Week2_Drug Structures and Principle of Drug Mechanism [Autosaved].pdf

DRUG STRUCTURES AND PRINCIPLE OF DRUG MECHANISM Presented by: apt. Evelyn, S.Farm., M.Farm.  LEARNING OUTCOME Understanding how general structure of drug implies the effect of drug 2  Introduction of Drug The word drug comes from D...

DRUG STRUCTURES AND PRINCIPLE OF DRUG MECHANISM Presented by: apt. Evelyn, S.Farm., M.Farm.  LEARNING OUTCOME Understanding how general structure of drug implies the effect of drug 2  Introduction of Drug The word drug comes from Drogue meaning ‘a dry herb’ WHO defines drug as: “A substance, material or product used or intended to be used to modify or explore the physiological processes or pathological states for the benefit of the recipient.” Drug is a chemical substance that can alter or influence the responsiveness of a biological system 4 (Food and Drug Administration) All drug is poison, but not all poison is drug General Features of a Drug: 1. Variability in molecular size 2. Variability in shape 3. Variability in chemical nature 4. Variability in lipid/water partition coefficient 5. Variability in degree of ionization 6. Physical Properties  1. Variability in molecular size Smaller sized molecules are easily absorbed than larger molecules. Ideally, the molecular weight is between 100-1000 Da but may be higher or lower. Streptokinase is an example of large molecular weight drug (Mw: 47,286.7 Da) while nitric oxide (Mw: 30.01 Da) is a small molecular weight. Streptokinase Nitric oxide  2. Variability in shape (3D structures) Drugs may be globular or linear in structure. Their shape is modified according to the receptor on which they act. pH responsive or temperature responsive polymeric drugs Hemoglobin, a globular protein 8 Chlorambucil conjugated PEG dendrimer  3. Variability in chemical nature Chemical structure of drugs influence the interaction between drug-receptor. Pharmacophore -> an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biologic target and to trigger (or block) its biologic response 9 Injury 10  Benzoic acid: WEAK anti 5-chloro salicylic acid: Salicylamide: INACTIVE inflammatory agent MORE POTENT anti anti inflammatory agent inflammatory agent  1 2 4. Variability in lipid/water partition coefficient (log P) Lipid soluble drugs (having higher lipid water partition coefficient) are more retained in the body while water soluble drugs are easily excreted out. [Compound]octanol= concentration of the compound in the octanol phase (lipid phase) [Compound]water​= concentration of the compound in the water phase (aqueous phase) 1 3 5. Variability in degree of ionization Ionized forms of drugs are polar and thus are water soluble. Unionized drugs are less polar and thus more lipid soluble. Ionized forms of drugs can pass through the specific places i.e. through channels like Na+ and K+ channels. 1 4 6. Physical Properties – Drugs may be solids, liquids or gases. Examples include halothane and nitrous oxide, both of which are gases. – Diffusion rate of gases is greater than that of liquids, while diffusion rate of liquids is greater than that of solids.  Terms Local effect: When the drug effect occurs in immediate vicinity of application, this is known as local effect. The effect limited on the specific tissues rather than whole body. Systemic effect: When the drug effect occurs away from the site of administration, this is known as systemic effect. Usually drugs enter the blood stream and go through whole body.  Mechanism of Drug Action There are 4 levels of drug action: Molecular– ion channel, enzyme, carrier molecules (ex: Aspirin inhibiting COX) Cellular – smooth muscle cell, others cell (ex: Calcium channel blocker) Tissue– Contraction, secretion, metabolic activity, proliferation (ex: salbutamol causing bronchodilatation) System– CNS, CVS, PNS (Atorvastatin decreasing overall LDL in the bloodstream-> decrease risk of CVD)  Molecular level 1. ligand-gated ion channels - LGIC (ionotropic receptorz)-> Driven by ligand binding-> opens the channel portion of the protein, allowing ions to cross the membrane and causing the membrane potential to change within 0.1 – 2 millisecond. 2. G-protein – coupled receptor - GPCR (metabotropic receptor)-> activation of a specific G-protein (Guanine nucleotide binding protein) will alter the state of ion channel. *GPCR can also alter cellular state (e.g: changes in protein expression) 1 9  20 https://www.youtube.com/watch?v=P4cuTwgfjBY  3. Voltage gated ion channel. The changes in the membrane potential will change the conformation of channel protein-> regulate the opening and the closing of the channel. Drugs can bind into the voltage gated ion channel from internal or external side or modifying channel gating through binding to the voltage-sensor domain or auxiliary subunits 21 https://www.youtube.com/watch?v=kxnb_TSqmFY 22  Enzyme-> drugs can mimic the natural substrate or become a fake substrate. Carrier molecules. A molecule that plays a role in transporting electrons through the electron transport chain or molecule that help to transport a substance. Drugs can bind with carrier molecules to block their function. 23 23 2 4 Cellular, Tissue and System Level https://www.youtube.com/watch?v=WEbPu1g-320 2 5 https://www.youtube.com/watch?v=4wg0tNGhwv0  Mechanism of Drug Action Most drugs act by altering the various body control systems, which may be receptors, enzymes or ion channels. These various mechanisms include: 1. Physical mechanisms 2. Chemical mechanisms 3. Drug- receptor interactions 4. Drug- enzyme interactions 5. Drug- channel interactions 6. Miscellaneous mechanism  Physical mechanism When the drug does not produce any chemical reaction or change in the cells of the body and the effect is only physical, the mechanisms involved are called physical mechanisms. These include: 1. Local Application Drugs are applied topically on the external surfaces like the skin and the mucous membranes. Ex: Emolients-> oily substances used to soften the skin especially dry skin. Counter Irritants-> substances applied locally on intact skin to abolish deep musculoskeletal pain. They mask the pain sensations. 2 9 2. Bulk forming Purgatives Purgatives are the drugs used to treat constipation. Bulk forming purgatives contain high fiber. This fiber by adsorbing water, swells, increasing the bulk of stools causing distention of the colon. This leads to an increase in peristalsis and evacuation of the bowel. 3. Activated Charcoal Activated charcoal is used to neutralize various poisons. It absorbs the poisons in the stomach.  Chemical mechanism In chemical mechanisms, drug act by producing chemical reactions in the body. Examples: 1. Chemically acting antacids antacids react chemically with HCl of stomach, causing neutralization. Ex: Na bicarbonate chemically binds HCl forming NaCl and water. 2. Chelating agents Chelating agents are the drugs used to treat poisoning with various metals. They incorporate or chelate metal ions into inner ring structure and in this way inactivate or neutralize the effects of metals. 3 1  Drug-receptor mechanism Receptor: Macromolecules protein or binding site located on the surface or inside the effector cell that serves to recognize the signal molecule/ drug and initiate the response to it. Drugs can mimic the natural ligands or compete with them. Ex: Opioid and opioid receptor Anti histamine and histamine receptor Affinity: the ability to bind with the receptor designated Instrinsic activity (IA)/ efficacy: the capacity to induce a functional change in the receptor designated Types of Receptors 4. Intracellular receptors 3 7 There are four forms of binding to receptors: 1. Agonists 2. Partial agonists 3. Antagonists 4. Inverse agonist  3 8 1. Agonists A molecule or chemical compound that can bind to a receptor, thus producing a biological response. An agent which activates a receptor to produce an effect similar to that of the physiological signal molecule. Affinity and maximal intrinsic activity (IA=1) Eg: acethylcholine-> muscarinic receptor Adrenaline, histamine, morphine  3 9 2. Partial Agonist A molecule or chemical compound that can bind to a receptor and weakly activates the receptor, thus producing a submaximal biological response. It has the property of affinity but has less intrinsic efficacy than a full agonist. Intrinsic activity greater than 0 but less than 1. Ex: Buprenorphine is a partial agonist of μ-opioid receptors  4 0 3. Antagonists An agent which prevents the action of agonist on receptor or the subsequent response, but does not have any effect of its own. Have affinity but show zero intrinsic activity (IA=0) Ex: Naloxone and μ-opioid receptors Divided into: - Competitive and Reversible - Competitive and Irreversible - Non-competitive 4 1 4 2 Example of competitive irreversible antagonist Ser530 Serine 530 43 4 4 4 5 4. Inverse agonist A drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A prerequisite is that the receptor must have a basal level of activity in the absence of any substrate. In this case, agonist INCREASE the activity of receptor above the basal level, whereas inverse agonist DECREASE the activity below the basal level. Ex: H1 receptor and antihistamine  Equilibrium state Tend to active state Pain, vasodilation, Hypotension, Bronchoconstriction Tend to inactive state Vasoconstriction, Tachycardia46, Bronchodilation  Drug-enzyme mechanism Enzymes-> a substance produced by a living organism which acts as a catalyst to bring about a specific biochemical reaction. Very specific. Only react with its substrate (lock & key mechanism) The drugs resemble the natural substrates, bind enzymes and cause change in their activity. This may take place by: 1. Activation of enzymes 2. Inhibition of enzymes 4 9 5 0  Drug-channel mechanism drug interfere with the flow of ions through the channels specific for these ions. These include the Na +, K +,Ca2+ and Cl – channels. “Gating mechanism”-> no stimulus, no response: presence of a ligand environmental pH Temperature membrane voltage differences. 5 Na Channel. The essential physiological processes, 2 which enable us to see, hear, move, sense, think, and experience emotion. Binds with neurotoxins local anesthetics, antiarrhythmic, and antiepileptic drugs. Ca Channel. trigger the action potential in smooth muscle and in cardiac pacemaker cells. Binds with anti hypertension (nifedipine) K Channel. Controlling neurotransmitter release, insulin secretion, differentiation, proliferation, apoptosis (programmed cell death). Cl Channel. regulation of the excitability of neurones, skeletal, cardiac and smooth muscle, cell volume regulation, transepithelial salt transport, the acidification of internal and extracellular compartments, the cell cycle and apoptosis  Miscellaneous mechanism Drugs work through other mechanism except those mentioned above. Ex: 1. Vinca alkaloid -> bind to microtubules, inhibiting cell division. https://www.youtube.com/ 53 watch?v=ES3v3VWmLyc  5 4 2. Ionizing Radiation-> radiation hits the DNA molecule and disrupts the molecular structure. Such structural change leads to cell damage or even cell death.  3. Disrupt membrane potential. Ex: Daptomycin-> antibiotic which disrupt the membrane potential of bacteria. Mechanism of action: step 1, daptomycin binds to the cytoplasmic membrane in a calcium- dependent manner; step 2, daptomycin oligomerizes, disrupting the membrane; step 3, the release of intracellular ions and rapid cell death.  Summary 6 general features of drugs 4 levels of drug action 6 mechanism of drug action 5  THANKS! Does anyone have any questions? [email protected] +91 620 421 838 yourcompany.com CREDITS: This presentation template was created by Slidesgo, Slidesgo including icons by Flaticon, infographics & images by Freepik Flaticon Freepik Please keep this slide for attribution