Industrial pharmacy REPLICA LATINA

HORMONES General information on hormones. • THYROID HORMONES structure, biogenesis, metabolism and SAR. Synthesis of T3 and T4. Drugs for thyroid disorders – Thionamides, propylthiouracil, methimazole and carbimazole. • DIABETES AND HYPOGLYCEMIC DRUGS Glucose homeostasis. Insulin, stability and delayed forms. First and second generation arylsulfonylureas (interaction with the target), glinides (rapaglinide), biguanides (metformin), Glitazones (pioglitazone), Gliptins (structural modifications to improve stability). • STEROID HORMONES. General information. Male hormones - Androgens: Testosterone, biosynthesis and metabolism. Structural modifications to improve pharmacokinetics and reduce metabolism. Testosterone synthesis. Synthetic anabolics. Derivatives of 17 methyl testosterone (synthesis) and nandrolone. Steroidal (cyproterone acetate) and nonsteroidal (N-arylpropionamides – SAR, flutamide, hydroxyflutamide) antiandrogens. Drugs for benign prostatic hypertrophy. Alpha1 adrenergic antagonists (see SNA drugs); 5-alpha-reductase inhibitors (finasteride – mechanism of action) Hormones of the female sphere - Estrogens: natural estrogens, estrogen receptors. Estradiol, biosynthesis and metabolism - chemical synthesis of estradiol and estrone. Structural modifications to improve pharmacokinetics and reduce metabolism. Synthetic estrogens, with steroidal (ethinyl estradiol – synthesis) and nonsteroidal (diethylstilbestrol and derivatives) structure, Antiestrogens. Ethylene triphenyls (tamoxifen, raloxifene). Aromatase inhibitors: mechanism of androstenedione and letrozole. Progestins – progesterone, biosynthesis and metabolism. progestin hormones (esters of 17-α-hydroxy progesterone, derivatives of 17-α-hydroxy progesterone, derivatives of estran and 17-alpha-hydroxy estran. Progestin SARs. Synthesis of progesterone and ethinyltestosterone. Progestin antagonists, mifepristone. Hormones of the adrenal cortex. Biogenesis of glucocorticoids and d-mineralcorticoids. Glucocorticoid hormones. Natural compounds (Cortisol and Cortisone), - synthetic compounds and SARs. Synthesis of Cortisol and Cortisone. Mineralcorticoid hormones. Aldosterone and Desoxycorticosterone. Vit. D: Biological role, structure and metabolic activation of provitamins. • H1 ANTIHISTAMINES. Histamine. Metabolism, Structure and ionization and conformational equilibria of histamine. Histamine receptors. Anti-H1 compounds and SAR. First generation derivatives: ethylenediamines, ethanolamines, propylamines (triprolidine synthesis), piperazines. Tricyclic derivatives and second generation compounds. • LOCAL ANESTHETICS. Types of anesthesia, Structure of the sodium channel – voltage dependent, conformational switch mechanism and channel opening. Mechanism of action of local anesthetics, effect of pKa, hydrophilic and hydrophobic access route. Cocaine: structure and molecular simplifications. Procaine and tetracaine (synthesis) and ester analogues. Stabilization towards hydrolysis. Amide derivatives, procainamide, anilide derivatives, Lidocaine, Levobupivacaine (synthesis). • DRUGS OF THE AUTONOMOUS NERVOUS SYSTEM Autonomic nervous system: general information. Sympathetic and parasympathetic system. Sympathetic system drugs  Alpha and beta adrenergic receptors. Adrenergic transmission. Natural adrenergic agonists, SAR, biosynthesis and metabolism of catecholamines. Drugs that affect adrenergic transmission.  Sympathomimetic drugs – SAR adrenergic agonists, selectivity and metabolic stabilization. Alpha1 -2 adrenergic agonists (general synthesis schemes of phenylatanolamines); alpha1 selective (imidazolines – naphazoline synthesis); alpha2 selective – clonidine (SAR). Non-selective beta adrenergic agonists (isoprenaline and orciprenaline), beta2 selective. Terbutaline synthesis  Sympatholytic drugs – non-selective alpha antagonists; uses. Selective alpha1 antagonists, uses. Quinazolines, SAR, Prazosin synthesis. Phenoxyalkylamines, mechanism of suicide inhibition and synthesis of phenoxybenzamine. Imidazolines. Indole alkaloids: ergotamine derivatives, uses. Nonselective beta-adrenergic antagonists, uses. Arylethanolamines, SAR; Aryloxypropanolamines, SAR, development of selective beta1 antagonists, uses and general synthesis scheme. Alpha/beta antagonists. Parasympathetic System Drugs. Biosynthesis and chemical characteristics of Acetylcholine. Muscarinic and nicotinic receptors: structure and functions.  Acetylcholinesterase inhibitors. Structure and mechanism of Acetylcholinesterase. Reversible inhibitors. Pseudo-irreversible inhibitors, mechanism of action, drugs with topical and central activity, uses and synthesis of neostigmine. Irreversible inhibitors: organophosphates, mechanism of action and uses. Antidotes for organophosphate poisoning: Pralidoxime, mechanism.  Parasympathomimetics: muscarinic agonists - methanechol, carbachol (synthesis), bethanechol; nicotinic agonists.  Parasympatholytics: Muscarinic antagonists: atropine, structure, uses and side effects; scopolamine structure, uses and side effects. Quaternary salts and molecular simplification products. SAR of muscarinic antagonists and interaction model.  Parasympatholytics: Nicotinic antagonists. Ganglioplegics, pentamethonium, hexamethonium, mecamylamine. Neuromuscular blockers: d-tubocurarine, benzylisoquinol derivatives, atracurium besilate. Steroid derivatives malouetin, pancuronium bromide. Succinylcholine. Spasmolytics: Papaverine (structure, mechanism and synthesis). • CNS DRUGS Introduction. VOLATILE AND INTRAVENOUS GENERAL ANESTHETICS: general principles, use - Volatile anaesthetics, characteristics that influence pharmacokinetics. MAC, oil/gas distribution, blood gas distribution. SAR, Meyer-Overton theory. Metabolism and toxicity (treatment with CO2 absorbers). Main Volatile general anesthetics. Halothane synthesis. Intravenous general anesthetics, Propofol, etomidate, ketamine. ANTIEPILEPTICS. Epilepsy, incidence and types of epilepsy. Mechanisms of antiepileptic drugs: Gabargic and Glutamatergic synapses. Barbiturates (Phenobarbital and Primidone), Hydantoins (Phenytoin), Oxazolidinediones and Succinimides, Iminostilbenes (carbamazepine, Oxacarbazepine, Eslicarbazepine), Valproic acid, Carbonic anhydrase inhibitors, GABA analogues (Gabapentin, Tiagabine, Vigabatrin – suicide inhibition mechanism), Lamotrigine (synthesis), Leviracetam (synthesis) Anti-Parkinson drugs. Neuropathological characteristics of the disease. Pharmacological treatments: muscarinic antagonists; Amantadine; Dopamine precursors, Levo-Dopa + Dopa-decarboxylase inhibitors; Dopaminergic agonists (aminotetraline - Rotigotine - synthesis); ergot derivatives. ANXIOLYTIC AND HYPNOTIC-SEDATION DRUGS. Physiological phenomena of anxiety, types of anxiety, anxiolytic drugs. Hypnotic-Sedatives: structure of sleep and types of insomnia.  Hypnotic-sedative drugs: aldehydes (chloral hydrate and paraldehyde); alcohols (ethanol - disulfiram); barbiturates (activity, mechanism of action, GABAA receptor, acid/base properties, tautomeric equilibrium, SAR and instability, classification, metabolism and metabolic effects, general synthesis schemes and synthesis of phenobarbital); isosteric analogues of barbiturates (piperidinediones, glutarimides, 4-oxoquinazolines,,  Benzodiazepines. Comparison with barbiturates, Mechanism of action. Uses in relation to pharmacokinetics. Discovery of chlordiazepoxide. General structure, SAR, interaction model with GABAA receptor – agonists, antagonists, inverse agonists. Metabolism of chlordiazepoxide. Synthesis of aminobenzophenones, synthesis of oxazepam and triazolam.  Z drugs. Mechanism, Zaleplon, Zolpidem (metabolism). Drugs of the serotoninergic system. Buspirone, mechanism and synthesis. Melatoninergic agonists. Ramelteon. PSYCHOLEPTIC DRUGS. Psychosis and schizophrenia: dopaminergic, glutamatergic and serotoninergic hypothesis. First generation neuroleptics: mechanism of action and side effects; Reserpine, Phenothiazines (SAR, metabolism, chlorpromazine and perphenazine synthesis), Thioxanthenes (chlorprotixene synthesis), Fluorobutyrophenones (SAR, metabolism and haloperidol synthesis), benzamides (SAR), Second generation neuroleptics: Dibenzothiazepines (clotiapine synthesis), dibenzooxazepines, dibenzodiazepines, Benzoisoxazoles (risperidone synthesis) THIMERETIC DRUGS. Depression: monoaminergic hypothesis, antidepressant drugs. First-generation drugs: MAOIs, oxidative deamination mechanism, hydrazides, hydrazines, amine (tranylcypromine synthesis), propargylamines (suicide inhibition mechanism). TCAs; general structures, SAR, synthesis of imipramine and amitriptyline. Second-generation drugs: SSRIs: Fluoxetine (synthesis), SAR. Notes on SNRIs, NARIs, NDRIs, serotonin reuptake inhibitors (SSRIs), 5-HT2 antagonists, α2-adrenergic agonists. NARCOTIC ANALGESICS. Pain pathways, use of opioids in pain therapy. Endogenous opioids: macroprotein precursors, enkephalins, endorphins and dynorphins, common characteristics, receptor interaction model and SAR. Opioid receptors, classification, tissue distribution and main mediated reactions. Morphine, structure, stereochemistry and pharmacophore and interaction model; metabolism of morphine. Morphine derivatives. Agonists and antagonists and interactions with the receptor. Derivatives of molecular simplification of morphine: morphinans (levorphanol, fenetylvorphanol, levallorphan); benzomorphans (synthesis of phenazocine and pentazocine); phenylpiperidines (meperidine, synthesis and metabolism); anilinopiperidines (fentanyl synthesis); phenylalkylamines (methadone, synthesis). Derivatives of molecular complication of morphine: oripavine, general characteristics. Codeine: metabolism and uses. • NON-STEROIDAL ANTI-INFLAMMATORY DRUGS. Inflammation, Autacoids. Arachidonic acid cascade: cyclooxygenase pathway, lipoxygenase pathway. LOX inhibition, notes. Mechanism of COX, isoforms. NSAIDs, general information, selectivity and toxicity. Salicylates: SAR, aspirin synthesis and mechanism of action. Fenamates, SAR, mefenamic acid synthesis. Arylalkanoic acids: SAR, indomethacin synthesis, sulindac synthesis and metabolism, Tolmetin synthesis, Diclofenac synthesis. Oxycams: SAR, piroxicam synthesis and metabolism. Selective COX2 inhibitors: Arylsulfonamides, nimesulide; Coxibs, celecoxib synthesis and metabolism. Arylpropionic acids: SAR, ibuprofen (metabolism), ketoprofen (synthesis, metabolism), Naproxen (synthesis), Para-aminophenols: SAR, paracetamol (synthesis and metabolism and toxicity). Pyrazzolidinediones: SAR, Phenylbutazone (synthesis, metabolism). Pyrazolones: Phenazone and derivatives, Metamizole (synthesis). • DIURETICS. Classification and uses of diuretics. Carbonic anhydrase inhibitors: mechanism, acetazolamide, SAR. Loop diuretics: Furosemide, ethacrynic acid; Na+/Cl- cotransport inhibitors: chlorothiazide, hydrochlorothiazide, trichlormethiazide SAR (synthetic scheme of thiazides and dihydrothiazides). K-sparing: aldosterone antagonists. Spironolactone (synthesis), Eplerenone, Osmotic diuretics. • LIPOPIDEMIC DRUGS. Cholesterol, triglycerides and cardiovascular diseases. Cholesterol biosynthesis and hypocholesterolemic drugs. HMG-CoA inhibitors; type I statins - Mevastatin, Lovastatin (metabolic activation and interactions with HMG-CoA), simvastatin; type II statins – notes. Bile acid sequestrants. Intestinal cholesterol absorption inhibitors – ezetimibe. Fibrates – clofibrate synthesis. Nicotinic acid and derivatives, acipimox, pyricarbate (synthesis). • CORONARY DIODYLATOR DRUGS. Ischemic cardiomyopathy, causes and therapeutic approaches. Nitrates: mechanism of action. Nitroglycerin, isosorbide dinitrate. Beta-blockers (see SNA drugs). Calcium channel blockers: Mechanism and pharmacological effects, therapeutic uses. 1,4-DHP: Nifedipine (Hantzch synthesis), SAR, interaction model. Nitrendipine (synthesis, metabolism). Benzothiazepines: Diltiazem (SAR, synthesis). Phenylalkylamines: Verapamil (SAR, synthesis). Khellina) mechanism). Amiodarone (mechanism, synthesis) Molsidomine (metabolic activation). • ANTIARRHYTHMIC DRUGS: Arrhythmias and classes of antiarrhythmic drugs. Examples of Class I (IA, IB) II, III and IV drugs. • ANTIHYPERTENSIVE DRUGS. General hypertension and contrast therapies. Alpha-blockers (prazosin and derivatives), beta-blockers (dichloroisoprenaline and derivatives). Direct-acting vasodilators (minoxidil – synthesis). Calcium channel blockers (DHP – general structure). Antihypertensive drugs with neurogenic mechanisms; alpha-2 antagonists (clonidine and derivatives – SAR); L-alphamethyl-DOPA (synthesis). Drugs of the Renin-Angiotensin system. Role of ACE and Renin, development of ACE inhibitors (Captopril - synthesis, Enalapril – synthesis, phosphine esters. AT1 antagonists, Losartan (synthesis) and congeners, Renin inhibitors.

For understanding the lessons of Pharmaceutical and Toxicological Chemistry II, are: ESSENTIAL - Good basic knowledge of organic chemistry, biochemistry, human anatomy, physiology. IMPORTANT: knowledge of Pathology, Pharmacology, Pharmacognosy, Toxicology. USEFUL: notions of Pharmaceutical Chemistry general part.

Gasco, Gualtieri, Melchiorre – Chimica Farmaceutica, seconda edizione, 2020 SEA Editore Foye – Principi di Chimica Farmaceutica, Piccin Editore Artico – Lezioni di Chimica Farmaceutica, CISU Editore

The course of Pharmaceutical and Toxicological Chemistry II consists in frontal lessons with students, possibly integrated with specific seminars. Course attendance is mandatory.

The evaluation methods of the course are characterized by an oral exam session set for each month of the year, excluding the months of May and August. The duration of the oral exam is on average half an hour/student. At the request of the teacher, the student presents a drug in all its aspects. At the end of the presentation, the teacher will ask critical questions about the presentation and will expand the discussion on the class of the drug, stimulating connections with other parts of the program. The same procedure is repeated 3 times to cover the main drug classes studied (hormones, nervous system drugs, cardiovascular drugs). The objective of the test is to certify the student's knowledge regarding the various classes of drugs covered in the course. The topics presented must be treated with a language appropriate to a drug professional. The elements taken into consideration for the evaluation are: knowledge of the subject, in all the parts covered by the exam program, the use of an appropriate language, active participation during the frontal lessons, the reasoning ability demonstrated in the exam interview, the ability to self-study on the texts indicated. To pass the exam with minimum marks (18) a sufficient presentation of the drug and sufficient knowledge of the activity-structure relationships are required, knowledge of the progenitor synthesis of a discussed therapeutic class and being able to describe the interactions of the progenitor of the class with the receptor. To achieve a full score of 30/30 cum laude, the student must instead demonstrate that he has acquired an excellent knowledge of all the topics covered during the course, being able to connect them in a logical and coherent way. He must also demonstrate to move appropriately and naturally between the various classes of drugs. In summary, he must demonstrate to pass 100% the common knowledge learning, having a profile of excellence.

The course of Pharmaceutical and Toxicological Chemistry II consists in frontal lessons with students, possibly integrated with specific seminars on the discovery of new active molecules. The lessons are interactive, so the teacher stimulates the students with questions that they have the potential to answer. This allows the teacher to make clear connections with subjects from some previous courses. The continuous references to notions of previous courses must accustom the student to correctly deal with the study of highly interdisciplinary topics and to ensure that at the end of the course a strong interconnection remains active between the topics of the course itself and between the subjects that form its basis. The student will find slides and teaching materials (exam program, recommended texts) useful for preparing for the exam on the e-learning platform. It is understood that the slides are a guide to the exam topics, but they can never absolutely replace the recommended texts and lectures held by the teacher. Course attendance is mandatory.