compete with an agonist for the same binding site on the receptor. The antagonist partially or completely prevents the effect of agonist. Antagonist dissociate rapidly from receptor. Inhibition can be reversed by ↑ the concentration of the agonist. Parallel shift of the dose-response curve to the right (↑ EC50), without any change in Emax. Example: acetylcholine and atropine. EC50 EC50 Competitive
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B-Non-competitive Antagonists: Antagonism cannot be overcomed by increasing concentration of agonist Cause downward shift of Emax 1-Irreversible Antagonists Bind to the receptor in an irreversible way by forming a covalent bond Example: Phenoxybenzamine, an irreversible α-adrenoceptor antagonist 2-Allosteric Antagonists Binds to a site (allosteric site) other than the agonist-binding site and prevent the receptor from being activated by the agonist Emax Emax Allosteric Allosteric D. Pharmacodynamic antagonism
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QUANTIFY ASPECTS OF DRUG ACTION Drug induced responses are not an “all or none” phenomenon Interaction of drug with receptor subjected to law of mass action Increase in dose, may Increase response Hyperbolic Curve reaching Maximum response when 100% receptors covered Sigmoid Curve ( by changing the dose to log dose) because 80% of it is straight line so we can easily compare between the drugs
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Dose-Response curves Maximum Efficacy (Emax): is the maximal biological response produced by a drug. Effective concentration (EC50): is the concentration of the drug that gives 50% of the maximal response (Emax).
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Concentration binding curves Concentration binding curves is a correlation between drug concentration [C] used (x- axis) and drug binding capacity at receptors [B] (y-axis). i.e. relation between concentration & drug binding Bmax KD (KD) = concentration of drug required to occupy 50% of receptors at equilibrium B max is total density of receptors in the tissue
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Concentration Binding Curves Bmax (the binding capacity): the total density of receptors in the binding sites. KD: the concentration of drug required to occupy 50% of receptors at equilibrium. The higher the affinity of D for receptor the lower is the KD.
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Concentration Binding Curves Potency: the amount of drug required to produce 50% maximal effect the drug is capable of inducing, or binds to 50 % of the receptors. Potency: is inversely proportional to EC50 - If 2 drugs has same effect but first produce this effect by 100mg, but second we must use 500mg to obtain same response, so first is more potent Efficacy: is the ability or degree of the drug to produce Maximum effect (response)
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QUANTIFY ASPECTS OF DRUG ACTION
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Dose-Response Curves Used to study how response varies with the concentration or dose. Is a correlation between drug concentration [D] used (x- axis) and drug response [R] (y-axis). i.e. relation between concentration & Response
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Dose-Response curves Applications If the sigmoid curve of two or more drugs is Identical That is means the two drugs are the same If drug A is Paracetamol, Drug B must be Paracetamol also If the curve reaches the maximum response, so it a Full Agonist 3- If the curve not reaches maximum response, so it a Partial Agonist
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Dose-Response curves Applications If the 2 curves are parallel, so the two drugs Act by the same Mechanism If the 2 curves are not parallel, so the two drugs Act by different Mechanisms Drug with low ED50 is more Potent Drug which reaches Maximum effect is Maximum Efficacy than other there is NO or relation between the Efficacy and the Potency
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Dose-Response curves Applications If we have 2 drugs one has sigmoid curves and the other has No Curve or response we suggest the following situations: A. The drug B doesn't work in this system B. The drug B is an antagonist 1. Competitive Antagonist 2. Non-Competitive Antagonist How we can determine that ?? By comparing between drug, A curve and the curve of A+B mixture If the 2 curves are parallel, so the two drugs Act by The Same Mechanism If the 2 curves are not parallel, so the two drugs Act by Different Mechanisms
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Dose-Response curves Applications A. If curve A is the same of curve of A+B mixture: That is mean drug B is not working in this system B. If curve of A+B mixture shifted to right (decreased potency): That is mean that drug B is Competitive Antagonist C. If curve of A+B mixture shifted to down (decreased Efficacy): That is mean that drug B is Non Competitive Antagonist
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Dose-Response curves Applications The response may be Therapeutic response, Adverse or Toxic effect or Lethal effect.
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The therapeutic index is a measure of a drug’s safety, because a larger value indicates a wide margin between doses that are effective and doses that are toxic. The therapeutic index (TI) of a drug is the ratio of the dose that produces toxicity in half the population (TD50) to the dose that produces a clinically desired or effective response (ED50) in half the population. Therapeutic Index = TD50/ED50 or LD50/ED50 TD50 (Median toxic dose) is the dose that produces a toxic effect in 50% of the population. LD50 (Median lethal dose) is the dose that is lethal in 50% of the population ED50 (Median effective dose) is the dose that produces therapeutic response in 50% of the population Large value = drug has wide margin of safety e.g. penicillin Small value = a narrow margin of safety e.g. digoxin Therapeutic Index (T.I.)
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Therapeutic Index (T.I.) Margin of Safety: margin between the therapeutic and lethal doses of a drug
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Tolerance Tolerance: reduced response to a drug following its repeated use. larger dose are then required to produce the initial desired effect. Pharmacodynamic tolerance Reduction in the reactivity of sites of drug action. Metabolic tolerance Reduction in the amount of drug which reaches site of action. Cross tolerance Exposure to one drug can produce tolerance to other similar acting drugs.
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Tachyphylaxis Tachyphylaxis is a subcategory of drug tolerance referring to cases of sudden, short-term onset of tolerance following the administration of a drug. An acute rapid decrease in response to repeated doses of a drug over a short time period.
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Drug Resistance Drug resistance: tolerance of micro‐organisms to inhibitory action of antimicrobials. Example: staphylococcus to penicillin G.
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Factors Influencing Dosage and Drug Response Placebo effect
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1- Age Standard dosages are based on the amount of a drug that will cause the desired effect in an average adult. The young and old patients do not have the same functions as the adult patients. In infants, body systems are not fully developed, they may have trouble breaking down or excreting drugs The body systems of the elderly may not function as efficiently as when they were younger – the aging process slows down the work of certain organs. Smaller doses or different drugs may be required when treating the very old or the very young patients. Physiological factors
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2- Body Size Physiological factors The usual doses for drugs are mentioned generally for 70 kg adult. The drug concentration at site of action is based on the ratio between the amount of drug administered and size of the body. The dose calculations for abnormally thin or obese patients are required to calculate on the basis of body weight.
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3- Metabolic Rate Physiological factors Patients with a higher metabolic rate tend to metabolize drugs more rapidly, thus requiring either larger doses or more frequent administration. The converse is true for those with lower than average metabolic rates.
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4- Sex Physiological factors Women may react more strongly to certain drugs than men. They are generally smaller and have a higher proportion of fat than men. This is particularly important in the case of treatment with sex hormones. Female adults generally require smaller doses than males due to the presence of more body fat. Consideration given to menstruation, pregnancy, and lactation.
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5- Genetic Factors Physiological factors The genetics differences among the races and certain people frim the same population can affect the drug action. Example: Genetic polymorphism + fast/slow acetylators (hydralazine and isoniazid)
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Avoid drugs during pregnancy due to teratogenic effects as some lipophilic drugs cross placenta barrier. Avoid drugs during lactation due to harm to baby as some drugs easily appear in milk but < therapeutic dose E.g., tetracycline, sedatives, hypnotics, opioids 5- Pregnancy and lactation Physiological factors
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1- Kidney diseases Maintenance dose of such drugs should be reduced . Some drugs worsen the existing clinical conditions in renal failure e.g. NSAIDs cause fluid retention . Nephrotoxic antibiotics should be avoided such as vancomycin. Pathological factors
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2- Liver diseases Bioavailability of drugs having high first pass metabolism is increased due to loss of hepatocellular function . Serum albumin is reduced – protein binding of acidic drugs is reduced and more drug is present in free form. When metabolism of some drugs are decreased, the dose should be reduced such as morphine, pentobarbitone, lidocaine, propranolol. Pro‐drugs requiring hepatic metabolism for activation are less effective such as: prednisolone and Bacampicillin . Pathological factors
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Exposure to insecticides , carcinogens, tobacco smoke , charcoal broiled meat induce drug metabolism. Type of diet can alter drug absorption. Time in which drug is taken – hypnotics work better when taken at night in quiet surroundings. Environmental factors
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Drug’s efficacy can be affected by patient’s expectations and attitude. Placebo is a medicine which has no inherent pharmacologic activity but is intended to be effective only by virtue of factor of suggestion. Psychological /Emotional factors
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Drug Discovery and Safety
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Preclinical Trail Usually done on animals to determine the drug is safe enough for human testing
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Phase I After Investigational New Drug IND to Evaluate Safety and Efficacy
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Phase II Evaluate Safety and Efficacy
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Phase III Evaluate Effectiveness and risk-benefit ratio
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Phase IV Post Marketing Surveillance, Monitor long term effects and effectiveness
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Drug Discovery and Safety
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THANK YOU FOR YOUR ATTENTION
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