Medicinal Chemistry for Pharmacy Students

This chapter is a comprehensive account of the medicinal chemistry of drugs affecting the cholinergic system. It provides the mechanism of drug action and the structure-activity relationship (SAR) of the cholinergic and related drugs. After a study of this chapter, students will be able to:

• Relate principles of acetylcholine (ACh) discovery, biosynthesis, storage, transport, and metabolism.

• Describe the effects of agonism and antagonism of cholinergic receptors and modulation of ACh levels at the synapse.

• Describe cholinergic biochemistry and neurochemical interactions. • Compare muscarinic and nicotinic receptor subtypes.

• Illustrate the mechanism of action, structure-activity relationship (SAR), metabolites, and clinical considerations of:

▪ muscarinic receptor agonists

▪ muscarinic receptor antagonists (anticholinergics)

▪ acetylcholinesterase (AChE) inhibitors

o reversible

o quasi-irreversible

o antidotes for irreversible inhibitors

▪ neuromuscular blocking agents

This chapter is a comprehensive account of medicinal chemistry of drugs affecting the adrenergic system. It provides the mechanisms of action of drugs and detail of structure-activity relationships of the adrenergic drugs to give the knowledge base for pharmacists. After the study of this chapter students will be able to:

• Comprehend the historical background of adrenergic neurochemistry and drugs acting on this system

• Explain adrenergic neurotransmitters and their functions

• Classify adrenergic receptors and their structures and binding

• Discuss direct and indirect acting sympathomimetic (adrenergic agonists) and sympatholytic (adrenergic antagonists) drugs

• Explain SAR for direct and indirect acting adrenergic receptor agonists and antagonists

• Delineate the clinical significance of these classes of drugs

• Identify the discovery process of these agents

This chapter is a comprehensive account of the medicinal chemistry of antipsychotic drugs. It provides the mechanism of drug action and detail structureactivity relationships of the first- and second-generation antipsychotic and related drugs to give the knowledge base for pharmacists. Upon completion of this chapter, students will be able to:

• Describe the historical background about the development of antipsychotic therapeutics.

• Apply the principles of fundamental pathophysiology of schizophrenia and other psychotic disorders and receptors associated with it to their pharmacological action.

• Recognize the dopamine and its chemical analogues and identify the essential structural features to become an antipsychotic agent.

• Differentiate between the positive and negative symptoms and extrapyramidal side effects and distinguish between the typical and atypical classes of antipsychotics.

• Apply the principles of structure-activity relationships to the antipsychotic drugs.

• Delineate the clinical significance of all classes of antipsychotic drugs and their therapeutic indications.

• Identify the therapeutic use, side effects and metabolic pathways of selected first- and second-generation antipsychotic agents.

This chapter is a comprehensive account of the medicinal chemistry of the antidepressant drugs. It provides the mechanism of drug action and details of the structure-activity relationships (SAR) of the antidepressant and related drugs to give the knowledge base for pharmacists. After a study of this chapter, students will be able to:

• Relate principles of affective disorders including the biogenic amine hypothesis and depression.

• Describe the roles of dopamine, serotonin and norepinephrine in depression and how these roles relate to the mechanism of action of antidepressant drugs.

• Describe different classes of antidepressant drugs with examples.

• Compare the chemical structures of all the classes of antidepressant drugs and relate their action with structures.

• Illustrate the mechanism of action, SAR, metabolites, and clinical considerations of: ▪ Serotonin and norepinephrine reuptake inhibitors

o Tricyclic antidepressants (TCAs)

o Phenylalkylamines

▪ Selective serotonin reuptake inhibitors (SSRIs)

o Phenoxyphenylalkyl amines

o Phenylalkylamine

▪ Monoamine oxidase inhibitors (MAOIs)

▪ Miscellaneous antidepressant drugs

The major objective of this chapter is to concisely explain and equip pharmacy students with the chemical and pharmacological knowledge of traditional/ conventional and newer sedative-hypnotics and anxiolytics, that is, barbiturates, benzodiazepines and non-benzodiazepine agents. Upon studying this book chapter, students will be able to:

• Categorize Chemically/Pharmacologically sedative-hypnotics and anxiolytics.

• Explain the mechanisms by which barbiturates, benzodiazepines, and nonbenzodiazepine sedative-hypnotics and anxiolytics exert their pharmacological effects.

• Summarize the benzodiazepine and barbiturate structure-activity relationships (SAR).

• Describe the key pharmacokinetic (ADMET) characteristics of individual drug molecules.

This chapter is a comprehensive account of the medicinal chemistry of antiepileptic drugs. It provides the mechanism of drug action and detailed structureactivity relationships of the antiepileptic and related drugs and their clinical relevance to give the knowledge base for pharmacists. After a study of this chapter, students will be able to:

• Relate principles of gamma amino butyric acid (GABA) biosynthesis, storage, transport, and metabolism to the action of antiepileptic drugs.

• Define and differentiate among different types of seizures and epilepsy.

• Illustrate mechanism of action, SAR, metabolites, and clinical considerations of different classes of antiepileptic drugs including: barbiturates, hydantoins, oxazolidinediones, succinimides, amides, benzodiazepines, valproic acid and its derivatives, GABA-analogs, and miscellaneous compounds.

This chapter is a comprehensive account of the medicinal chemistry of general and local anesthetic drugs. It provides the mechanism of drug action and details about structure-activity relationships of these drugs for pharmacists. After the study of this chapter, students will be able to:

• Select appropriate intravenous general anesthetic therapy based on patient-specific contraindications regarding cardiac and septic status.

• Evaluate inhaled general anesthetics about therapeutic regimens based on individual patient characteristics and medical procedures.

• Compare and contrast the potency, onset of action, and recovery time of the inhaled anesthetic based on MAC, blood: gas partition coefficients and oil:gas partition coefficients.

• Identify chemical metabolites of the inhaled anesthetics that increase the risk of nephron and hepatotoxicity.

• Identify the chemical classification to which a local anesthetic belongs based on drug structure.

• Select an appropriate local anesthetic for a patient with a specific allergy to PABA.

• Communicate the chemical rationale for local anesthetic buffering to health professionals.

This chapter is a comprehensive account of Parkinson's disease and the medicinal chemistry of antiparkinsonian drugs. It provides the mechanism of disease progression and drug action and detail structure-activity relationships of the antiparkinsonian drugs to give the knowledge base for pharmacists. After a study of this chapter, students will be able to:

• Discuss the epidemiology and etiology of Parkinson disease (PD)

• Describe the clinical features of idiopathic PD and differentiate between cardinal motor features and non-motor symptoms

• Discuss various risk factors and corresponding mechanisms responsible for the development of PD symptoms

• Review biosynthesis of dopamine, its metabolic outcomes, dopaminergic pathways, receptor distribution and corresponding signal transduction mechanisms

• Explain in detail the pathophysiologic mechanisms responsible for the clinical features of idiopathic PD

• Evaluate the clinical role of L-DOPA and discuss its mechanism of action, pharmacokinetics, adverse effects, motor complications, drug interactions, contraindications and precautions

• For each medication class listed below, discuss their mechanism of action, pharmacokinetics, adverse effects, motor complications, drug interactions, contraindications and precautions

o Dopamine agonists

▪ ropinirole (Requip®, Requip® XL); pramipexole Mirapex®, Mirapex® ER); rotigotine transdermal patch (Neupro®), and apomorphine (Apokyn®)

o Catechol-O-methyltransferase (COMT) inhibitors

▪ entacapone (Comtan®) and tolcapone (Tasmar®)

o Selective monoamine oxidase-B (MAO- B) inhibitors

▪ selegiline (Eldepryl® and Zelapar® ODT) and rasagiline (Azilect®)

▪ amantadine (Symmetrel®)

o Anticholinergic agents (benztropine (Cogentin®) and trihexyphenidyl)