Industrial pharmacy REPLICA LATINA

Antihistamines. Generality. Overview of classic anti-H1 antihistamines. General formula, mepyramine, antazoline, diphenhydramine, promethazine. Phenothiazine neuroleptics. Etiological hypotheses on schizophrenia. Discovery of chlorpromazine. Chlorpromazine: synthesis and structure-activity relationships (SAR). Perazines and Phenazines. Trifluperazine, thioridazine, mesoridazine, perphenazine, prochlorperazine, fluphenazine, trifluperazine. Chlorprothyxene (synthesis), thiotixene. Depot forms of phenothiazine and thioxanthene neuroleptics. Metabolism of phenothiazine neuroleptics. Atypical antipsychotics. Clozapine (synthesis), clotiapine, loxapine, perlapine. Butyrophenone neuroleptics. Discovery of haloperidol. Haloperidol: synthesis and SAR. Trifluperidol, spiperone, droperidol, penfluridol, fluspirilene, pimozide. Benzamide neuroleptics. From local anesthetics to benzamide neuroleptics: benzocaine, procaine, procainamide, metoclopramide, sulpiride, amisulpride. Rauwolfia alkaloids: outline. Anxiolytics. Discovery of benzodiazepines (chlordiazepoxide). The GABAA receptor for GABA; the benzodiazepine receptor (BZR). BZR: full agonists (e.g. diazepam, flunitrazepam), inverse agonists (e.g. β-carbolines), antagonists (e.g. flumazenil). Therapeutic activities of benzodiazepines. Chlordiazepoxide, diazepam (synthesis), nor-diazepam, bromazepam, nitrazepam, clonazepam, flunitrazepam, clorazepate potassium, lorazepam, oxazepam, alprazolam, triazolam (synthesis). SAR of benzodiazepines. Metabolism of benzodiazepines. BZR agonists with non-benzodiazepine structure (z-drugs): zolpidem, zaleplon, zopiclone. Partial agonists of BZR: imidazenil, bretazenil. Hypnotics-sedatives. Barbiturates: mechanism of action on the GABAA receptor, general formula, synthesis. Lipophilicity/hydrophilicity and SAR requirements. Amobarbital, aprobarbital, butabarbital, pentobarbital, secobarbital, thiopental, phenobarbital, mephobarbital, cyclobarbital, hexobarbital. Sodium thiopental. Barbiturate metabolism. Melatonin agonists: ramelteon. Anticonvulsants. Excitatory (glutamate) and inhibitory (GABA) amino acids: biogenesis and catabolism. Ionotropic and metabotropic receptors. Drugs active on GABA: sodium valproate, gabapentin, tiagabine, barbiturates, primidone, benzodiazepines, felbamate, topiramate. Drugs active on glutamate: felbamate, topiramate, lamotrigine. Drugs blocking T-type Ca+2 channels: succinimides (ethosuximide, methosuximide, phensuximide), oxazolidinediones (trimethadione), sodium valproate, zonisamide. Drugs activating K+ channels: retigabine. Drugs blocking Na+ channels: hydantoins (phenytoin, mephenytoin, ethotoin), iminostilbenes (carbamazepine, oxacarbazepine). Synthesis of phenytoin and phenobarbital. Antiparkinsonian. Biogenesis and catabolism of dopamine and nor-adrenaline. Hypotheses on the etiology of PD. L-DOPA, carbidopa, benserazide. Anti-MAO: selegiline, rasagiline. COMT inhibitors: tolcapone, entacapone. Amantadine, memantine. Bromocriptine, pergolide and dopaminergic agonists. Anticholinergics: trihexyphenidyl, procyclidine, biperiden. Drugs active on serotonin receptors. 5-HT1A receptor agonists: buspirone, gepirone; 5-HT1A receptor antagonists: spiperone, 2-methoxyphenylpiperazine; 5-HT1B,D,F receptor antagonists: sumatriptan, zolmitriptan, rizatriptan (triptans); 5-HT2 receptor antagonists: spiperone, clozapine, trazodone, mirtazapine; 5-HT3 receptor antagonists: cocaine, ondansetron, alosetron, granisetron (setrons); non-selective serotonergic agonists: Ergot alkaloids. Antidepressants. Aminergic hypothesis. NSRIs (non-selective reuptake inhibitors): tricyclics: imipramine (synthesis), clomipramine, trimipramine, amitriptyline (synthesis), doxepin, dothiepin; non-tricyclics: venlafaxine, duloxetine. NSRIs (nor-adrenaline-selective reuptake inhibitors): tricyclics and tetracyclics: desipramine, nortriptyline, butriptyline, amoxapine, maprotiline, mianserin; non-tricyclics: nisoxetine, atomoxetine, reboxetine. SSRIs (serotonin-selective reuptake inhibitors): zimeldine and nor-zimeldine, fluoxetine (synthesis) and nor-fluoxetine, paroxetine, talopram and talsupram, citalopram and desmethylcitalopram, sertraline and desmethylsertraline, fluovoxamine. DNRIs (dopamine/nor-adrenaline reuptake inhibitors): bupropion, mazindol, amitifadine. SARI (serotonin antagonist reuptake inhibitor): trazodone. NaSSA (nor-adrenalin/serotonin selective antagonist): mirtazapine. Anti-MAO (iproniazid, phenelzine, tranylcypromine, moclobemide). Hypercholinergic hypothesis: mecamylamine. Melatonergic hypothesis: agomelatine. Glutamatergic hypothesis: ketamine (synthesis). Mood stabilizers: Lithium salts. Analeptics. Strychnine, pretcamide, niketamide, pentylenetetrazole (synthesis). Xanthine alkaloids (synthesis of caffeine), theophylline salts, phenethylline, istradefylline. Opioid analgesics. Opium alkaloids: morphine, codeine, thebaine, papaverine. Endogenous opioids: enkephalins and endorphins. Molecular mechanism of opioid µ-receptor agonists. Neurochemical basis of the mechanism of abuse and dependence (unitary hypothesis): cocaine, amphetamine, μ-opioid agonists, κ-opioid agonists. Opioid receptors (µ, κ, δ, NOR). Morphine: structure, stereochemistry, SAR studies. Model of Beckett and Casy. Importance of pharmacokinetics: morphine, 6-acetylmorphine, heroin, codeine. Hydromorphone and hydrocodone; oxymorphine, oxymorphone and oxycodone. Substituent in N17 (agonists and antagonists): naloxone and naltrexone, nalorphine, nalbuphine, N-phenethylmorphine. Molecular simplification: morphinans: N-methylmorphinan, levorphanol and dextromethorphan, levallorphan, N-phenylenevorphanol, butorphanol; benzomorphans: metazocine, phenazocine (synthesis), pentazocine, bremazocine; 4-phenylpiperidines and 4-anilinopiperidines: meperidine (synthesis), ketobemidone, fentanyl, sufentanil, alfentanil, remifentanil; 3-phenylpropylamines: methadone (synthesis), acetylmethadol, dextro- and levo-propoxyphene, loperamide, diphenoxylate. Molecular complication: oripavines: etorphine (synthesis), diprenorphine, buprenorphine. Models of the µ opiate receptor: Beckett and Casy (1954 and 1971), Portoghese (1965 and 1981), Snyder (1976). Non-steroidal anti-inflammatory drugs. Salicylic acid, acetylsalicylic acid (synthesis). Arachidonic acid cascade. Diflunisal. Phenamates (mefenamic acid, meclofenamic acid). Arylacetic and α-arylpropionic acids: indomethacin (synthesis), sulindac, diclofenac (synthesis), ketoprofen (synthesis), ibuprofen, flurbiprofen, naproxen, etodolac, ketorolac. Pyrazolidinediones and pyrazolinones: phenylbutazone, aminophenazone, dipyrone. Oxicam: piroxicam (synthesis), sudoxicam, isoxicam, meloxicam. Paracetamol, acetanilide, phenacetin. Selective COX-2 inhibitors: nimesulide, celecoxib (synthesis), rofecoxib, valdecoxib, lumiracoxib. Cholinergic nervous system drugs. Nicotinic and muscarinic receptors. Cholinergic agonists: acetylcholine, acetyl-α-methylcholine, methacholine, carbachol, bethanechol, pilocarpine. Indirect cholinomimetics: reversible acetylcholinesterase (AchE) inhibitors: carbamoylants: physostigmine, neostigmine, pyridostigmine, rivastigmine; non-carbamoylants: tacrine, donepezil, galantamine; irreversible AchE inhibitors: sarin, malathion, parathion, paraoxon. Antidotes for phosphoric organ poisoning: 2-PAM. Muscarinic antagonists: atropine, scopolamine, homatropine; pharmacophore processing: adiphenine, glycopyrrolate, trihexyphenidyl. Nicotinic antagonists: d-tubocurarine, decamethonium, succilinylcholine, hexamethonium. Adrenergic nervous system drugs. Nor-adrenaline and adrenaline: SAR, adrenergic receptors. Selective β-Agonists: isoprenaline, orciprenaline, isohetarine, tert-butyl-noradrenaline, terbutaline, salbutamol. Breakdown of the catecholamine structure: synephrine, phenylephrine, metaraminol; ephedrine, nor-ephedrine; amphetamine, methamphetamine. Selective α-agonists: naphazoline (synthesis), clonidine (synthesis), α-methylDOPA. α–Selective antagonists: prazosin (synthesis), terazosin, doxazosin; mirtazapine; dihydroergocristine, dihydroergotoxine. β-Selective antagonists: dichloroisoprenaline, pronethalol, propranolol (synthesis). Difference between aryl-ethanol-amines and aryloxy-propanol-amines. Oxprenolol, Timolol, Pindolol, Nadolol. Selective β1-Blockers: acebutolol, atenolol, metoprolol, betaxolol. “Intelligent” β1-Blockers: xamoterol. α/β Non-selective blockers: labetalol and carvedilol. Cardiovascular drugs. Antiarrhythmics: Quinidine, procainamide, lidocaine, phenytoin, propranolol, oxprenolol, nadolol, acebutolol. Calcium channel blockers: verapamil, diltiazem, bepridil, 1,4-dihydropyridines (DHP). Nifedipine (synthesis and SAR), nitrendipine, nimodipine, isradipine. Coronary vasodilators: β-blockers, Ca+2-antagonists, organic nitrates (glycerin trinitrate, isosorbide dinitrate). Antihypertensives: adrenergics and antiadrenergics (prazosin, clonidine, α-methylDOPA, β-blockers); direct-acting vasodilators (hydralazine, minoxidil, diazoxide); ACE inhibitors: captopril, enalapril and enalaprilat (SAR), lisinopril, fosinopril and fosinoprilat; sartans: losartan, eprosartan. Diuretics: osmotics (mannitol, sorbitol, isosorbide); carbonic anhydrase inhibitors (acetazolamide); loop diuretics (furosemide, ethacrynic acid); thiazide diuretics (chlorothiazide, hydrochlorothiazide, trichlormethiazide, hydroflumethiazide); potassium-sparing diuretics (spironolactone, canrenone, potassium canrenoate; triamterene, amiloride). Lipid-lowering agents: fibrates (clofibrate, fenofibrate, ciprofibrate), bile acid sequestrants (cholestyramine), statins (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin). Mechanism of inhibition of HMG-CoA reductase. Steroids. Sterochemistry. α-gonane and β-gonane. Steroid hormones, bile acids and cardiokinetic glucosides. Bile acids: chenodeoxycholic acid, ursodeoxycholic acid, obeticholic acid. Cardiokinetic glucosides: lanatoside A, digitoxin, digoxin, ouabain. Notes on the biogenesis of steroid hormones. Androgens: testosterone and its esters as depot forms, androsterone, methyltestosterone. Progestogens: progesterone, ethisterone. Estrogens: estrone, estradiol, ethinylestradiol, mestranol, quinestrol. Corticosteroids: mineralocorticoids (corticosterone, aldosterone), glucocorticoids (hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone). Mechanism of action of steroid hormones. Steroid hormone receptors. Hours required by the topics: CNS drugs: 45 hours; opioid drugs and NSAIDs: 15 hours; SNA and cardiovascular drugs: 15 hours; steroids: 6 hours.

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.