PREBOARD REVIEW PCHEM4 2024.pdf

ORGANIC MEDICINAL CHEMISTRY PREBOARD REVIEW University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  PCHEM4 DRUG RECEPTORS University of San Agustin -...

ORGANIC MEDICINAL CHEMISTRY PREBOARD REVIEW University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  PCHEM4 DRUG RECEPTORS University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department PREBOARD REVIEW RECEPTOR Protein molecule usually embedded within the cell membrane with part of its structure exposed on the outside of the cell. Site where the drug exerts its characteristic effects or where the drug acts. Contain specific regions that react with complementary functional groups University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  RECEPTOR Drug Receptor Interactions are also referred to as Ligand - Receptor Interactions University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department HOW ARE RECEPTORS ACTIVATED? University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  The following are theories to explain AFFINITY: ROLE OF how the binding of an agonist to the CONFORMATION receptor produces a response: Occupancy Theory Rate Theory Induced-fit Theory Macromolecular Perturbation Theory Activation - Aggregation Theory University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department OCCUPANCY THEORY Predicts that the biological response is directly related to the number of receptors occupied by the agonist Response ceases when the drug dissociates from the receptor Antagonists occupy with high affinity but do not produce a biological response University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department RATE THEORY Predicts that the biological response is proportional to the rate of the drug- receptor complex. Activation is proportional to the total number of encounters of a drug with its receptor. The basis of a drug's activity is the kinetic rate of the onset and offset of the drug's binding to the receptor. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department INDUCED-FIT THEORY Predicts that as the drug approaches the inactive state of the receptor it induces a specific conformational change that leads to effective drug binding and biological response According to this theory, antagonists induce a nonspecific conformational change that fail to produce the desired biological response University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department THE MACROMOLECULAR PERTURBATION THEORY A combination of induced - fit and rate theory For this theory, it suggests that there are two types of specific receptor conformational perturbations: One leading to the biological response & the other to no activity Rate & ratio of their existence determines the observed biological response University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department THE ACTIVATION - AGGREGATION THEORY Postulates that the receptor is always in the state of equilibrium between active and inactive states Agonists function by shifting the equilibrium to the active state while antagonists prevent the active state This can account for the activity of inverse agonists which can produce responses opposite to that of an agonist University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department DRUG METABOLISM University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department METABOLISM Chemical reaction that occur in the body to maintain life Allow organisms to grow and reproduce, maintain their structures, and respond to their environments University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  METABOLISM CATABOLISM breaks down organic matter ANABOLISM uses energy to build up or construct components of cells such as proteins and nucleic acids. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  DRUG METABOLISM Also known as BIOTRANSFORMATION biochemical changes that drugs and xenobiotics (foreign chemicals) undergo in the body which leads to the formation of different metabolites with different effects University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department Metabolism plays a central role in the formation of: University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  GENERAL PATHWAYS DRUG METABOLISM University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  PHASE I / FUNCTIONALIZATION RXNS Oxidative Reaction Reductive Reaction Hydrolytic Biotransformation University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  PHASE I / FUNCTIONALIZATION RXNS NOTE: Oxidative Reaction Polar functional groups are introduced into the Reductive Reaction molecule or unmasked by oxidation, reduction, Hydrolytic or hydrolysis Biotransformation University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department PHASE I: OXIDATION REACTION majority occurs in metabolic sites are catalyzed by the liver the extrahepatic cytochrome P450 tissues (intestinal (CYP450) bound to mucosa, liver,& smooth kidney) ER of the liver and require both NADPH and a porphyrin prosthetic group University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department FEATURES OF CYP450 Enzyme responsible for transferring an Oxygen atom to the substrate is called Cytochrome P-450 Plays a vital role in oxidation of lipophilic xenobiotics University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  To create more polar functional groups that can be eliminated in the urine CYP450 system might be involved in some reduction reactions University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department ENZYMATIC HYDROLYSIS addition of water across a bond results in a more polar metabolites Esterase enzymes nonspecific and catalyze de- esterification reactions University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department ENZYMATIC HYDROLYSIS Amidase enzymes amides are converted into amines and acids (deamination) Occurs in the liver University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department ENZYMATIC HYDROLYSIS Amidase enzymes amides into amines and acids (deamination), occurs in the liver University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  PHASE II OR CONJUGATION REACTION Glucuronic Acid Conjugation Sulfate Conjugation Conjugation with Glycine, Glutamine and other Amino Acids Glutathione or Mercapturic Acid Conjugation Acetylation Methylation University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department PHASE II OR CONJUGATION REACTION Functional groups of the original drug or the metabolite Phase I reactions are masked by a conjugation reaction Most conjugates are very polar resulting in rapid drug elimination University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department CONJUGATION RXNS combine the parent drug (or its metabolites) with certain endogenous constituents: University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department CONJUGATION RXNS Conjugates are highly polar and unable to cross cell membrane, making them always pharmacologically inactive and of little or no toxicity. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  FACTORS INFLUENCING DRUG METABOLISM University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  CHEMICAL STRUCTURE The presence or absence of functional groups determine the necessity, route, and extent of metabolism University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  DRUG DOSAGE Increase in drug dosage results in increased drug concentrations and can saturate metabolic enzymes. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  FACTORS INFLUENCING DRUG METABOLISM: Physiologic or Disease State Pathologic factors that alter liver function can affect a drug’s hepatic clearance Congestive heart failure decrease hepatic blood flow by reducing cardiac output which alters the extent or drug metabolism. Alteration in albumin production decrease in plasma albumin can increase the fraction of unbound (free) drug to exert a more intense pharmacologic activity University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  FACTORS INFLUENCING DRUG METABOLISM: Genetic Variation Acetylation rate depends on the amount of N-acetyltansferase present Fast acetylators are more prone to hepatoxicity from the antitubercular agent isoniazid than slow acetylators, whereas slow acetyaltors are more prone to isoniazid’s other toxic effects. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  NUTRITIONAL STATUS Low protein diet lead to deficiency of certain amino acids, also decrease oxidative drug metabolism capacity. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  NUTRITIONAL STATUS Deficiency of certain dietary minerals: Mg, Ca, Zn deficiency decrease drug-metabolizing capacity Fe deficiency increase drug- metabolizing capacity University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  NUTRITIONAL STATUS Deficiencies of vitamins Vit. C deficiency – decrease in oxidative pathways Vit. E deficiency – retard dealkylation and hydroxylation University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  FACTORS INFLUENCING DRUG METABOLISM: Age Metabolizing enzyme systems are not fully developed at birth, thus infants and young children need to receive smaller doses of drugs than adults to avoid toxic side effects. In elderly, metabolizing enzymes system decline, thus slows the rate of drug elimination, causing higher plasma drug level per dose than young adults. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  FACTORS INFLUENCING DRUG METABOLISM: Gender Metabolism of diazepam, caffeine, acetaminophen is slightly faster in women. Oxidative metabolism of propranolol, chlordiazepoxide, lidocaine, and some steroids occurs faster in men. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  FACTORS INFLUENCING DRUG METABOLISM: Circadian Rhythms The nocturnal plasma levels of drugs, such as theophylline and diazepam, are lower than diurnal plasma levels. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  FACTORS INFLUENCING DRUG METABOLISM: Drug Administration Route Oral administration. The drug is absorbed from the GIT and transported to the liver through the hepatic portal vein before entering the systematic circulation (first-pass effect, or presystematic elimination). Thus, the drug is subject to hepatic metabolism before it reaches the site of action University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  FACTORS INFLUENCING DRUG METABOLISM: Drug Administration Route Intravenous administration. The drug is delivered directly to the bloodstream without being metabolized in the liver. Intravenous doses undergoing first-pass effect are much smaller than oral doses. Sublingual administration and rectal administration also bypass first- pass effects. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department EXTRAHEPATIC METABOLISM Drug biotransformation that takes place in tissues other than the liver. Sites: Portal of entry – GI mucosa, nasal passages, and lungs Portals of excretion – kidney METABOLISM SITES: Plasma contains esterases which are responsible for hydrolysis of esters Lipid-soluble drug that passes through the intestinal mucosa is metabolized into polar or inactive metabolites before entering the blood. University of San Agustin - Iloilo City www.reallygreatsite.com College of Pharmacy and Medical Technology - Pharmacy Department  EXTRAHEPATIC METABOLISM METABOLISM SITES: Nasal mucosa provides a high level of CYP450 activity which alter the amount of drug that reaches the systemic circulation. Lung is responsible for the first-pass metabolism of drugs administered intravenously, intramuscularly, transdermally, or subcutaneously. The lung provide second-pass metabolism for drugs leaving the liver. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  EXTRAHEPATIC METABOLISM PLACENTAL AND FETAL METABOLISM If a drug or other xenobiotic is lipid soluble also pass through the placenta. Drugs in their active form in the maternal circulation pass unchanged into the fetal circulation. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  STRATEGIES TO MANAGE DRUG METABOLISM University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  A. PHARMACEUTICAL STRATEGIES STRATEGIES TO MANAGE - involve the use of different dosage DRUG METABOLISM forms to either avoid or compensate for rapid metabolism. decreasing the overall extent of metabolism and increasing the duration of action. Sublingual tablets directly into the systemic circulation and bypassing hepatic first-pass metabolism. Nitroglycerin, a rapidly acting antianginal agent, if given sublingually. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  PHARMACEUTICAL STRATEGIES Transdermal patches and ointment formulations provide a continuous supply of drug over an extended period of time. Intramuscular depot injections provide a continuous supply of drug over an extended period of time. Hydrolysis of estradiol and testosterone produces a steady supply of these rapidly metabolized hormone. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  PHARMACEUTICAL Enteric-coated formulations can protect acid sensitive drugs as they pass through STRATEGIES the acidic environment of the stomach. e.g. methenamine, erythromycin, omeprazole. Nasal administration delivery of peptides (calcitonin salmon) which have very low oral bioavailability. Aerosolized drugs penetrate a thin epithelial layer to reach abundant capillary beds. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  B. PHARMACOLOGIC STRATEGIES Concurrent use of enzyme inhibitor to decrease drug metabolism. Concurrent use of an additional agent prevents the toxicity caused by metabolites. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  EXAMPLE: LEVODOPA: amino acid precursor of dopamine,treatment of parkinsonism penetrate blood-brain barrier and reach CNS; in brain it is decarboxylated to dopamine University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  EXAMPLE: LEVODOPA: to assure the adequate concentrations of L-dopa reach the CNS, peripheral metabolism of the drug must be blocked concurrent administration of carbidopa cannot penetrate the BBB, prevents the peripheral formation of dopamine. University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  EXAMPLE: BETA-LACTAM ANTIBIOTICS: antibacterial activity is reduced by microorganisms capable of secreting beta-lactamase which hydrolyzes the beta-lactam ring and inactivates the antibiotic beta-lactamase inhibitor (clavulinic acid) is used in conjunction with a penicillin (amoxicillin) to treat infections University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  ENZYMES CATALYZING PHASE I METABOLISM Cytochrome P-450 Aldehyde and alcohol dehydrogenase Deaminases Esterases Amidases Epoxide hydratases University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department  ENZYMES CATALYZING PHASE II METABOLISM Glucuronyl transferase (glucuronide conjugation) Sulfotransferase (sulfate conjugation) Transacylases (amino acid conjugation) Acetylases Ethylases Methylases Glutathione transferase University of San Agustin - Iloilo City College of Pharmacy and Medical Technology - Pharmacy Department