MODULE AND PRACTICAL PHARMACOKINETICS AND PHARMACODYNAMICS PROCESS

Code :MKK :BS-4, BA : L-7 SKS :3 Semeste : !

"#$%&t' o( Med)$)*e UNI+ERSITAS BRA,I-ATA !.//

PHARMACOKINETICS AND PHARMACODYNAMICS PROCESS Code :MKK :BS-4, BA : L-7 SKS :3 Semeste : ! THE AIM:
To study the general concepts of: pharmacokinetics, pharmacodynamics in a normal conditions and in a special considerations, the concept of autonomic nervous system, the general properties of endogenous substances (autacoids, peptide and their analog, biogenic amine), the general properties of antimicrobials agents and anti cancer, and the drug development and formulation.

DESCRIPTION AND OR0ANI1ATION:

Pharmacokinetics and pharmacodynamics process is a 3-credit course offered for graduate students ( !) in "aculty of #edicine. This course is divided into $ topics
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LEARNIN0 E2PERIENCES:: The course format 6ill consist of lectures, practices and small group discussion

RECOMMENDED TE2TBOOK:
!. T,2 P,-'#-+(.(/%+-. 4- % (" T,2'-P2*T%+ : !!th 2dition (7889) -(/oodman : /ilman). 7. 4- %+ -&) +.%&%+-. P,-'#-+(.(/0: !8th 2dition (788;)- (4ertram /. 1at<ung) 3. #()2'& P,-'#-+(.(/0 9th 2dition (788=) -(+raig : tit<el) =. P,-'#-+(.(/0 >th 2dition (788=)- ('ang, )ale, : 'itter). >. "-'#-1(.(/% )-& T2'-P% (7889), Published by *%

+((')%&-T(' T2-+,%&/ T-""

)r. &ur Permatasari, drg.,# i %&T'()*+T%(& T( P,-'#-+(.(/0 &2*'(T'-& #% %(&: -*T(&(#%+ &2'3(* 0 T2# (-)'2&2'/%+ -&) +,(.%&2'/%+) "-+%.%T-T(' )'*/ )232.(P#2&T "-+%.%T-T(' P,-'#-+()0&-#%+ "-+%.%T-T(' -*T(+(%) -&) -&T% %&".-##-T%(& -/2&T +.%&%+-. T(5%+(.(/0 "-+%.%T-T(' P,-'#-+(1%&2T%+ )'*/ %&T2'-+T%(& -&) %)2 2""2+T "-+%.%T-T(' +2.. +0+.2 -&) -&T% +-&+2' "-+%.%T-T(' P,-'#-+()0&-#%+ (" -&T%#%+'(4%-. -/2&T )'*/ "('#*.-T%(& "-+%.%T-T(' P'-+T%+-. "-+%.%T-T(' P'-+T%+-. "-+%.%T-T(' P'-+T%+-.

Prof. #. -ris ?idodo, dr.,# .,Ph)., p"1

Prof.)r.dr.#ulyohadi -li, p"1 )r.dr. etya6ati 1, #1es

)r. &urdiana, dr.,#1es

)r. &ur Permatasari, drg.,# i )ra. )iana :yra6ati, -pt, # , Ph) Team of microbiology and parasitology )rs. 4ambang idharta, -pt, # *mi 1alsum, dr,. #1es )ian &ugraheni, dr 2lly #ayangsari, dr

SCHEDULE O" PHARMACODYNAMICS AND PHARMACOKINETICS SEMESTER II -!./.3!.//

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+oordinator &*' P2'#-T- -'% &%P. !$98!88> !$$!83 7 88!

1eterangan : #: Prof.)r.dr.#och.-ris ?idodo, p"1 #-? : Prof.)r.dr.#och.-ris?idodo,# , p"1,Ph) 1 : )r.dr. etya6ati oeharto,#1es &) : )r.dr.&urdiana, #1es &P : )r.drg.&ur Permatasari,# *1 : dr.*mi 1alsum,#1es ). : )ra.)iana .yra6ati,-pt,Ph) 4 : )rs.4ambang idharta,-pt )& : dr.)ian &ugrahenny 2# : dr.2lly #ayangsari T%# : )r.)ra. ri ?inarsih,-pt,# i )r.dr..oeki 2nggar "itri,#1es, pPark

Mod%& /:
PHARMACOKINETICS I-I+

Le# *)*4 O56e$t)7es *nderstand the physical processes that govern the movement of drugs and other small molecules across cell membranes *nderstand the concept of bioavailability and ho6 first-pass metabolism can affect it *nderstand the various routes of administration of drugs, and ho6 role of the nature of the drug and the target organ(s) play in selecting a method of administration. *nderstand the concepts of parameters are used in designing a dosage regimen (volume of distribution, half-life, and clearance) *nderstand the routes of elimination of drugs, and the that biotransformation reactions play in this process *nderstand ho6 the biotransformation process of one drug can be affected by another can be affected by *nderstand ho6 age, genetics, and disease state can affect pharmacokinetic profiles PART I: ABSORPTION O" DRU0S AND METHODS O" DRU0 DELI+ERY -ll drugs must cross one or more cell membranes to reach their site(s) of action and to be eliminated from the body. )rugs cross membranes either by passive or active (energydependent) processes. (ther factors can influence the absorption of compounds across cell membranes: -dissolution rate (if solid), -surface area of absorption site, -rate of blood flo6, -drugDs concentration at the site of absorption. -ssignment: !. 2Bplain the different types of transmembrane transport 7. 2Bplain ho6 gastric p,, gastric emptying and intestinal motility affect drug absorption. 3. 2Bplain the definition of first pass effect (pre systemic elimination) and its correlation 6ith drug delivery and bioavailability. PART II: DRU0 DISTRIBUTION (nce a drug is absorbed into the bloodstream, it may be distributed to interstitial and cellular fluids. Plasma protein binding influences a drugDs inter-compartmental distribution because only unbound drug may passively diffuse from plasma into tissue. #any drugs accumulate in tissues at higher concentrations than those in the eBtracellular fluids and blood. Ass)4*me*t: !. &ame the organs (7) that are able to become drug reservoir organs and eBplain 6hy that is possible. 7. )escribe 6hat possibilities may occur 6hen giving 7 drugs that have different protein binding strength (strong and 6eak).

PART III: BIOTRANS"ORMATION REACTIONS AND E2CRETION )rug is converted to another molecular form. +onversions may be anabolic (synthetic) or catabolic (degradative), and may result in activation or inactivation.. 4iotransformations: !) often inactivate the drug (terminate pharmacological action), and 7) often generate polar, highly ioni<ed metabolites susceptible to rapid kidney eBcretion. ome drugs, ho6ever, are metaboli<ed into an active or a toBic metabolite. The en<ymes that play a role in metabolism can be inhibited or induced by certain drugs. -ssignment: !. 2Bplain the definition of a prodrug and give its eBample. 7. ,o6 is the toBicity mechanism of a drug in a hepatic cell related to its metabolismE 3. 2Bplain the possibility that may occur 6hen giving 7 drugs 6here one drug is an metabolism en<yme inducerE The kidneys are the main organs that function in drug eBcretion. - drug or its metabolite may appear in the urine as a result of: !) glomerular filtration 6ithout tubular reabsorption, 7) filtration 6ith partial reabsorption (active or passive), 3) tubular secretion, or =) a combination of these processes. %ncreasing the drug eBcretion is one 6ay to handle drug poisoning, 6here the urinary p, 6ould determine the drug reabsorption in the tubuli. Ass)4*me*t: !. 2Bplain ho6 a change of urinary p, (to more acidic or basic) caused by certain drugs or food can affect the drug eBcretion and ho6 it correlates 6ith the half life of another drug (6eak acidic or basic). 7. ome drugs go through the enterohepatic cycle. 2Bplain ho6 that occurs and its affect on the pharmacologic activity of a drug. PART I+: P8# m#$o9)*et)$s +# )#5)&)t' Therapeutics 6ould be a great deal easier if responses to the same dose of drug 6ere al6ays the same. %n reality, inter- and even intraindividual variation is often substantial. Physicians need to be a6are of the sources of such variation to prescribe drugs safely and effectively. 3ariation can be caused by different concentrations at sites of drug action. That pharmacokinetic variation can occur because of differences in absorption, distribution, metabolism or eBcretion. -ssignment !. 2Bplain ho6 the changes of age, genetics, and physiologic conditions can affect the drug absorption, metabolism and eBcretion and ho6 these factors correlate 6ith the drugDs half life

Mod%& !: PHARMACODYNAMICS I: DESCRIPTION )efinition and (vevie6 Pharmacodynamics deals 6ith the study of the biochemical and physiological effects of drugs and their mechanisms of action. The pharmacodynamic process (the actions of drug to the body) cause pharmacological respons. Pharmacological responses are initiated by molecular interactions of drugs 6ith cells, tissues or other body constituents. -rea of competence : 3th of the )octor +ompetencies tandart from %ndonesian #edical +ouncil To apply the concept and principles of drug action, agonistantagonist drugs, desensiti<ation-supersensiti<ation of drugs, and therapeutics indeB -ctive learning 6ith module task, group discussion, and eBpert lecture +lassroom, 6orksheet, computer, .+) and screen )'.dr. etya6ati 1, #1es #idle eBams at the end of module programmes and final eBams at the end of semester 6ith multiple choice Fuestions. !. /oodman : /ilmanGs The Pharmacological 4asis (f Therapeutics - !!th 2d. (7889) : +hapter ! 7. 1at<ung 4asic : +linical Pharmacology -$th 2d.(788;) H+hapter 7

+ompetency -rea +ompetency +omponent

.earning #ethode 2Fuipment .ecturer 2valuation uggested 'efferences

Le# *)*4 o56e$t)7es : 4y the end of this session, the students should be able to :

o o

o o o o o

)escribe the properties of membrane-bound drug receptors and specific vs. nonspecific binding of drugs. 2Bplain the four maIor transmembrane signalling mechanisms and describe the seFuence of steps involved in each path6ay in response to receptor stimulation. This is particularly important for the / protein-linked path6ays. +ompare these t6o / protein-linked transduction path6ays: the calcium -phosphoinositide path6ay, and the c-#P path6ay. 2Bplain the difference bet6een agonist and antagonist receptors. +ompare the dose-response curve base on the graded response 6ith Fuantal response *nderstand the receptors regulatory mechanism and compare homologous desensiti<ation 6ith heterologous desensiti<ation )efine factors that affecting drug response

II: O+ER+IE, Pharmacodynamics deals 6ith the study of the biochemical and physiological effects of drugs and their mechanisms of action. The actions of the drug on the body are termed pharmacodynamic processes. - drug enters the body through various 6ays, then goes through many changes in its Iourney to the target site (target cellJ target organ). The effects of most drugs result from their interaction in target cell 6ith macromolecular components of the organism. These interactions alter the function of the pertinent component and thereby initiate the biochemical and physiological changes that are characteristic of the response to the drug. The term receptor denotes the component of the organism 6ith 6hich the chemical agent is presumed to interact. #ost drugs effects by interaction 6ith receptors and the other 6ithout receptors. )rug acting on receptor 6ould stimulate transduction signal mechanism 6hich 6ill cause cellular response or pharmacologic effect. There are four maIor transmembrane signalling mechanisms. (ne of this mechanism is receptor coupled to / protein to regulate generation of intracellular second messengers (c-#P, inisitol tri phosphates, +alcium). The drug that interacts 6ith a receptor may be an agonist, 6hish has an affinity 6ith the receptor and also has an efficacy, or antagonist, 6hich has an affinity 6ith a receptor but not has an efficacy. 4inding bet6een drug and receptor molecules occurs according to the la6 of mass action, the concentrations (dose) of drug and receptor are key variables. %t is therefore appropriate to address the Fuestion of ho6 much drug is needed to produce a given response in terms of Kconcentration (dose) -responseK relationships. 4ased on the occupancy theory can calculate the dose of drug and the receptor. 4iological responses to drugs are usually graded. -lthough many drugs produce graded responses, there are other drugs for 6hich the observable response can be described only as an all-or-none event called a KFuantalK response. 'eceptors not only initiate regulation of biochemical events and physiological function but also are themselves subIect to many regulatory and homeostatic controls. These controls include regulation of the synthesis and degradation of the receptor by multiple mechanisms, covalent modification, association 6ith other regulatory proteins, andJor relocali<ation 6ithin the cell. .oss of receptor responsiveness to an agonist is termed desensiti<ation. III: MODULE TASK !. - fe6 drugs 6ork 6ithout an interaction to a receptor. &ame those types of drugs and ho6 it 6orks to create a pharmacologic effect. 7. 4ase on the transmembrane signaling mechanisms, the receptor is classified into = types. )escribe those classification and the seFuence of steps involved in each path6ay in response to receptor stimulation. 3. 2Bplain the difference bet6een the calcium phosphoinositide path6ay and the c-#P path6ay. ?hat the receptors by those path6ays E =. )efine agonist, partial agonist and antagonist in terms of receptor affinity and efficacy. )ra6 graded dose-response curves for agonists of differing potency at the same receptor. )ra6 graded dose-response curves for agonists of differing efficacy at the same receptor. >. The interaction 6ith the receptor and the drug, 6hether it is 6ith an agonist or antagonist 6ould cause a regulation of receptor aside from creating a pharmacologic effect. )escribe the mechanism of receptor regulation that occurs and give an eBample of receptor regulation that can happen clinically. 9. 2Bplain the difference bet6een dose-response curve base on the graded response 6ith Fuantal response

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;. ,o6 is therapeutic indeB determined and 6hat does it tell youE A. )escribe the factors that can affect drug response and need a dosage adIustment. I+: SU0ESTED READIN0 !. /oodman : /ilmanGs The Pharmacological 4asis (f Therapeutics - !!th 2d. (7889) : +hapter ! 7. 1at<ung 4asic : +linical Pharmacology -Ath 2dH+hapter 7

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Mod%& 3:

P8# m#$o&o4' A%to*om)$ Ne 7e S'stem

.earning (bIectives:
By the end of this session, the students should be able to: o o o o o o o +ompare and contrast the anatomy of the sympathetic and parasympathetic divisions of the autonomic nervous system (-& ). .ist and compareJcontrast the physiological responses of end organs produced by activation of the sympathetic and parasympathetic nervous systems 2Bplain 6hat tone is, and apply kno6ledge of predominant tone to the regulation of dually-innervated organs. )escribe the biosynthetic steps and regulation of the biosynthesis of catecholamines )escribe the biosynthetic steps and regulations of the biosinthesis of of acetylcholine 2Bplain the actions of the transmitters of the autonomic nervous system )escribe ho6 the transmitters of the autonomic nervous system regulates vascular and cardiac function, respiratory system and /%T system

%ntroduction ympathic and Parasympathic autonomic nerve system is centered in the hypothalamus. *nlike the voluntary motoric nerve system, autonomic nerve system is involuntary, meaning, it cannot be controlled like controlling a striated muscle. -utonomic nerves innervate most visceral organs inside the body, such as in the heart, intestines, blood vessels, lungs and glands. To communicate bet6een the nerve cells and the visceral organ cells, the end autonomic nerve cells, 6hether praganglionic or postganglionic 6il eBcrete a certain chemical substrate 6hich is kno6n as a neurotransmitter. %n its Iourney, the sympathic and parasympathic autonomic nerve cells 6ill eBit from the central nerve and medulla spinalis to the visceral organs. Ass)4*me*t /: !. )escribe the anatomical and physiological difference and also the receptor in the effector cells 6hich is located in the post synaptic nerve Ioint bet6een the sympathic and parasympathic nerves (make a table or a diagram). 7. There are a fe6 eBceptions to some organs or effector cells above 6hich is different from the usual regulations. )escribe those eBceptions. %t is very interesting to study neurotransmitters, because the synthesis mechanisms, storage, and release can be used to eBplain a fe6 disorders in the nerve and be used to do a drug intervention in the diseases that is related to autonomic nerve cell neurotransmitters. Those principles can also be used to eBplain physiologic and pathologic processes 6hich are related to gland secretion and cell mediator. Ass)4*me*t !: !. )escribe ho6 dopamine, noradrenaline and adrenaline is synthesi<ed in the nerve cells. 7. ,o6 is noradrenaline and acetylcholine metaboli<ed in the nerve cellsE ?hat en<ymes and processes is involved in the synthesis and metabolism of noradrenaline. 3. #ention the chemicals or drugs that affects synthesis process, storage, release,

!7

uptake and metabolism of neurotransmitters. -re those substrates useable in medicine related to neurotransmittersE &eurotransmitters 6ork on an organ effector through many receptors. 4inding 6ith those receptors cause an increase of second messenger numbers inside the cells and cause the opening of various ion channels. Ass)4*me*t 3: !. ,o6 is the adrenegic and cholinergic receptor subtype division and name the main specific receptor in these organs: heart, blood vessels, bronchiolus, intestinals, liver, urogenital tract and pupilE 7. ,o6 is the pharmacodynamic mechanism of neurotransmitter bounded 6ith a certain receptor, and ho6 is the biochemistry cascade inside the cellE %nside our body, there are some vital organs 6hich are important to maintain the physiologic function of our body. Those physiologic functions are maintained by the activity of the sympathic or the parasympathic nerve cell activity in the organ or system. Those nerve activities is depends on the receptor distribution on those organs and also the sympathic and parasympathic nerve domination on those organs. -ssignment: !. ?hat is the effect of autonomic nerve cell activity in the heart ( - node, -3 node, PurkinIe and ventricle muscle)E 7. ?hat is the effect of autonomic nerve cell activity on the vascular system and blood pressureE 3. ?hat is the effect of autonomic nerve cell activity on the respiration system (bronchiolus)E =. ?hat is the effect of autonomic nerve cell activity on the gastrointestinal tractE -utonomic nerve cell activity depends on the availability of the endogenic neurotransmitter, such as noradrenaline and acetylcholine. ,o6ever, many eBogenic substrates can be in the form of agonist, antagonist, or chemicalsJdrugs that can increase the neurotransmitter in the synaptic gap 6hich of course 6ould effect the activity of the organ or system inside the body. -ssignment: !. &ame and describe the mechanisms other drugs that can increase the norepinephrine and acetylcholine concentration in the synaptic gap. 7. 4ased on the adrenergic receptor distribution in the cardiovascular, ho6 does eBogenic noradrenaline and adrenaline intake affect the blood pressure and heart (dra6 the effect of the drug on the blood pressure increase graphic). 3. ?hat happens to the heart, blood vessels, and bronkhiolus if given a selective beta-! blockerE =. ?hat happens to the heart and bronchus if given a non selective beta agonist.

!3

MODUL 4: A%to$o)ds #*d A*t)-)*(&#mm#to ' A4e*ts .earning (bIectives:

By the end of this session, the students should be able to: o *nderstand the concept of local hormones or autocoids. o "amiliar 6ith the compounds or materials that is grouped as autocoids. o *nderstand the source, synthesis, storage and distribution of autocoids. o *nderstand the pharmacological effects of autocoids and its mechanism. o *nderstand the role of autocoids in inflammation. o *nderstand the role of antiinflammaotry agents and its relation 6ith autocoids in inhibiting inflammatory processes. o *nderstand the proinflammatory cytokines and anti-inflammatory cytokines %ntroduction (ther than hormones and neurotransmitters, there are compounds 6ith a short life span and 6orks in its origin of synthesis. +ompounds 6ith these characteristics are gathered into one group and named autocoid L derived from the 6ord autos (greek, meaning MaloneN) and akos (greek, meaning Mmedicinal compoundN or MmedicineN). These compounds are also kno6n as local hormones. The study of autocoids is reFuired because autocoids functions in the many process in the human body, 6hether it is physiological or pathological. 3arious organs are affected by autocoids, resulting in different effects depending on the type of the autocoid and 6here it 6orks. Ass)4*me*t: Inflammation is affected by many mediators, among them, the autocoid. &ame the types of autocoids that play a role in inflammation. H)st#m)*e. ,istamine is considered an autocoid. ,istamine functions in many physiological and pathological processes in the human body, such as, in urticaria, allergy, hipersensitivity, etc. Thus, the study of its mechanism and role in those processes is needed. *nderstanding its mechanism can be used to eBplain ho6 those processes occur. Ass)4*me*t !. &ame the distribution of histamine and ho6 it is synthesi<ed, stored and metaboli<ed. 7. &ame the regulation of histamine release and the factors that affect it. 3. 2Bplain the mechanism of histamine in allergy =. &ame histamine subtype receptors and some organs that those receptor reside in. >. &ame some eBamples of the effects of histamine in some organs in the body. 9. 2Bplain ho6 the effects of histamine causes edema. ;. &ame the groups of antihistamines and eBplain its mechanism and some eBamples of its effect in the organs of the human body. A. &ame some antihistamine that has an local anaesthetic effect.

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 B #d)9'*)* 4radykinin and kalidin (peptide autocoids) occurs in tissue damage, allergic reaction, virus infection and in inflammatory events cause by other things, 6hich activates the proteolytic process. These peptides are autocoids 6hich 6orks locally in causing pain, vasodilatation, and an increase in vascular permeability. The activity of this autocoid is associated 6ith mediator release stimulation such as prostaglandin, &(, or endotheliumderived hyperpolari<ing factor (2),"). Ass)4*me*t !. )escribe the formation and destruction of kinin. 7. &ame the groups of bradikynin receptors. 3. /ive some eBamples of bradikynin effects in subtype receptors and its organ response. ;-H'd o<'t '=t#m)*e >;HT, Se oto*)*? >-hydroBytryptamine (> ,T, serotonin)is a regulator of smooth muscle function in the cardiovascular and gastrointestinal tract, a regulator in platelet function and a neurotransmitter in the central cnervous sytem (+& ). There is a high concentration of > ,T in enterochromaffin cells in the gastrointestinal tract, it is stored in platelet granules and 6idely spread in the +& . Ass)4*me*t !. &ame the source of > ,T. 7. 2Bplain the synthesis and metabolism of > ,T. 3. &ame the subtype receptors of > ,T, its distribution, post receptor mechanism and some eBamples of its prototype antagonist receptor. =. 2Bplain ho6 > ,T regulates smooth muscle function in the cardiovascular system and gastrointestinal tract. >. 2Bplain the mechanism of ondansetron. L)=)d de )7ed A%to$o)ds >E)$os#*o)d #*d P&#te&et A$t)7#t)*4 "#$to s3PA"? The lipid cell membrane supplies substrate for the synthesis of eicosanoid and the platelet activating factor (P-"). 2icosanoid is an arachidonic metabolite, it includes prostaglandins, prostacyclines, thromboBane -7 and leukotriens, all are not stored in the cell yet produced by most cells. 3arious induction in the cells, such as physical, chemical and hormonal induction 6ill activate acyl hydrolases en<ymes that 6ould eventually form arachidonic acids. /lycerophosphocholine derivates in the cell membrane can be en<ymatically modified to produce platelet activating factors (P-"). P-" is formed by leukocytes, platelets and endothels. 2icosanoid and P-" derived from lipids contributes in )*(&#mm#t)o*, smooth muscle tonus change, homeostasis, thrombosis, secretion in the gastrointestinal tract, and birth. ome medicinal groups, especially aspirine, is grouped into traditional non-steroidal anti-inflammatory agents (t& -%)) and special cyclooBygenase-7 (+(5-7) inhibitors such as coBibs, that has the therapeutic principle of blocking the formation of eicosanoids. To understand the therapeutic potential of a selective inhibitor to the synthesis and function of eicosanoids, a study on the synthesis, metabolism, and mechanism of eicosanoid and P-" is needed. Ass)4*me*t: !. 2Bplain the synthesis, metabolism, and mechanism of eicosanoid. 7. 2Bplain the role of eicosanoid in inflammation. 3. 2Bplain the synthesis, metabolism, and mechanism of P-". =. 2Bplain the mechanism of t& -%) (non selective +(5 inhibitor) and +(5 specific inhibitor and their role as an anti-inflmmatory agent.

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C'to9)*es

+ytokines are soluble (glyco)proteins, nonimmunoglobulin in nature, released by living cells of the host, 6hich act nonen<ymatically in picomolar to nanomolar concentrations through specific receptors to regulate host cell function. +ytokines make up the fourth maIor class of soluble intercellular signaling molecules, alongside neurotransmitters, endocrine hormones, and autacoids. P o)*(&#mm#to ' $'to9)*es are produced predominantly by activated macrophages and are involved in the up-regulation of inflammatory reactions. A*t)-)*(&#mm#to ' $'to9)*es belong to the T cell-derived cytokines and are involved in the do6n-regulation of inflammatory reactions. Ass)4*me*t: !. &ame the source of cytokine. 7. 2Bplain the role of cytokine in inflammation. 3. 2Bplain the mechanism of cytokine =. &ame the proinflammatory cytokines and anti-inflammatory cytokines and eBplain the mechanism.

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PRACTICAL 0UIDANCE I*t od%$t)o* o( t8e = #$t)$#& The teaching of pharmacology given to medical faculty students is incomplete, 6hether using the classical methodology or the more ne6er Problem 4ased .earning (P4.) methodology, 6ithout a conducting a pharmacological practice. This practice isnGt aimed to increase the practical skill of the students L its purpose is to help the participants obtain a direct eBplanation from observing the effects and responses of a drug in various levels of an organisms: organs, tissues and even to6ards cell cultures. The participants 6ould actively give a predetermined treatment to the organs or tissues, observe and not the changes or responses that occur, report in groups and in class, and, more importantly, conduct an analysis an discuss any results found deviating from the eBisting theories. "or that purpose, and also as a guide in completing the practice and a practice report, is this module -s for the practice itself, participants are eBpected to prepare and learn beforehand the pharmacological effects of the certain drug used in the forthcoming practice, as it 6ould ensure that the practice runs smoothly. Participants should 6ork earnestly, seriously, 6ith discipline and peacefully, so the practice 6ould give benefit to the teaching of pharmacology.

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PRACTICAL /A: THE E""ECTS O" DRU0S ON THE BLOOD +ESSELS INTRODUCTION 4lood vessels disorders are mostly found in the pathomechanisms of several diseases, such as hypertension, vascular angiopathy on diabetes, etc. %n order to solve this problem, many drugs have been developed - some target the smooth muscle of the blood vessels (alpha-! blocker, isosorbide dinitrate), others the endothelial cells indirectly (help to maintainJincrease the Fuantity and Fuality of the endothelial cells). To observe or develop drugs and even eBplain the pathomechanism of the blood vessel disorder, an eBperimental method takes place, in 6hich is used a separated blood vessels. The blood vessels used are artery and aorta 6ith or 6ithout endothelial cell. OB-ECTI+ES: !) (bserve the vasoconstriction and vasodilatation effects from the separated aorta 6ith and 6ithout endothelial cell. 7) *nderstand the mechanism of a drug that has a vasodilatation effect 6hich 6orks at the smooth muscle of blood vessels or endothelial cell. METHODS: !. 2Bperiment -nimal: #armot 7. The drugs used are: Phenylephrine 8,> ml !8 -=# Phenylephrine follo6ed by isosorbide dinitrate 8,> ml !8-=# Phenylephrine follo6ed by acetylcholine 8,> ml !8-=# 3. 2Fuipment: organ bath, #ac-lab computer =. 2Bperimental methods: %solate the marmotGs aorta from itGs thoraB cavity Prepare the 6hole blood vessel 6ith and 6ithout endothelial cell (after 6iped 6ith a cotton) in a length of more than ! cm long. "iBate the aorta 6ith 7 hooks in to the organ bath 6ith 1rebs solution inside, and maintain the temperature at 3;o+. 2nsure the organ bath content is more or less > ml 2nsure the 6eight of aorta is ! g, and connect to an isotonic contraction recorders using isotonic transducers. %nsert the drugs in the organ bath and observe the response from the recorder. "igure: - techniFue diagram of an -ortic ring preparation )etails: a) TissueJ (rgan b) ,enselheit 1rebGs olution c) )ouble Oacketed +hamber d) Transducer )% +* %(& -&) - %/&#2&T PhenylephrinGs effect on the blood vessels a) ?hat effect did you observe after phenylephrine 6as administered to the stockE b) ,o6 is the mechanism of actionE c) &ame the same type of drugs 6hich has the same effect. d) 4ased on the effect, 6hat are the side-effects of this drugE 7. %sosorbidGs effect on the blood vessels a) ?hat effect did you observe after isosorbid 6as administered to the stockE b) ,o6 is the mechanism of actionE

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c) &ame the same type of drugs 6hich has the same effect. d) 4ased on the effect, 6hat are the side-effects of this drugE 3. -cetylcholineGs effect on the blood vessels a) ?hat effect did you observe after acetylcholine administered to the stockE b) ,o6 is the mechanism of actionE c) &ame the same type of drugs 6hich has the same effect d) 4ased on the effect, 6hat are the side-effects of this drugE

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PRACTICAL /B: THE E""ECT O" HISTAMIN AND ISOPRENALIN TO THE SEPARATED TRACHEA STOCK INTRODUCTION Bronchus spasm in asthma is a result of an inflammation process and a hyperactive bronchus. -sthma therapy, besides using anti-inflammation drugs to manage the underlying process of asthma also uses bronchodilators 6hich functions mainly as a symptomatic drug. To observe or develop drugs 6hich 6ould function as a bronchodilator or bronchoconstrictor, an eBperimental method takes place in 6hich a separated trachea stock is used. %n this isolated tissue method, the trachea is more often used than bronchus smooth muscle because it is structurally and functionally (the distribution and number of receptors) similar to bronchus smooth muscles, but it is easier to prepare. OB-ECTI+ES: !. To observe the bronchocontriction and bronchodilatasi effects on the separated stock of respiratory tract smooth muscles. 7. To understand the mechanism of bronchocontriction and bronchodilatation. METHOD: !. 2Bperiment -nimal: #armot 7. )rugs used: histamine and isoprenaline 3. 2Fuipment used: organ bath, #ac-.ab computer =. 2Bperimental method: a) %solate the trachea of the marmot from the thoraB, and make a connected ring stock. b) "iBate stock using t6o strings 6ith one end hooked 6ith an isotonic transducer. c) *se 1rebGs solution as the media solution, 6ith the volume of the organ bath up to 7> ml. d) The trachea load is about 8.>88 grams. e) %nsert the drugs in to the organ bath and observe the response on the recorder. >. )rugs used: a) !8-> # histamine (it 6ould give A8P of the maBimum effect 6hich is 8.! ml 7.>B!8-3). b) -fter the effect of histamine reaches maBimum, administer isoprenalin 6ith succesive concentration !8-A #, !8-; #, !8-9 #, and !8->#. 9. (bserve the changes of contraction on the recorder follo6ing the administration of drugs "igure: TechniFue )iagram of eparated Trachea Preparation DISCUSSION: !. The effect of histamine on the respiratory tract smooth muscle a) ?hat effect did you observe after histamine is administered to the stockE b) ,o6 is the drugs mechanism of actionE c) &ame the same type of drugs 6ith the same effects. d) 4ased on the effect, 6hat are the side effects of this drugE e) 2Bplain the mechanism of histamine release follo6ing an allergic reaction. 7. The effect of %soprenalin on the respiratory tract smooth muscle a) ?hat effect did you observe after isoprenalin is administered to the stockE b) ,o6 is the drugs mechanism of actionE c) &ame the same type of drugs 6ith the same effects. d) 4ased on the effect, 6hat are the side effects of this drugE

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