L1 Basic Pharmacodynamics PDF

Drug body interaction Pharmacokinetics Drug Pharmacodynamics Body Therapeutic window Optimal dosage regimen which produce The required effect without toxicity and without failure of therapy. Toxicity...

Drug body interaction Pharmacokinetics Drug Pharmacodynamics Body Therapeutic window Optimal dosage regimen which produce The required effect without toxicity and without failure of therapy. Toxicity Safe use Failure Factors affecting drug concentration at site of action: 1- Dose 2- Pharmacokinetics (ADME). Definition of pharmacodynamics It is a branch of pharmacology which describe 1- The drug effects on the body. 2- Moreover, it deals with the mechanism(s) of drug action. It is derived from the Greek words “pharmakon” = meaning drug and “dynamikos”= meaning power. What are the differences between 1- Drug actions and 2- Drug effects? Accordingly, pharmacodynamics deals with the relationship between 1- Drug concentration in the body and 2- Its effects , both A- desirable and B- undesirable. Therapeutic and toxic effects of drugs result from their interactions with molecules in the patient. Most drugs act by associating with specific macromolecules (called receptors) leading to Change in biochemical activities Response (effect). Accordingly, receptors are component of a cell or organism that interacts with a drug and initiates the chain of events leading to the drug’s observed effects. Drugs act via: 2) Non receptors mediated. 1) Receptors mediated. 2- N o n - r e c e p t o r m e d i a t e d : Some drugs act by 1) Direct chemical interaction e.g. As antacids which neutralize gastric acidity and used in treatment of peptic ulcer. 2)Other drugs act through their physicochemical properties e.g. purgatives and osmotic diuretics which owe their action to osmotic effect.  1-Receptor mediated What is a receptor? The term "receptor" has been used to denote any cellular macromolecule to which a drug binds to initiate its effect. The most important drug receptors are cellular proteins. - Drugs produce their effects by………….. Binding to receptors, either 1- Stimulating (increase)or 2- Inhibiting(decrease) these sites. Sites of receptors: Most of drugs act by binding to specific receptors located either: 1) On the cell membrane (e.g. adrenoceptors & cholinoceptors) or 2) Inside the cells (e.g. steroid receptors).  ‫ا‬ Receptor functions: The receptor has two functions: 1)Ligand (drug) binding and 2) Message propagation (i.e. signaling) to produce the intended response in the target cell for the binding ligand. Therefore, it is suggested that within the receptor there are two domains 1- Ligand binding domain and 2) Effector domain. Ligand binding (Drug binding):- Ligands are molecules (e.g. drug molecules) that attach selectively to a particular receptor. (Active chemical groups of the drug that fit with active chemical sites in the receptors) The interaction of the drug with the receptor is analogous to "lock and key" where the drug would fit properly into the receptor and activate it. What is the results of binding of the ligand with its receptors? Following this binding, the receptor exerts its regulatory actions directly on A) Its cellular targets. B) Effectors proteins. OR Indirectly through intermediate cellular signaling molecules called "transducers". What is the transducer? The transducers may be A) An enzyme, or B) Second messenger which is a transport proteins that a) Create, b) Move or c) Degrade a small metabolite (e.g. cyclic nucleotide, inositol triphosphate or ions like Ca++). What is the function of the second messenger? The second messengers can diffuse inside the cell and transmit information to a variety of cellular targets to produce its effects. 1-Ionotropic receptors (ligand-gated ion channel receptors) They are linked directly to ion channels in plasma membrane so that when a drug (ligand) binds to these receptors it leads to opening of the ion channels leading to ionic transport. Example: nicotinic cholinergic receptors. 2-G-protein coupled receptors (GPCRs): G-protein coupled receptors are a class of large membrane bound proteins with an A) Extracellular part for ligand binding (GPCRs) and B)Intracellular part for G-protein binding. G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. G protein-coupled receptor (GPCRs) Protein located in the cell membrane that binds extracellular substances and transmits signals from these substances to an intracellular molecule called a G protein (guanine nucleotide-binding protein). G-proteins mainly relay the information from GPCRs on the plasma membrane to the inside of cells to regulate various biochemical functions. Composition of the GPCRs 1- The extracellular part consists of an amino terminus and several loops that comprise the site of binding. 2- Transmembrane intermediate. 3- The intracellular part has a carboxy terminus end of the receptor that protrude into the cytoplasm The intracellular G-protein consists of α, β and γ subunits. Examples of GPCR: 1- Muscarinic cholinergic receptors. 2- Adrenergic, dopaminergic receptors. 3- Serotonin (5-HT)receptors. 4- Opiates receptors. Examples of diseases involved via GPCRs: 1- Type 2 diabetes mellitus (T2DM). 2- Obesity. 3- Depression. 4- Cancer. 5- Alzheimer’s disease.  Examples of GPCR acting drugs 1- Histamine receptor blockers. 2- Opioid agonists. 3- β-blockers. 4- Angiotensin receptor blockers. Examples of GPCR acting agonist: 1- mu-opiate agonists for treatment of pain. 2- β2-adrenergic agonists used to treat Asthma. 3- α2-adrenergic agonists to treat glaucoma. G-protein has 4 families: Gs, Gi, Gq and G12 based on the second messenger stimulated. G proteins are classified into four families according to their α subunit: Gi, Gs, G12/13, and Gq. The Gs and Gi families regulate adenylyl cyclase activity, while Gq activates phospholipase Cβ and G12/13 can activate small GTPase families ). Binding of a drug to this type of receptor leads to activation of a G-protein which regulates the activity of effectors components (e.g. adenyl cyclase, phospholipase enzymes) leading to change in the concentration of an Intracellular second messenger such as A) cAMP, B) cGMP, C) inositol triphosphate (IP3) or D) Ca++. 3-Receptors linked to tyrosine kinase: These are transmembrane receptors that have two domains: A) An extracellular domain for drug binding and B) A cytoplasmic domain with enzymatic activity (tyrosine kinase enzyme). What about drug receptor binding in this type? Binding of the drug to the extracellular domain stimulates the enzyme tyrosine kinase ------------------- leading to phosphorylation of target proteins to produce the desired effect. Example of this mechanism is insulin receptors What is the function of tyrosine kinase receptors? A member of a group of proteins called tyrosine kinases that are found on the surface of cells. 4- Intracellular receptors: These receptors are not associated with plasma membrane and are located intracellular. The ligands related to these receptors are lipid soluble and can cross the cell membrane e.g. steroid hormones, thyroid hormone and vitamin D.