PHARMACODYNAMICS Presented by Dr. Sannithi Nagarjuna Coordinator for RIPER-GPAT Cell, Hyderabad Academy & Online GPAT Academy 7899107907 9885784793 [email protected] It is a branch of pharmacology deals with the study of mechanism of action, pharmacological actions and uses of drugs. (What the drug does to the body) (OR) It is defined as the response of the body to the drug. It refers to the relationship between drug concentration at the site of action and resulting effect. (OR) It is the study of biochemical, physiological and molecular effects of drugs on the body. Most of the drugs produce their mechanism of action by binding to the receptors. DEFINITIONS 1. RECEPTORS → defined as specific binding sites for drug molecules/ ligands and chemically they are protein in nature. All receptors are proteins but all proteins are not receptors. 2. LIGAND → defined as a substance that selectively attaches to the receptors, activates the receptors and produces maximum pharmacological action. Both receptors and ligand are highly specific. Receptors Ligand Muscarinic and Nicotinic Acetylcholine receptors (Cholinergic) Adrenergic receptors Noradrenaline Histamine receptors Histamine Dopamine receptors Dopamine 5-HT receptors 5-HT (Serotonin) GABA receptors GABA 3. AFFINITY → ability of an agent to bind with the receptors 4. INTRINSIC ACTIVITY ( EFFICACY)→ ability of an agent to activate the receptors and produces pharmacological action 5. AGONIST : Affinity + Maximum Intrinsic activity (IA= + 1) Agonist and ligand both are same, the only difference is agonist is exogenous and ligand is endogenous. Agonist produces actions similar to ligand or Agonist increases the actions of ligand 6. ANTAGONIST: Affinity + No Intrinsic activity (IA= 0) Antagonist blocks or stops the actions of ligand hence it is otherwise called as blocker. Source : Google Source : Google Ligand Agonist Antagonist Acetylcholine Carbachol, Atropine Bethanechol Noradrenaline Dobutamine Propranolol Histamine 2-methyl histamine Diphenhydramine TYPES OF RECEPTORS ❖ Receptors will not exist as alone and they are always present in attached manner (Coupled manner) ❖ Based upon the coupled substance receptors are classified into 4 types 1. G-Protein Coupled Receptors ( Receptors coupled to G-Protein ) 2. Ionotropic receptors ( Receptors coupled to Ion channels ) 3. Enzyme linked receptors ( Receptors coupled to Enzymes) 4. Nuclear receptors ( Receptors coupled to nucleus) G-Protein Coupled Receptors ( Receptors coupled to G-Protein ) ❖ Receptors located across/on/within the cell membrane ❖ Hence called as transcellular receptors ❖ Here there are two parts one is G-protein and another one is Receptor Receptor consist of 7 transcellular helical structures 3 loops -NH2 group present on extracellular side -COOH group present on intracellular side G-protein is trimeric in nature consist of 3 subunits called as α, β, and γ and these three subunits attached to GDP. binding of ligand with the receptors GDP replaces with GTP G-Protein dissociated into 2 complexes GTP α β γ Interacts with the pathways Release of substances called as secondary messengers Produces pharmacological actions Source : Google Source : Google PATHWAYS 1. ADENYL CYCLASE PATHWAY ATP -------------→ cAMP -----------→ Inactive ❖ cAMP acts as a second messenger ❖ Enzyme Phosphodiesterase involved in the inactivation of cAMP Source : Google ACTIONS OF CAMP In cardiac muscle/Heart -- Increases force of contraction, Increases cardiac output, Increases blood pressure, Increases heart rate. In smooth muscles (GIT, Bronchi, Uterus) – Smooth muscle relaxation In Liver – Glycogenolysis In adipose tissue Lipolysis In Platelets Decreases platelet aggregation 2. PHOSPHOLIPASE PATHWAY Stimulation of this pathway results in the breakdown of cell membrane phospholipids. Cell membrane phospholipids upon breakdown will release Inositol-1,4,5- triphosphate (IP3)and Diacylglycerol (DAG) which act as second messengers. IP3 & DAG always produce stimulation. ACTIONS OF IP3 AND DAG Location Action Cardiac muscles Contraction Smooth muscles Contraction Skeletal muscles Contraction Glands Increase in secretions CNS CNS Stimulation GS → Increased levels of cAMP Gi → Decreased levels of cAMP Gq → Increased levels of IP3 and DAG EXAMPLES: 1.Muscarinic receptors (M1- M5) 2. Adrenergic receptors (α1- α2 & β1- β3) 3.Histamine receptors (H1-H3) 4.Dopamine receptors (D1-D5) 5.5-HT receptors (5-HT1 to 5-HT 7 except 5-HT 3) 6.Opiod receptors 7.GABAB receptors MUSCARINIC RECEPTORS(M1 - M5) Gq Gi M1 M2 M3 M4 M5 Type of Second Location Pharmacological actions receptor Messenger M1 Gq ❖ Gastric Parietal Cells ❖ Ciliary Muscles of Iris M3 Gq ❖ Smooth muscles like Bronchi, Uterus, GIT ❖ Glands like sweat glands, salivary glands & lacrimal glands M5 Gq CNS Type of Second Location Pharmacological actions receptor Messenger M1 Gq ❖ Gastric Parietal Cells ❖ Increase in acid secretion ❖ Ciliary Muscles of Iris ❖ Contraction of Ciliary Muscles of Iris (Miosis) M3 Gq ❖ Smooth muscles like ❖ Smooth muscle contraction like Bronchi, Uterus, GIT Bronchoconstriction, Uterus constriction, Contraction of GIT, Increase in motility of GIT ❖ Glands like sweat ❖ Increase in secretions glands, salivary glands like sweating, salivation and & lacrimal glands lacrimation M5 Gq CNS ❖ CNS stimulation Type of Second Location Pharmacological receptor Messenger actions M2 Gi Heart M4 Gi CNS Type of receptor Second Location Pharmacological Messenger actions Decrease in M2 Gi Heart force of contraction, Decrease in cardiac output, Decrease in blood pressure, Decrease in heart rate No action M4 Gi CNS Source: Google PHARMACOLOGICAL ACTIONS OF ACETYLCHOLINE Location Pharmacological actions Heart Decrease in force of contraction, Decrease in cardiac output, Decrease in blood pressure, Decrease in heart rate Smooth muscles like Smooth muscle contraction like Bronchoconstriction, Bronchi, Uterus, GIT Uterus constriction, Contraction of GIT, Increase in motility of GIT Gastric Parietal Cells Increase in acid secretion Ciliary Muscles of Iris Contraction of Ciliary Muscles of Iris (Miosis) Glands like sweat glands, salivary Increase in secretions like sweating, glands & lacrimal glands salivation and lacrimation CNS CNS stimulation ADRENERGIC RECEPTORS {α1 – α2 & β1- β3} Gq Gi GS α1 α2 β1 β2 β3 Type of Second Location Pharmacological actions receptor Messenger α1 Gq ❖ Blood vessels α2 Gi ❖ CNS Type of Second Location Pharmacological actions receptor Messenger Vasoconstriction, α1 Gq ❖ Blood vessels increase in blood pressure No Action α2 Gi ❖ CNS Type of Second Location Pharmacological actions receptor Messenger β1 GS ❖ Heart β2 GS ❖ Smooth muscles ❖ Bronchi ❖ Liver β3 GS ❖ Adipose tissue Type of Second Location Pharmacological actions receptor Messenger Increase in force of β1 GS ❖ Heart contraction, Increase in cardiac output, Increase in blood pressure, Increase in heart rate ❖ Smooth muscle β2 GS ❖ Smooth muscles relaxation ❖ Bronchi ❖ Bronchodilation ❖ Liver ❖ Glycogenolysis β3 GS ❖ Adipose tissue ❖ Lipolysis PHARMACOLOGICAL ACTIONS OF NORADRENALINE Location Pharmacological actions Heart Increase in force of contraction, Increase in cardiac output, Increase in blood pressure, Increase in heart rate Smooth muscles Smooth muscle relaxation Bronchi Bronchodilation Blood vessels Vasoconstriction, increase in blood pressure Metabolic effects Glycogenolysis & Lipolysis IONOTROPIC RECEPTORS (RECEPTORS COUPLED TO ION CHANNELS ) ❖ Receptors coupled to ion channels ❖ Receptors located across/on/within the cell membrane ❖ These are also transcellular receptors ❖ Also called as ligand gated ion channels Ligand binds to the receptors Opening of ion channelsO will take place p Result in either influx or efflux of ions depending upon concentration gradient Result in pharmacological actions which may be stimulation or inhibition Source : Google Sodium, Calcium & Chloride ions present extracellularly so when these ion channels get opened that result in influx of ions. Potassium ions present intracellularly so when these ion channels get opened that result in efflux of ions. Ligand binds to the receptors → Sodium channels → Influx of sodium ions→ Ligand binds to the receptors → Calcium channels → Influx of Calcium ions→ Ligand binds to the receptors → Chloride channels → Influx of chloride ions→ Ligand binds to the receptors → Potassium channels → Efflux of potassium ions → Ligand binds to the receptors →Sodium channels → Influx of sodium ions→ Stimulation Ligand binds to the receptors → Calcium channels → Influx of Calcium ions→ Stimulation Ligand binds to the receptors → Chloride channels → Influx of chloride ions→ Inhibition Ligand binds to the receptors → Potassium channels → Efflux of potassium ions →Inhibition Location Stimulation Inhibition Contraction, Relaxation, Cardiac Increase in force of Decrease in force of contraction, contraction, muscle/Heart Increase in cardiac Decrease in cardiac output, output, Increase in blood Decrease in blood pressure, pressure, Increase in heart rate Decrease in heart rate Smooth muscles Contraction Relaxation Skeletal muscles Contraction Relaxation Glands Increase in secretions Decrease in secretions CNS CNS Stimulation CNS depression EXAMPLES: 1. Nicotinic receptors (NM & NN receptors) 2. 5-HT3 receptors 3. GABAA receptors 4. NMDA receptors Type of Type of ion Location Pharmacological actions receptor channel attached NM Sodium ❖ Skeletal muscles NN Sodium ❖ Autonomic ganglia 5-HT3 Sodium ❖ CTZ GABAA Chloride ❖ CNS NMDA Calcium ❖ CNS Type of Type