Neuropharmacology

PG-Course

Touqeer Ahmed PhD14th February, 2017

Atta-ur-Rahman School of Applied Biosciences

National University of Sciences and Technology

NeuropharmacologyCourse Contents

• Introduction to neuropharmacology

• Chemical signaling in the nervous system

• Transmitters and modulators:– Nor-adrenaline– Dopamine– Acetylcholine and serotonin– Other CNs mediators

• Autonomic Nervous System (ANS) and ANS drugs– Cholinergic neuron– Cholinergic agonists and antagonist

(neuromuscular blockers)– Adrenergic neuron– Adrenergic agonists and blockers

• Neurodegenerative diseases and their treatments

• Drug Classification– Analgesic Drugs– Local anesthetics and other drugs

affecting sodium channels– Anxiolytic and hypnotic drugs– Antiepileptic drugs– Antipsychotic drugs– Antidepressant drugs– CNS Stimulants and

psychotomimetic Drugs

• Harmful Effects of Drugs

• Drug Addiction, Dependence and Abuse

Text Books

NeuropharmacologyEvaluation System

• Assignment 05

• Quiz 15

• First Sessional 10

• Second Sessional 10

• Final Exams (Terminal Exams) 50

Introduction to Neuropharmacology

Touqeer Ahmed PhD17th February, 2017

Atta-ur-Rahman School of Applied Biosciences

National University of Sciences and Technology

Pharmacology Today

Neuropharmacology: The study of the action of drugs on the nervous system

Basic Concepts in Pharmacology

• Pharmacology (Derived from a Greek word)

• What is a drug?– A drug can be defined as a chemical substance of known structure, other than a

nutrient or an essential dietary ingredient,1 which, when administered to a living organism, produces a biological effect.

– To count as a drug, the substance must be administered, rather than released by physiological mechanisms. Many substances, such as insulin or thyroxine, are endogenous hormones but are also drugs when they are administered intentionally.

• What is a medicine?– A medicine is a chemical preparation, which usually but not necessarily contains

one or more drugs, administered with the intention of producing a therapeutic (healing/recovery from disease) effect.

– Medicines usually contain other substances (excipients, stabilisers, solvents, etc.) besides the active drug, to make them more convenient to use.

1Like most definitions, this one has its limits. For example, there are a number of essential dietary constituents, such as iron and various vitamins, that are used as drugs/medicines.

Basic Concepts in Pharmacology

• Pharmacodynamics: is the study of the biochemical and physiologicaleffects of drugs on the body or on microorganisms or parasites within oron the body and the mechanisms of drug action and the relationshipbetween drug concentration and effect.

• Pharmacokinetics: is the study of what the body does to a drug

• Protein targets for drug binding Four main kinds of regulatory protein are commonly involved as primary

drug targets, namely:

1.receptors (activate signaling pathways) 3.enzymes

2. carrier molecules (transporters) 4.ion channels.

Basic Concepts in Pharmacology

• Agonists and antagonists

Agonists, which 'activate' thereceptors, and antagonists,which combine at the same sitewithout causing activation,and block the effect of agonistson that receptor.

Touqeer Ahmed PhD21st February, 2017

Atta-ur-Rahman School of Applied Biosciences

National University of Sciences and Technology

Basic Concepts in Pharmacology

Basic Concepts in Pharmacology

THE BINDING OF DRUGS TO RECEPTORS

– Why do we plot it on the Log scale?

Agonist vs Antagonists

• Agonist: An agonist binds to a receptor and produces a biologic response. An agonist may mimic the response of the endogenous ligand on the receptor, or it may elicit a different response from the receptor and its transduction mechanism.

• Full agonists: If a drug binds to a receptor and produces a maximal biologic response that mimics the response to the endogenous ligand (e.g. phenylephrine is an agonist at α1-adrenoceptors)

• Partial agonistsPartial agonists have efficacies (intrinsic activities) greater than zero but less than that of a full agonist. Even if all the receptors are occupied, partial agonists cannot produce an Emax of as great a magnitude as that of a full agonist. (e.g. aripiprazole, used to treat schizophrenia)– A unique feature of these drugs is that, under appropriate

conditions, a partial agonist may act as an antagonist of a full agonist.

• Inverse agonists: Some receptors show a spontaneous conversion from R to R* in the absence of agonist (that is, they can be active without the presence of agonist). These receptors, thus, show a constitutive activity that is part of the baseline response measured in the absence of drug. Inverse agonists, unlike full agonists, stabilize the inactive R form. (some scientist categorize these along with antagonist)

Agonists (Types)

Agonists (Quantifying Agonism)

Drugs have two observable properties in biological systems: – Potency

Potency is controlled by four factors: 1. Receptor density in a tissue2. Efficiency of the stimulus-response

mechanisms present by default in the tissue

3. Affinity of the drug for its receptor4. Efficacy

– Efficacy/Magnitude of effect (when a biological response is produced)• The advantage of using efficacy is that

this property depends solely on efficacy, whereas potency is a mixed function of both affinity and efficacy

Comparison of Efficacy and Potency

Antagonism

• Antagonists are drugs that decrease or oppose the actions of another drug or endogenous ligand.

• An antagonist has no effect if an agonist is not present.

• Antagonism may occur in several ways. Many antagonists act on the identical receptor macromolecule as the agonist and in that situation antagonists have no intrinsic activity and, therefore, produce no effect by themselves.

• Although antagonists have no intrinsic activity, they are able to bind avidly to target receptors because they possess strong affinity.

Antagonism (Quantifying Antagonism)

A. Competitive antagonism B. If the antagonist binds to the same site as the agonist but does so irreversibly or

pseudo-irreversibly (competitive but irreversible)C . Allosteric effect occur when the ligand I binds to a site, where agonist

does not bind on the receptor, and inhibit response. (non-competitive)D. or potentiate response e.g. interaction of benzodiazepines with the GABAA

Affinity of the Antagonist for its Receptor

• The Schild plot is a pharmacological method of receptor classification.

• The pA2 value indicates the concentration of antagonist when double the agonist is required to have the same effect on the receptor as when no antagonist is present.

• A. Competitive antagonists• B. Irreversible antagonists

• C. Functional and chemical antagonismAn antagonist may act at a separate receptor, initiating effects that are functionally opposite those of the agonist. A classic example is the functional antagonism by epinephrine to histamine induced bronchoconstriction. Histamine binds to H1 histamine receptors on bronchial smooth muscle, causing contraction and narrowing of the bronchial tree. Epinephrine is an agonist at β2-adrenoceptors on bronchial smooth muscle, which causes the muscles to actively relax.– This functional antagonism is also known as “physiologic antagonism.”

• A chemical antagonist prevents the actions of an agonist by modifying or sequestering the agonist so that it is incapable of binding to and activating its receptor. For example, protamine sulfate is a chemical antagonist for heparin. It is a basic (positively charged) protein that binds to the acidic heparin (negatively charged), rapidly preventing its therapeutic as well as toxic effects.

• Chelation of the drugs in GIT is another example

Antagonism (Types)