Clinical Pharmacology - General Principles PDF

█ Intro oductory definitions Medica al pharma acology is a basic c science.. It the science s deealing with h small molecu ules used tot prev...

█ Intro oductory definitions Medica al pharma acology is a basic c science.. It the science s deealing with h small molecu ules used tot prevent, diagnose , or treat diseases. d Clinicaal pharma acology is s the scieence concerned with the raational, sa afe and effectivve use of drugs d in hu umans. It ccombines elements of o basic phharmacoloogy with clinical medicine e; in other words, it involves the t complex interacction betweeen the drug and the pattient. A drug g is any chemical molecule that can interact with w bodyy systems at the molecu ular level and produc ce effect. The drrug-body interaction ns Part 1 1: Ph harmaco odynamiics (Mec chanism of drug a action) Pharmaacodynam mics is summmarized a as what a drug does to the b body; a drug may produc ce its effectts through: Interraction witth body co ontrol systtems (regulatory prote eins): (a a) Receptorrs (b) Ion n channelss (c c) Enzymess (d) Caarrier molec cules Direc ct chemica al or physic cal mecha anisms. Interraction with certain metabolic m p pathways. 1  A. REC CEPTORS S Receptors: they are protein macrom molecules. When W they y combine with a dru ug, they may be e activated d or blocke ed. Ligand d: is any molecule tha at can com mbine with the recepptors. A ligaand that ac ctivates the rec ceptor is called agonist. a A ligand that t block ks the reeceptor is called antago onist. Affinity y: it is the empathy ofo the rece eptor to the ligand. It determinnes the nummber of receptoors occupied by the drug. █ Typ pes of rec ceptors Ion channel--linked re eceptors (direct ligand-gated d ion channnels): - The receptor is an ion s of 5 n channell consists transsmembran ne subunits s (α1, α2, β,, γ, δ). - Bindding of thee agonist to t the extrracellular part p of the rreceptor causes c opeening of th he channe el for a speccific ion. - The response of these re eceptors iss very fast and their duration d is very shortt. - Exam mples:  N Nicotinic Ach A recepttors in the motor end d-plate: the e ion channnel opens for Na+ ions in ressponse to stimulation s n by Ach.  The Gama a aminobuteric acid (GABA) re eceptors in n the brainn: the ion channel c opens for Cl ions in response to stimulation by GA - ABA. G-protein-lin nked rece eptors: onsists of 7 membran - The receptor co ne subunits. - Bind ding of the e agonist too the extra acellular part of the receptor ca auses ac ctivation of intra acellular G--protein. - Wheen the G-p protein is activated, a its α subu unit bindds to GTP to be pho osphorylateed and bring stimulatory or inhibitory response. - Their responsse is slow wer than ion chann nel receeptors but their t duration is long ger. - Stim mulatory G-protein G (Gs) leadss to increa ase ade enyl cyclase enzyme → ↑ cAMPP → activation of specific proteins s (proteinn kinase es). Exa amples of Gs-couple G ed receptorrs are the β1 and d β2-adrenergic receptors. 2 - Inhibitory G-protein (G Gi) leads to o decrease e adenyl cy yclase enzzyme → ↓ cAMP c → inhibition of protein kinases. Exxamples of o Gi-coup pled recep ptors are the t α2- adreenergic rec ceptors an nd M2 musscarinic rec ceptors. - Gq--coupled receptorrs: they increase inositol triphosp phate (IP3 3) and diac cylglyceroll (DAG). IP3 3 increasess free intrac cellular Ca. Exampl es of Gq-c 2+ coupled rece eptors are the α1-ad drenergic reeceptors, M1M and M3 3 muscarinnic recepto ors. Tyro osine kinase (TK)--linked re eceptors:: - The receptor consists of 2 largee domainss: an extraacellular hormone-b h binding doomain and d an intra acellular TKK-binding domain c onnected by a transsmembran ne segment. - Bindding of the e agonist to the hoormone-binnding dommain cause es activattion of th he intrace ellular dommain to ac ctivate TK enzyme → activatio on of seveeral protein ns known as a “signalin ng proteinss”. - Exam mples: insu ulin recepttors. Intra acellular recepto ors: - Theyy are located inside the t cell eith her in the cytoplasm c or directlyy on the DNA. D - Theyy regulate transcripti t on of genees in the nuucleus or the mitoch ondria. - Their agonist must m enter inside the e cell to reaach them. - Theyy have twoo importantt features:  Their response is slo ow (time iss required for f synthes sis of new proteins).  Their effeccts persist for long tiime after the agonistt is removeed. mples: receptors for corticoste - Exam eroids, sexx hormone es, thyroxinn, etc. Types s of drug g-recepto or bonds s The ionic bon nd: It is an electric cal attraction betwee en two opp posing cha arges. It is strong but reeversible. The hydrogen n bond: It is an attraction betwe een two h hydrogen bonds. b It is weak and reversible. The covalent bond: Veryy strong an nd irreversible. If oc ccurred bettween drugg and rece eptor, the receptor r be ecomes permmanently blocked. b 3