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Aims
To gain knowledge about the chemistry and pharmacological activity of drugs acting on autonomic nervous system and cardiovascular system
Objectives
At the end of the course you should know how to: A. Define and identify the role of Medicinal Chemistry in the process of Drug Discovery and Drug Development. B. Describe drug-target interactions including drugreceptor and drug-enzyme interaction. C. Discuss the effect of different physicochemical properties on biological activity. D. Discuss qualitative and quantitative structure-activity relationships. E. Identify various Pharmacokinetic and Pharmacodynamic properties of specific drug classes such as drugs acting on the autonomic nervous system, drugs acting on the cardiovascular system and diuretics.
Curriculum
Introduction to medicinal chemistry. Drug action on enzymes. Drug action on receptors. Drug development. Quantitative structure-activity relationship. Drugs acting on
Autonomic nervous system. Cardiovascular system (cardiotonics, antiarrhythmics, vasodilators, antihypertensive, antihyperlipedemic, drugs affecting blood and diuretics) Drug design for related drugs.
Evaluation Methods
Quizzes : 10% MCQs, True and false & Fill in the blank. Mid Term examination : 30% MCQs, Fill in the Blank, Short answers. Assignments / projects : 10%
Reference books
1- Medicinal Chemistry: An Introduction T.B., G. Thomas; Publisher; John Wiley & Sons Ltd. Ed. 2nd 2007 . 2- Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry. John H. Block, John M. Beale, Jr. Publisher; Lippincott Williams and Wilkins, Ed. 12th 2010.
Text books
1- An Introduction to Medicinal Chemistry, Graham L. Patrick, Publisher; Oxford University Press Inc, New York, Ed. 4th 2009. 2- Principles of Medicinal Chemistry, T. L. Lemke, W.O. Foye, David A Williams, Victoria F Roche, S. William Zito, Wolters Kluwer, Publisher; Lippincott Williams and Wilkins, Ed. 6th 2008.
Pharmacokinetics: Processes by which the drug passes during its way from the site of administration to the site of action. Pharmacodynamics: Drug-target interaction at the site of action. Drug targets: Protein biomolecules such as receptors and enzymes at which drugs bind .
Its mission is to discover and develop new agents for treating diseases. In addition to studying the chemistry of receptors. Thus, medicinal chemistry occupies a strategic position at the interface of chemistry and pharmacology. Development of new pharmaceutical involves: chemistry, biochemistry, molecular biology, physiology, pharmacology, pharmaceutics and medicine.
Discovery of drug what are the characteristics that must be found in new drugs?
More efficient. Less toxic. Minimal side effects. How can we improve the binding interaction of the drug and its target? By studying the steric features of the drug. Improvement of its chemical stability and pharmacokinetic properties. Studying quantitative structure activity relationship QSAR of the designed new drug.
1) 2) 3) 4) 5) 6)
Screening of natural materials. Medical folklore. Existing drugs. Serendipity. Screening synthetic bank. Natural neurotransmitters.
Morphine
Inactive
Heroin
Nalorphine
CH2-CH=CH2
Physicochemical properties
These properties have an important role in the pharmacokinetics [ADME] or mechanism of action of the drug. A drug can be superior to another just because it has good ADME, rather than good interaction with its target. Oral Storage site
GIT
Circulation
Site of action
Parentral
Excretion
Metabolism
Routes of administration
1) Parentral:
I.V, intra arterial, intraspinal: No absorption barrier. 2) GIT: The drug must be dissoluted before absorption. This is affected by: i. pH of the GIT site from which the drug is absorbed. Stomach: 1-3.5 colon: 5.6-7 Duodenum: 6-7 Lower ileum: 8 ii. Dissociation rate of the drug at that pH.
I.M, S.C, intra-dermal, intraperitoneal: Drug passes some membrane barriers till reaching circulation.
Drug Dissolution
It is the solubility of the drug in the fluids of the GIT. What are the factors affecting dissolution of drug? 1. Particle size: lower particle size increased surface area exposed to fluids of GIT increased dissolution. e.g. Griseofulvin is formulated as micronized form to improve bioavailability. 2. pH of the medium: Weakly acidic drugs dissolved in alkaline region of GIT. Weakly basic drugs dissolved in acidic region of GIT. N.B. most drugs are absorbed from intestine than stomach due to the large surface area of the intestine.
Many physical, structural and chemical properties have been studied by SAR approach but the most common are:
1. Hydrophobicity. 2. Electronic effect. 3. Steric factors.
1. Hydrophobicity
The hydrophobic character of a drug is vital to how easily it crosses cell membranes and may also be important in receptor interactions.
affects
Hydrophobic character
Biological activity.
Generally
Increasing hydrophobicity of a lead compound.
Results in
Crossing hydrophobic barriers such as cell membranes. Binding to target site ( enzyme or receptor).
so
2- Electronic effects
The electronic effects of various substituents
affect
The easily passage through cell membranes. Or the strong interaction with the binding site.
Bronsted-Lowry Theory
An acid is any substance capable of yielding a proton (H+). A base is any substance capable of accepting a proton. A drug exist in equilibrium between the ionized (more water soluble) and non-ionized (more lipophilic) forms. When acid loses its proton, it is referred to as having undergone dissociation.
COOH COO
+
Non-ionized form (Lipophilic) Ionized form (Hydrophilic)
neutral
amphoteric
ne utral ne utral
F O
acidic
COOH
basic
HN
we ak base
we ak base
What is the Predominate forms of ciprofloxacin at the different locations within the GIT?
O
O
COOH
O
COO
COO
N H2N
N H2N
N
HN
At stomach pH 1-3.5
At colon pH5.6-7
At duodenum pH 6-7
Dissociation constant KH
Is the relative proportion of the ionized and non-ionized forms of the drug found in equilibrium. i.e degree of ionization. e.g benzoic acid is a weak acid and only partially ionizes in water.
For acids:
For bases:
What is the most suitable location in the GIT (stomach or intestine) for absorption of the following drugs:
O
H2 N COOH O O
Ibuprofen
S
Procainamide
O N
HN
O
NH
Phenytoin
O HN O HN
N Cl N
Chlorpromazine Diazepam
Phenobarbital
A truck driver complaining of seasonal allergies asks you to recommend an agent that will act as antihistamine but will not cause drowsiness. Choose between Cetirizine and Clemastine. If he takes a drug for indigestion which neutralizes stomach acid to pH 3.5 at the same time of taking antihistaminic
O O N N OH O N Cl
Cetirizine
Cl
Clemastine