GTB 214/3 BASIC PHARMACOLOGY

GTB 214/3 BASIC PHARMACOLOGY This course exposes students to the basic pharmacology with drawing of knowledge, concepts & techniques derived from biochemistry, physiology, biophysics and other divisions of biological science. It addresses the sources, formulations, routes of administration of drugs with special emphasis on the concepts of pharmacokinetics, pharmacodynamics and relationship between chemical structure and activity of drugs. Aspect of cellular pharmacology and biochemical pharmacology are also included. The course also exposes the students to the use of drugs for medicinal and social purposes. Some areas of Systemic Pharmacology (Autonomic, Cardiovascular, Respiratory, Gastrointestinal, Endocrine, Antimicrobials, Central Nervous System, Analgesics-Anti-inflammatory) will also be addressed. Methods of assessing effects of drugs and measurement of blood levels using the latest techniques of chemical analysis will be introduced. Goals of the course The goals of the course are to provide the students the knowledge of the fundamental scientific principles of Pharmacology relating it with other branches of life science and the role of drugs in physiological & pathological states in living body. Specific Objectives On completion of the course, students will be able to: 1 Define pharmacology and its various divisions 2 Define drugs and describe the physico-chemical properties of drugs 3 Describe & compare different drug formulations 4 Describe & compare different routes of drug administration 5 Describe pharmacokinetic principles addressing drug absorption, distribution, biotransformation & excretion 6 Describe pharmacodynamic principles with mechanism of drug action at various levels 7 Describe Autonomic Nervous System with special emphasis in neurotransmitters 8 Describe Cholinergic agonists & antagonists 9 Describe Adrenergic agonists & antagonists 10 Describe physiological control of blood pressure & role of antihypertensive drugs 11 Describe normal lipid metabolism & role of lipid regulating agents 12 Describe the diuretics with their clinical uses 13 Understand Central Nervous System neurotransmitters & the drugs affecting CNS 14 Describe endocrine related problems (especially pancreatic hormones & steroids) and concept of contraception 15 Describe & compare the drugs used in common respiratory tract problems 16 Describe the pathophysiology of pain & inflammation in relation to therapeutic intervention 17 Describe NSAIDs with their selection criteria 18 Describe opioid analgesics & their effects 19 Understand drug addiction & it s socioeconomic impact 20 Describe common GIT problems & use of drugs for these problems 21 Describe the principles of antimicrobial drug therapy 22 Describe the common antimicrobial, antifungal & antiparasitic drugs 23 Understand Adverse Drug Reactions (ADRs) & factors related to ADRs 24 Describe the steps of new drug development 25 Demonstrate the methods of assessment of plasma drug concentration by using spectrometer & other advanced techniques 26 Show the various effects of drugs in experimental animals 1

Contents of the Course No. Title General Concepts 1 Introduction and overview of the course 2 Branches of pharmacology, drugs, agonists, antagonists, sources, criteria, names of drugs, formulations, route of administration 3 Interaction of drug-human body pharmacokinetics & pharmacodynamics 4 Drug absorption & factors influencing it 5 Drug distribution throughout the body, Plasma protein binding, crossing of special barriers in the body 6 Drug metabolism, sites of metabolism & factors influencing it 7 Excretion of drug, route of drug excretion & factors influencing it 8 Mechanism of action of drugs & factors influencing the drug effects 9 Therapeutic & adverse effect of drugs Autonomic Nervous System 10 Neurotransmitters 11 Physiology of parasympathetic & sympathetic nervous system 12 Cholinergic neurotransmitter, receptors & cholinergic agonists 13 Cholinergic receptor blockers & therapeutic importance 14 Adrenergic neurotransmitter, receptors & adrenergic agonists 15 Adrenergic receptor blockers & therapeutic importance Cardiovascular System 16 Blood pressure & physiological control of blood pressure & hypertension 17 Commonly used antihypertensive drugs 18 Physiology of normal cholesterol metabolism & common drugs used in dyslipidaemia 19 Diuretics with their sites of action & brief clinical uses 20 Antianginal 21 Digitalis and glycosides Central Nervous System 22 CNS neurotransmitters & their physiological importance 23 Sedatives and hypnotics 24 Antidepressive drugs & Antipsychotic drugs Anesthesia 25 General anesthetics 26 Local anesthetics 27 Neuromuscular blockers Endocrine System 28 Important hormones & their physiological importance s 29 Insulin & other common drugs used in Diabetes Mellitus 30 Adrenocortical steroids & their physiological role 31 Female hormones & contraception (a mention of male contraception) Respiratory System 32 Common respiratory problems & their drug treatments Pain & Inflammation 33 Phenomenon of pain & inflammation 34 Non-steroidal anti-inflammatory drugs & appropriate uses 35 Opioids & appropriate uses Gastrointestinal Tract 36 Common GIT disorders and drug uses 37 Drugs used in Peptic Ulcer with their mechanism of action Antimicrobials 38 Common anti-bacterial drugs with their brief mechanism of action 39 Common antiparasitic and antifungal drugs 2

Special topics 40 Adverse drug reactions & types of ADRs 41 Drug addiction, it impacts & responsible drugs Practicals No. Title 1 Drug administration by different routes in Rats & mice Oral/Topical/Intramuscular/Intravenous/Subcutaneous etc 2 Demonstration of effects in Rabbit s eye of the administration of Homatropine/Pilocarpine 3 Demonstration of Analgesic effects of different drugs in mice (Hot Plate, Tail Flick Test & Writhing Test) 4 In-vitro demonstration of drug effects on Rabbit s ileum 5 Drug administration in Human Volunteers (students) Sublingual & Orally - onset of effects of drugs & statistical methods in Pharmacology Beside the practical above, student will be shown demonstrations of spectrophotometer & other analytical instruments. Methods of Instruction 1. Lectures 2. s 3. Seminars 4. Practicals and demonstrations in laboratory Assessment Formative (in-course) & summative (end of course) assessment will be utilised 1. Written examination 2. Oral examination (viva) 3. Presentation of practical reports Course Period and Study Hours 2 nd Semester : November February (14 weeks) Lecture : 42 hours : 20 hours Practical : 30 hours Recommended Books for Study 1. Brody TM, Larner J, Minnemann KP, Neu HC; Human Pharmacology: Molecular to Clinical, 2 nd Edition, Mosby, 1995. 2. Katzung BG, Basic and Clinical Pharmacology, 9 th Edition, McGraw-Hill Professional Publishing, 2004. 3. Hitner H: Basic Pharmacology, McGraw-Hill Books Co, 1999. 4. Benett PN and Brown MJ, Clinical Pharmacology, 9 th Edition, Churchill Livingstone, 2003. 5. Syed Zahar Idid, Farmakologi Sistem Saraf Pusat, Kuala Lumpur: Dewan Bahasa dan Pustaka, 1994 3

Practical 1: Drugs administration in different routes and sampling Introduction Drugs are administered in the human body in different routes according to convenience of the patient and the severity of the diseases. Primarily and most commonly drugs are administered orally, but due to special physico-chemical nature of drugs and the severity of the disease drugs are administered in other routes. All routes have got some benefits and risks. Generally the routes are chosen in such a way that the administered drugs reach easily and adequately at the site of action. Special precautions should be taken when the drug is administered parenterally because there is a risk of severe adverse reaction. Objectives: 1. To expose students to various routes of drug administration via: 1. a) Intraperitoneal (IP) 1. b) Intramuscular (IM) 1. c) Intravenous (IV) 1. d) Subcutaneous (SC) 1. e) Topical 1. f) Oral 2. To expose students on effects of drug administration in various routes and to understand their differences. 3. To expose students to different kinds of sampling and identify the location of the organ 4. To expose students to special kinds of samplings from: 4. a) Veins 4. b) Animal tails 4. c) Intracardiac Instruments: 1. Pentobarbitone (dose: 50 60mg/kg) 2. Mouse: Spargue Dawley - 10 3. Syringe 1 ml - 10 pcs 4. Needle 26 G - 10 pcs 5. Needle 18 G - 30 pcs 6. Equipment for operation 7. Diethyl ether 8. Tissue container 9. Test-tube containing 9.1. EDTA 9.2 Heparin related to type of blood test 9.3 Empty 9.4 Citrate 10. Bius container 11. Gauze 12. Normal saline Demonstration will be conducted for every analysis. Full attention must be given by every student to conduct each test. Observation: Students are required to observe techniques shown and the procedures demonstrated with each method. 4

Table: Time of onset of sleeping Study Question: 1. Explain why IV administration is more effective? 2. Give a short summary on the effects of pentobarbitone. Group Type 1 2 3 4 Intraperitoneal ( IP ) Intramuscular ( IM ) Intravenous ( IV ) Subcutaneous ( SC ) Oral Practical 2: Demonstration of effects of different drugs in Rabbit Eye Introduction The size of pupil is controlled by Parasympathetic & Sympathetic innervations. Neurotransmitters & Drugs act on muscles of Iris (Circular & Dilator muscles) to control the size of pupil. Contraction of circular muscles causes constriction of pupil (miosis) & contraction of dilator muscles causes dilatation of pupil (mydriasis). Mydriasis also happens due to relaxation of circular muscles. This experiment shows the effects of the drugs on size of the pupil & changes of light reflex. Objectives: 1. To determine the effects of different drugs in rabbit s pupil size. 2. To understand the effects of Autonomic Nerve System on eye. Apparatus / material: 1. Laboratory animal (Rabbit) 2. Penlight 3. Rabbit restrainer 4. Drug (Eye Drop) a. Homatropine - 5% solution (0.05mg/ml) b. Pilocarpine - 5% solution (0.05mg/ml) 5

Method: 1. Put the rabbit into the rabbit restrainer container and let it comfort in the container. 2. Observe the rabbit s normal pupil size of both the eyes. 3. By using Penlight, torch the light to the rabbit s eye and observe the light reflex in both eyes of the rabbit. 4. Drop the drugs: Homatropine - Right Eye Pilocarpine - Left Eye 5. Observe the pupil sizes. 6. Torch the penlight to the rabbit s eye and observe the changes occur especially to the pupil size & light reflex in both eyes. 7. Repeat it for every 2 minute until 8 minute. Study Questions: 1. Explain how normal pupil size are maintained? 2. What are the effects of Pilocarpine and Homatropine on eye? Practical 3: Animal study of the effects of different analgesic drugs. Introduction Analgesics are the drugs that relieve pain. There are two main groups of analgesics. a) Opioid analgesics-these drugs act on opioid receptors & produces analgesia. As they produce effects on CNS, they also are known as narcotic analgesics. b) Non-opioid analgesics-these drugs act by inhibiting PGs synthesis & causes analgesic effect. As these drugs also have anti-inflammatory effect, they are known as Non Steroidal Anti-Inflammatory Drugs (NSAIDs). They don t produce any CNS effect (Nonnarcotic analgesics). The analgesic drugs reduce the perception of pain & these studies demonstrate this effect. Objective: 1. To determine the analgesic drug effect in the group of narcotic and NSAID 2. To differentiate methods of analgesic test and their advantages. 3. To determine the appropriate method of analgesic test. Apparatus/ Material: 1. Laboratory animals Rat Mice 2. Tail Flick machine 3. Hot Plate machine 4. Water bath 5. Stop watch 6. Syringe and needle 26 G Drugs / Reagents 1. Aspirin (NSAID) - dose: 20mg/kg 2. Morphine (Opioid) - dose: 0.4mg/kg 3. Normal Saline 4. Acid Acetic 0.1 % 6

Procedure a) Hot Plate 1. Maintain the hot plate at 50 0 C. 2. Put the rat on the hot plate and start measure the time. 3. Observe the rat normal action when it is placed on hot plate and immediately stop measure time when rat show the hot reactions ( Cut-off reactions) such as jumping, licking legs, ground etc. 4. Repeat step 2 and step 3 for three times to get the base time interval for rat reaction, to determine the normal reaction for rat. 5. Inject the following drugs IP in the Rats: Drug Aspirin Group A Drug Morphine Group B Normal Saline Group C 6. Put the rats on the hot plate and observe. 7. Take the time when rat is put on the hot plate until it shows the cut-off reaction. 8. Repeat step 5 and step 6 for every 15-minute until 2 hour to get 8 readings. b) Tail Flick: Method A (Tail Flick Machine) 1. Slowly put the rat on the hot plate. 2. Switch on the reading lamp (60 watts) and focus on the rat-tail. 3. Observe and take the time from the rat-tail is placed on the tail flick machine until it starts to move from the light source that focuses on its tail. Figure out this reaction as pain avoidance. 4. Give the following drugs IP into Rats: Drug Aspirin Group A Drug Morphine Group B Normal Saline Group C 5. Put the rat on the tail flick machine and observe the rat until it show the hot reaction. 6. Take the time from putting on machine until it shows the pain avoidance reaction. 7. Repeat step 5 and step 6 for every 15-minute until 2 hour to get 8 readings. c) Tail Flick: Method B (water bath) 1. Maintain the water temperature at 50 0 C in the water bath. 2. Mark the mice tail to make sure the same dunk level for every demonstration. 3. Slowly dunk the mice tail into water bath up to the mark 4. Observe it and take the time until mice moves its tail. Figure out this reaction as pain avoidance. 5. Give the following drugs IP to Rats: Drug Aspirin Group A Drug Morphine Group B Normal Saline Group C 6. Slowly dunk again the mice into the water bath up to the mark and observe its reaction. 7. Take the time from dunking mice into the water bath until it start show pain avoidance reaction. 8. Repeat step 5 and step 6 for every 15-minute until 2 hour to get 8 readings. d) Writhing Test 1. Calm the mice and let it calm for a while. Figure this as normal mice respond. 2. Give the following drugs Intramuscular (IM) into Rats: Drug Aspirin Group A Drug Morphine Group B 7

Normal Saline Group C 3. Let the mice with the drugs settle for 30 minute. 4. Give Acid Acetic (0.1%) 0.1 ml to the every mouse. 5. Observe and take the time when mice start show pain and count it reaction until 5 minute. 6. Repeat this observation for every 5 minute until 1 hour. Study Question: 1. Explain the mechanism of analgesic effect of NSAIDs? 2. Describe the Central Nervous System effects of Morphine? 3. Describe briefly the pain pathway? 8

Practical 4: In-Vitro demonstration of the effect of Acetylcholine on Rabbit s Ileum and showing the Dose-Response relationship with plotting of D-R curve Introduction Acetylcholine (Ach) acts on the Muscarinic receptors (MR) of ileum and causes contraction. With the increase in dose of Ach there will be increase in response. But when the maximum response will be obtained then there will be no increase in response with increasing the dose of Ach. Apparatus Organ bath Biopac system Graph paper Dissecting instruments Reagents Ach Physiological solution Distilled water Specimen Rabbit Ileum Methodology The rabbit will be decapitated after overnight fasting. Then it will be dissected and a small piece of ileum will be cleaned. The tissue will be kept in the nutrient fluid. The small piece of ileum will then be set using tissue holder in the organ bath containing the physiological solution. Then Ach will be given in different doses & the contraction will be recorded accordingly. The doses will be increased as follows: A) 1 microgram/ml B) 2 microgram/ml C) 10 microgram/ml D) 50 microgram/ml E) 500 microgram/ml Tabulation Experiment Dose of Ach Log dose Contraction in mm % of max. Contraction A B C D E F **The maximum contraction will be taken as 100% and other contractions will be calculated accordingly. Plotting of Graphs The D-R curve will be plotted by taking the log dose of Ach in Abscissa and % of maximum response in Ordinate in the graph paper. The shape of the curve will be S-shaped 9

Inference The response of a drug will be increased with the increasing the dose of the drug. But when maximum response will be obtained then there will be no further increase in response with increasing the dose. Study Question: 1. Describe the effects of Ach on different muscles of the body (smooth muscle, skeletal muscle and cardiac muscle) and the drugs used to antagonise these effects? 2. Why log dose-response curve is preferred? 10

Practical 5: Drug Administration via the Oral & Sublingual routes in Human Volunteers Introduction Drugs are commonly administered in oral routes except some special circumstances. But some drugs are not given orally as because their bioavailability in oral route is very poor & desired effect is not found. Nitroglycerine is an antianginal drug. It is not given orally because it is almost totally metabolized in 1 st pass hepatic metabolism. So it is given sublingually (SL) & immediate effects are found. The effects can be observed by recording HR & BP in human volunteers. Statistical analysis is also done to see significant difference in the effects of the drug by administering nitroglycerine orally & SL. Objectives 1. To understand difference of drug absorption in different routes. 2. To know the effects of drugs in human volunteers. 3. To know the simple statistical analysis for calculating the difference. This experiment expects students to volunteer. Requirements: 1. Nitroglycerine tablets (0.3mg per tablet) 2. BP recording machine. Methodology Volunteer grouping: 2 groups Group A: 10 volunteers Group B: 10 volunteers Procedure 1. Pulse Rate & BP of all volunteers are recorded as a baseline. Mean of PR & mean blood pressure of the groups are calculated. 2. 1 tab of Nitroglycerine is given orally to each of the volunteer of group A 3. 1 tab of Nitroglycerine is given sublingually to each of the volunteer of group B 4. The volunteers are rested in relaxed chair. 5. PR & BP are again recorded after 15 & 30 minutes 6. Means are calculated 7. Comparison is done between the results of group A 8. Comparison is done between the results of group B 9. Statistical analysis is done by Students t test Inference: Nitroglycerine is ineffective when given orally due to lack of adequate bioavailability. GTN responses very quickly on sublingual administration and has significant effect on cardiovascular system. 11

Table: Recordings of Heart Rate & Blood Pressure Baseline 15 minutes after GTN oral/sublingual 30 minutes after GTN oral/sublingual HR BP HR BP HR BP Study Question: 1. Explain the 1 st pass hepatic metabolism? 2. What are the effects of GTN on cardiovascular system? 12

Lectures for Session 2004/2005 2 nd Semester Lectures will be carried out as follows: day - 8am 8.50am sday - 4pm 4.50pm nesday - 11am 11.50am Date & Day Title Lecturer General Concepts 23/11/04 Introduction 24/11/04 Branches of pharmacology, drugs, agonists, antagonists, sources, criteria, -am names of drugs, formulations, route of administration I 24/11/04 Branches of pharmacology, drugs, agonists, antagonists, sources, criteria, -pm names of drugs, formulations, route of administration II 28/11/04 Interaction of drug-human body pharmacokinetics & pharmacodynamics 30/11/04 Drug absorption & factors influencing it 01/12/04 Drug distribution throughout the body, Plasma protein binding, crossing of -am special barriers in the body 01/12/04 Drug metabolism, sites of metabolism & factors influencing it -pm 05/12/04 Excretion of drug, route of drug excretion & factors influencing it 07/12/04 Mechanism of action of drugs & factors influencing the drug effects 08/12/04 Therapeutic & adverse effect of drugs Autonomic Nervous System 12/12/04 Neurotransmitter 14/12/04 Physiology of parasympathetic & sympathetic nervous system 15/12/04 Cholinergic neurotransmitter, receptors & cholinergic agonists 19/12/04 Cholinergic receptor blockers & therapeutic importance 21/12/04 Adrenergic neurotransmitter, receptors & adrenergic agonists 22/12/04 Adrenergic receptor blockers & therapeutic importance Cardiovascular System 26/12/04 Blood pressure & physiological control of blood pressure & hypertension 28/12/04 Commonly used antihypertensive drugs 29/12/05 Physiology of normal cholesterol metabolism & common drugs used in dyslipidaemia 02/01/05 Diuretics with their sites of action & brief clinical uses 04/01/04 Antianginal 05/01/04 Digitalis and glycosides 13

09/01/05 11/01/05 12/01/05 16/01/05 18/01/05 19/01/05 23/01/05 25/01/05 26/01/05 30/01/05 01/02/05 Central Nervous System CNS neurotransmitters & their physiological importance Sedatives and hypnotics Antidepressive drugs & Antipsychotic drugs Anesthesia General anesthetics Local anesthetics Neuromuscular blockers Endocrine System Important hormones & their physiological importance Insulin & other common drugs used in Diabetes Mellitus Adrenocortical steroids & their physiological role Female hormones & contraception (a mention of male contraception) Respiratory System Common respiratory problems & their drug treatment Pain & Inflammation 02/02/05 Phenomenon of pain & inflammation 06/02/05 Non-steroidal anti-inflammatory drugs & appropriate uses 08/02/05 Opioids & appropriate uses Gastrointestinal Tract 13/02/05 Common GIT disorders and drug uses 15/02/05 Drugs used in Peptic Ulcer with their mechanism of action Antimicrobials 16/02/05 Common anti-bacterial drugs with their brief mechanism of action 20/02/05 Common antiparasitic and antifungal drugs Special topics 22/02/05 Adverse drug reactions & types of ADRs 23/02/04 Drug addiction, impacts & responsible drugs NB: Prof Syed Mohsin Syed Sahil Jamalullail (ext 3809) - smohsin@kb.usm.my - Dr Mohd Ismail Khan (ext 3977) - drismail@kb.usm.my - Dr Wan Amir Nizam Wan Ahmad (ext 3979) - wanamir@kb.usm.my 14

Practical for Session 2004/2005 2 nd Semester Students will be divided into 2 groups. One group will have a practical session on nesday at 2.00pm 5.00 pm. The other group will have a tutorial session on Monday at 2.00pm 4.00pm. Date Title Group Personnel involved 08/12/04 Drug administration by different routes in Rats & mice A Oral/Topical/IM/IV/SC etc B 15/12/04 Drug administration by different routes in Rats & mice B Oral/Topical/IM/IV/SC etc A 23/12/04 Demonstration of effects in Rabbit s eye of the administration A of Homatropine/Pilocarpine B 30/12/04 Demonstration of effects in Rabbit s eye of the administration B of Homatropine/Pilocarpine A 05/01/05 Demonstration of Analgesic effects of different drugs in mice A (Hot Plate, Tail Flick Test & Writhing Test) B 13/01/05 Demonstration of Analgesic effects of different drugs in mice B (Hot Plate, Tail Flick Test & Writhing Test) A 20/01/05 In-vitro demonstration of drug effects on Rabbit s ileum A B 27/01/05 In-vitro demonstration of drug effects on Rabbit s ileum B A 02/02/05 Drug administration in Human Volunteers (students) SL & A Orally onset & effects of drugs & statistical methods in Pharmacology B 09/02/05 Drug administration in Human Volunteers (students) SL & B Orally onset & effects of drugs & statistical methods in Pharmacology A 15