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Pharmacology Introduction to Pharmacology

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Title: Pharmacology Introduction to Pharmacology


1
PharmacologyIntroduction to Pharmacology
2
  • Drugs should be used to prevent, to cure
    and to diagnose diseases.
  • Pharmacology is the study of the actions,
    uses, mechanisms, and adverse effects of drugs.
  • Pharmacodynamics, Pharmacokinetics
  • Toxicology

3
  • Pharmacodynamics is the study of the
    biochemical and physiological effects of drugs
    and their mechanism of action

4
  • 1. General classification of Drugs effects

5
  • A. Excitation is an increase or enhancement
    of mental activity by a drug. For example,
    stimulation of mental activity by caffeine.
    Inhibition is a decrease of the function produced
    by a drug. For example, barbiturates induced
    sedative-hypnotic effect.

6
  • B. Direct Action refers to the action produced
    directly by a drug at the site of contact with
    drug. A direct action at one part can at times
    elicit effects on remote organs or tissues, which
    are designated as indirect action.

7
  • For example, norepinephrine constricts the
    blood vessels directly, increases blood pressure,
    It is the direct action. It reflexively
    decreases heart rate. That is the indirect
    action.

8
  • C. Selectivity A drug is usually described
    by its most prominent effect or by the action
    thought to be the basis of that effect. Cardiac
    glycosides mainly stimulate myocardium diazepam
    inhibits central nervous system streptomycin
    suppresses tubercle bacilli.

9
  • D. Therapeutic effect is the effect affecting
    the physiological and biochemical functions of
    the organisms and pathogenic processes. It is
    used to prevent and treat diseases.

10
  • Etiological treatment means that the drug may
    eliminate the primary pathogenic factor and cure
    disease. Such as, antibiotics eliminate
    pathogenic organisms within body.

11
  • Symptomatic treatment means that the drug may
    improve the symptoms of disease, such as, use
    aspirin to treat high fever. In some critical
    condition, shock, convulsion, congestive heart
    failure, high fever, severe pain, symptomatic
    treatment is more urgent than etiological
    treatment.

12
  • E. adverse effect
  • Any response to drug that is noxious and
    unintended and that occurs at doses used in man
    for prevention, diagnosis and therapy of a
    disease, or for the modification of physiological
    function.

13
  • Side effects of drugs are the effects which we
    do not want to have , but are nondeleterious,
    such as dry mouth with atropine which treat the
    spasm of intestine .

14
  • Toxic effects mean noxious effects induced by
    over dosage of drugs or accumulation of large
    amount of drugs.

15
  • They include acute toxicity which may damage
    the functions of circulatory system, respiratory
    system and nervous system, and chronic toxicity
    which may damage hepatic, renal, bone marrow and
    endocrine function.

16
  • Carcinogenesis, teratogenesis and mutagenesis
    belong to chronic toxicity. Toxic effect are
    necessary prelude to avoidance of them or, if
    they occur, to rational and successful management
    of them.

17
  • Allergy is an adverse reaction that result
    from previous sensitization to a particular
    chemical or to one that is structurally similar.
    Such reactions are mediated by the immune system.
    The terms hypersensitivity and drug allergy are
    often used to describe the allergic state.

18
  • After effect The effect still exists , after
    withdrawal of the drug, the drug concentration
    is below the threshold, such as, the patient
    feels hangover next morning, after taking
    barbiturates.

19
  • Secondary reaction After long term of using
    broad spectrum antibiotics, due to the change of
    intestinal normal flora, the sensitive bacteria
    are abolished, then it appears the overgrowth of
    non-sensitivity bacteria such as staphylococcus
    and fungi, staphylococcus enteritis or candida
    infection (candidiasis) appears, This called
    secondary reaction.

20
Dose-Effect Relationship

21
  • Graded Dose- Response curve
  • As the dose administered to a single subject
    or isolated tissue is increased, the
    pharmacologic effect will also increase. At a
    certain dose, the effect will reach a maximum
    level.

22

Graded dose-response curve
23
  • Efficacy The maximum effect of drug, Emax is
    a measure of drug efficacy. Efficacy is also
    called intrinsic activity.

24
  • Potency A comparative measure, refers to the
    different doses of two drugs that are needed to
    produced the same degree of effect. These two
    drugs have similar chemical structure and
    mechanisms of action. The lower the dose of drug
    effect, the higher the potency of drug.

25
  • Graded dose-response curve for three
    drugs
  • Efficacy and potency

26
  • B. Quantal Dose Response Curve
  • 1. A quantal response is an all or none
    response to a drug and relates to the frequency
    with which a specified dose of a drug produces a
    specified response in a population.

27
  • 2. The quantal dose-response curve is a
    cumulative graph of the frequency distribution
    curve . The dose of drug required to produce a
    specified magnitude of effect in a large number
    of individual patients or experimental animals
    are plotted the cumulative frequency distribution
    of responses versus the log dose.

28
  • The specific quantal effect may be chosen on
    the basis of the clinic relevance (e.g. relief of
    headache or it may be in experimental animal).
    When these responses are summated, the resulting
    cumulative frequency distribution constitutes a
    quantal- dose-effect curve of the proportion or
    percentage of individuals who exhibit the effect
    plotted as a function of log dose.

29
  • Quantal dose effect plots

30
  • Quantal dose effect curve may also be used
    to generate information regarding the margin of
    safety to be expected from a particular drug used
    to produced a specified effect

31
  • ED50 The dose at which 50 of the
    individuals exhibit the specified quantal effect.
  • LD50 The dose at which 50 of the animals
    exhibit death.

32
  • Therapeutic index (TI) LD50 / ED50

33
  • Dose-response curve of effect and toxicity of
    A,B equal ED50 and LD50, toxicity BgtA

34
A and B to have same TI, difference slope
35
  • III. Receptor Theory and Drug Receptor
    Interaction

36
  • Receptor. Macromolecular structure to which a
    drug binds in such a way as to initiate or modify
    a biological function.

37

K1
  • DR DR E

K2
Note D drug R receptor DR drug receptor
complex E effect K rate constant.
38
  • A. Receptor Theory

39
  • 1. Receptor occupation theory

40
  • When the receptors are occupied, the
    pharmacological effects will occur. The effects
    of drug are directly proportional to the numbers
    of receptors occupied. Stephenson revised the
    opinion it is not necessary to occupy all the
    receptors, when the maximal effect occurs.

41
  • Affinity It is the tendency of a drug to form
    a combination with the receptors
  • Affinity 1/KD KD dissociation constant

42
  • Intrinsic activity Its inherent ability to
    produce an effect

43
  • Dissociation constant, KD is a characteristic
    of the drug and of the receptor, it has the
    dimensions of concentration and is numerically
    equal to the concentration of drug required to
    occupy 50 of the sites of equilibrium (50 of
    the maximal effect. Minus log KD is pD2 -log
    KD), which is called affinity index. The higher
    the affinity of the drug for the receptor, the
    lower will be KD, at the same time, the higher
    pD2, the stronger will be the effect of the drug.

44
  • A
    B
  • A a, b, c (equal pD2 ,
    difference Emax)
  • B a, b, c (equal Emax
    , difference pD2)
  • Intrinsic activity and affinity of a
    drug

45
  • 2. Rate Theory The response of a drug is the
    function of the rate of dissociation of drug
    receptor complex.

46
  • 3. Two model theory Receptors have to
    different conformation, activated conformation
    (R ) and resting conformation (R ). They may
    change to the other one. Activated form may
    combine with agonists, then may show its effect
    resting conformation may combine with antagonist,
    which has no effect.

47
  • Ligand chemical substances which can combine
    with receptors are called ligands, ligands
    include drug, hormones and neurotransmitters.

48
  • Spare receptors For a highly active agonist
    with a high efficacy, the maximal response will
    be produced by a concentration that dose not
    occupy all receptors. The receptors remain
    unoccupied are termed spare receptors.

49
  • B. Agonists and Antagonists

50
  • 1. An agonist has high affinity to receptors
    and high intrinsic activity. An agonist is a
    drug that produces a pharmacological effect when
    it combine with receptors

51
  • An antagonist binds to the receptors to
    inhibit the action of an agonist, but initiate no
    effect themselves. Sometimes, the inhibition can
    be overcome by increasing the concentration of
    the agonist, ultimately achieving the same
    maximal effect. Examples of pure antagonists are
    atropine and curare, which inhibit the effects of
    acetylcholine.

52
  • Partial agonists They have agonistic
    activity but also have antagonistic activity

53
  • Pharmacological Antagonism occurs when an
    antagonist prevent an agonist from acting upon
    its receptors to produce an effect

54
  • 1. Competitive antagonism Competitive
    antagonists compete with agonists in a reversible
    fashion for the same receptor site. When the
    antagonist is present, the log dose-response
    curve is shifted to the right. In the presence
    of a fixed concentration of agonist, increasing
    concentration of a competitive antagonist
    progressively inhibit the agonist response high
    antagonist concentrations prevent response
    completely.

55
  • Non competitive antagonism The
    noncompetitive antagonist binds irreversibly to
    the receptor site or to another site that
    inhibits the response to the agonist. For
    example, drugs such as Verapamil and Nifedipine
    prevent the influx of calcium ions through the
    cell membrane and thus block non-specifically the
    contraction of smooth muscle produced by other
    drugs.

56
  • Graded dose-response curve illustrating the
    effect of competitive antagonists

57
  • Graded dose-response curve illustrating the
    effect of non-competitive antagonists

58
  • Two state model of receptor

59
  • D. Enhancement of drug effect

60
  • 1. Additive drug effects occur if two drug
    with the same effect, when given together,
    produce an effect that is equal in magnitude to
    the sum of the effects when the drugs are given
    individually
  • EAB EA EB

61
  • 2. Synergism occurs if two drugs with the same
    effect, when given together, produce an effect
    that is greater in magnitude than the sum of the
    effects when the drugs are given individually.
  • EAB gt EA EB

62
  • 3. Potentiation occurs if a drug lacking an
    effect of its own increases the effect of a
    second, active drug
  • EAB gt EA EB

63
  • IV. Cellular Response of Receptor- Effector
    Linkage.

64
  • Drugs or ligands combine with receptors induce
    a series of cellular responses and hence
    physiological or biochemical effects. These are
    four types of cellular responses.

65
  • A. Direct Regulation of Membrane Permeability
    to Ions

66
  • After drug combine with receptors, the
    receptors are activated. This has effects on ion
    channel of membrane, changing ion flow across the
    transmembrane, generating membrane potential or
    changing intracellular ion concentration, that
    may induce physiological effect. Such as when
    cholinergic receptors are activated at
    neuromuscular junction, Na influx will be
    increased.

67
  • B. Regulation via Intracellular Second
    Messages

68
  • After the receptors are activated, the second
    message C-AMP / C-GMP increases or decreases,
    phosphatidyl-inositol-4.5-biphosphate(PIP2)
    decomposes to the second messagers inositol
    triphosphate (IP3) and diacylglycerol (DG).

69
  • Effect of second message

70
  • C. Direct Modulation of Protein
    phosphorylation, such as insulin receptor

71
  • D Regulation of DNA Transcription

72
  • Regulation of protein synthesis it induces
    biochemical and physiological effect, such as
    steroid hormones.

73
  • Type of receptor effector linkage
  • CR-receptor, GG-protein Eenzyme

74
  • V. Receptor Families and Their Transducer and
    Effector Molecules.

75
  • Receptor has ligand binding domain and
    effctor domain.

76
  • A. Receptors as Enzymes

77
  • This class of receptor molecules mediates the
    first step in signaling by insulin, epidermal
    growth factor (EGF), platelet- derived growth
    factor (PDGF), atrial natriuretic factor (ANF),
    transforming growth factor ß (TGFß), and many
    other topic hormones. These receptors are
    polypeptides consisting of an extracellular
    hormone binding domain and a cytoplasmic enzyme
    domain, which may be a protein tyrosine kinase,
    a serine kinase, or a guanylyl cyclase.

78
  • Catalytic activities
  • Tyrosine kinase growth factor receptors,
    neurotrophic factor receptors
  • Insulin, epidermal growth factor (EGF)
    receptors, platelet- derived growth factor (PDGF)
    receptors

79
  • B Multisubunit ligand-gated Ion Channels
  • Nicotinic Ach receptor
  • Glutamate receptor, GABAA receptor
  • Glycine receptor, 5-HT3 receptor

80
  • C. G-protein Coupled Receptor Systems

81
  • G- protein coupled receptors comprise many
    of the receptors, 5-HT receptors, opiate
    receptors, receptors for many peptides, purine
    receptors and many others, including the
    chemoreceptors involved in olfaction.

82
This system divided to three parts
  • 1. G protein coupled binding site.
  • They consist a single polypeptide chain of
    400-500 residues. They all possess seven
    transmembrane - a helics. Both the
    extracellular amino terminus and the
    intracellular carboxyl terminus vary greatly in
    length and sequence. Agonists combine with the
    receptors.

83
  • 2. G protein
  • G protein is the short term of guanine
    nucleotide binding protein (also called
    GTP-binding protein). The G proteins are bond to
    the inner face of plasma membrane. They are
    heterotrimeric molecules (subunits are designated
    a,ß and? )

84
  • When the system in inactive, GDP is bond to
    the a subunit. An agonist receptor complex
    facilitates GTP binding to the subunit in part
    by promoting the dissociation of bond GDP.
    Binding of GTP activates the a subunit, and the
    aGTP subunit is then thought to dissociate from
    the ß,? subunit and interact with a membrane
    bound effector.

85
  • There are two types of G-protein, one is
    excitatory G-protein (Gs) which stimulates
    adenylyl cyclase (AC) to increase cAMP. Another
    is inhibitory G-protein (Gi) which inhibits AC
    and decrease cAMP

86
  • GDP-binding protein activation of effectors
    is regulated simultaneously by a GTPase cycle and
    a submit association / dissociation cycle. The
    GTP-liganded subunit activates some processes
    exclusively, and release of ß ? subunit, upon
    activation of Ga allows for regulation by ß ?
    subunit of shared or distinct effectors.

87
  • The regulatory cycles involved in G
    protein-mediated signal transduction.

88
  • 3. Effectors.

89
  • D Nucleus Receptors
  • Regulation of transcription Receptor for
    steroid hormones, thyroid hormone, retinoid are
    soluble DNA-binding proteins that regulate the
    transcription of specific genes.

90
  • VI. Relationship Between Regulatory
    Mechanisms of Receptors and the Pharmacological
    Action

91
  • Receptors are themselves subject to regulatory
    control, superstimulation or subnormal response
    may occur if the receptor activity or receptor
    numbers have been modified by up-or down
    regulation. Such regulatory mechanisms are
    usually evident with chronic use of a agonist or
    an antagonist.

92
  • Receptor down regulation (desensitization)
    may follow continued stimulation of cells with
    agonists. Several mechanisms are possible (1)
    phosphorylation of the receptors, destruction of
    the receptors, re-localization, sequestiation
    (isolation of receptor) (2) decreased synthesis
    and number of receptors. For example, chronic
    use of isoprenaline for asthmatic patient the
    bronchial relaxation effect will be decreased.

93
  • Receptor up-regulation (supersensitivity) may
    follow continued use of antagonists (or
    denervation), usually synthesis of additional
    receptors. Up-regulation is connected with
    increase of sensitization for chronic use of in
    antagonist or having symptoms induced by withdraw
    of drugs, such as after chronic use of
    propranolol for hypertensive patient, suddenly
    stop to use it, it will induce rebound (increase
    of blood pressure)

94
  • VII. Mechanism of Action

95
  • A. Change the Physical and Chemical
    Properties of the cellular Environment
  • Antacid neutralizes gastric acid, IV mannitol
    induces diuretic effect (osmotic diuretic)

96
  • B. Interfere or Incorporate into Metabolic
    Process Sulfarages inhibit dihydrofolic
    synthetase, and interfere the synthesis of
    dihydrofolic acid, nucleic acid and protein.
    Cholinesterase inhibitors increase the effect of
    Ach.

97
  • C. Influence of Biologic Membrane
    anti-arrhythmic drugs influence Na, Ca2, K
    transport. Polymycin B, E can damage bacterial
    cytoplasmic membrane.

98
  • D. Influence Physiological Transmitters and
    hormones Ephedrine enhances the release of NA
    from the adrenergic nerve endings. Tolbutamide
    enhances the release of insulin and decreases the
    blood sugar concentration.

99
  • E Influence of enzyme omeprazole inhibit
    the Na-KATPase of stomach to treat stomach
    ulcer

100
  • F Influence of nucleic acid metabolism
    nucleic acid metabolism of bacteria is influenced
    by antibiotics to abolished the life of bacteria.

101
  • F. Receptors.

102
  • Pharmacokinetics That considers drug
    disposition and the way the body affects the drug
    with time i.e. the factors that determine its
    absorption, distribution, metabolism and
    excretion. So, we know how rapidly and in what
    concentration and for how long the drug will
    appear at the target organ.

103
  • Drug transportation In order to reach its
    site of action (receptor site), a drug have to
    traverse a succession of membranes
  • 1. Passive diffusion passive diffusion take
    place when a drug molecule moves from a region of
    relatively high to one of low concentration
    without requiring energy, carrier, saturation and
    competitive inhibition. Simple diffusion is
    major state of passive diffusion for drug
    transportation.

104
  • The rate of diffusion depend on the state,
    area and a concentration gradient of membrane.
    Nature of drug is key point to across the cell
    membrane. The drug which are small molecules
    (lt200D), lipid solubility of drug, unionized form
    are easy to across the membrane.

105
  • Most drugs are either weak acid or bases.
    Therefore, the pH of environment in which they
    dissolve, as well as the pKa of the drugs will be
    important in determining the fraction in
    unionized form that is in solution and able to
    diffuse across cell membrane.

106
The pKa of drug is define as the pH at which 50
of the molecules in solution are in the ionized
form Handerson Hasselbalch
equationFor an acid For a
bases

107
  • Drugs exist in non-ionized and ionized forms.
    The non-ionized form of drugs are more lipid
    soluble and able to penetrate the cellular
    membrane, but ionized form of drugs are very
    difficult to penetrate the membrane. That is
    called ion trapping.

108
  • Weak acids (e.g. barbiturates) are more
    readily absorbed from the stomach than from other
    regions. Weak base drugs are more absorbed from
    the intestines than from stomach.

109
  • 2. Active transport is a carrier mediated
    process. This process require energy and proceed
    against a concentration gradient. Such as
    methyldopa. The carriers of drug are selective
    and saturable in transport process. Like
    Probenecid blocks the active tubular secretion
    of Penicillin and hence prolong its action.

110
  • With facilitated diffusion, the transport
    process is selective and saturable, but the drug
    is not transferred against a concentration
    gradient. Such as absorption of glucose.

111
  • The mechanisms and disposition of drugs by the
    body.

112
  • Absorption (1). Administration of
    gastrointestinal tract most drugs are
    administered orally. The tablet and capsule need
    to be disintegration and dissolution, then that
    may be absorbed

113
  • The major portion of drug absorption is in
    small intestine, which has considerably greater
    absorptive surface, to wriggle slowly,
    particularly, pH 7.4 (neutral)

114
  • Drugs that are administered orally and enter
    the portal circulation of liver and can be
    biotransformed by this organ prior to reaching
    the system circulation. This is called first pass
    elimination. Some drugs are reduced by first
    pass elimination. so the sublingual and rectum
    administration are recommended to avoid the first
    pass elimination

115
  • (2) Injection Intravenous injection and
    intravenous infusion are administration which
    directly enter circulation and rapidly act in the
    body

116
  • (3) Other parenteral method. Such as
    intramuscular injection and subcutaneous
    injection are important method. The drugs via
    these methods are absorbed better, which are
    related to the temperature of site. massaging of
    the site where a drug has been administered
    increases the rate of absorption.
    Vasoconstrictive substance may prolong the
    absorption of drug.

117
  • (4) Special method such as intra-artery,
    local anesthetics were also used in order to
    avoid the side effect of body. Administration of
    respiration tract Aerosol vaporize the drug
    solution into small particle (5µm), so it may be
    absorbed through the capillaries which adhere to
    the pneumoaheolus face, but the face area is
    larger and the blood volume of lung is rich.
    Such as aerosol of isoprenaline is used to treat
    asthma

118
  • Transdermal administration the lipophilic
    drugs may pass through the skin, so it is
    absorbed slowly, such as, toxicosis of pesticide,
    and Transderm-nitro (nitroglycerin) and
    Nifedipine are used to prevent the angina from
    attack.

119
  • Drug distribution

120
  • The drug has the plasma protein binding after
    the drug enters the circulation. Nonbinding
    drugs are called free drugs. More acidic drugs
    are bound to albumin, more basic drugs are bound
    to a1 acid glucoprotein. Less drugs are bound to
    globulin. The state of binding similar to
    receptor binding of drug . The percent protein
    binding is very important, because the part does
    not exert any pharmacological effects, but has a
    store form in plasma.

121
  • Plasma protein binding is a reversible
    process, that is influenced by DP, D, and KD of
    plasma. The binding site of protein are not
    unlimited and subject to saturation. The percent
    protein binding of drugs varies dramatically.
    Drugs may alter the protein binding of other
    agents. Such as, only a slight displacement of a
    highly bound drug like bishydroxycoumarin can
    oral anticoagulant by phenvlbutazone, can cause
    serious haemorrhage. Because only 1 of
    anticoagulant is free, and additional
    displacement of 1 increase its effect by 100.

122
  • The rate of distribution of drug from blood to
    tissue depend on the blood volume of organs. The
    more blood volume the organ has, the faster the
    amount of drug diffused. Then there is a
    redistribution in some organs. e.g. Thiopental
    is lipophilic drug, and it diffuses into brain
    more quickly, then, redistribute to the fat and
    other tissues.

123
  • The concentration of drug at target organ
    should be measured through the concentration of
    plasma. So the effect of the drug may be
    estimated at target organ.

124
  • The pKa and pH are other key points.
    Generally, weak base drugs penetrate the cellular
    membrane facilely when the toxicity of weak acid
    drug take place, the basic substance should be
    used to alkalify the blood in order to transfer
    the acid drugs out of the cells

125
  • Blood-Brain Barrier Drug can enter the
    brain from circulation by pass through the
    blood-brain barrier. This boundary consist of
    several membranes, including those of capillary
    wall, the glial cells closely surrounding the
    capillary, and neuron. Such a structure limit
    the entry of many drugs into the brain.

126
  • Some drugs may be modified to avoid the centre
    nervous system reaction. Such as Atropine
    methyl-atropine. Haloperidol N-n-butyl
    haloperidol iodide

127
  • The placental barrier is membrane separating
    fetal blood from maternal blood in intervillous
    space. It resembles the capillary, and almost
    all drugs may penetrate the placental barrier.
    During pregnancy, the drugs which affect fetal
    developing should be contraindicated.

128
  • Drug Biotransformation

129
  • Drug is a xenobiotic. Before being excreted
    from body, most drugs are metabolized. A small
    number of drug exist in their fully ionized form.
    More lipid-soluble drugs are metabolized by the
    liver. The goal of metabolism is to produce
    metabolites that are polar, or charged, and can
    be eliminated by the body.

130
  • Using two general sets of reaction, called
    phase I and phase II. Phase I metabolic reaction
    include oxidation, reduction and hydrolysis.
    Phase II reaction involve conjugation. During
    phase I , most drugs are inactivated
    pharmacologically, a few drugs become more active
    and toxic in nature. Phase II result in the drug
    being more hydrophilic and thus more easily
    excreted from the body.

131
  • The hepatic cytochrome P450 is the most
    important enzyme (hepatic drug enzyme). It
    consist of more than 70 enzymes. A drug
    substrate binds to cytochrome P450, then the
    complex acquired two hydrogen ions, a molecular
    oxygen from NADPH and cytochrome b5 and the drug
    undergoes hydroxylation by O, the another O bind
    the two H to H2O.
  • RH NADPH O2 2 H ROH NADP H2O
  • The enzyme system is called mixed function
    oxidases or monooxygenase

132
  • Enzyme activation and inhibition. Some drugs
    are able to increase the activity of certain
    isoenzyme forms of cytochrome P450 and thus
    increase their own metabolism, as well as that of
    other drugs. So that it may enhance the
    tolerance of drugs for the body. Such as
    phenobarbital. In contrast, some drugs inhibit
    cytochrome P450 activity and therefore increase
    their own activity as well as that of other
    drugs, like cimetidine.

133
  • In cytochrome P450 system, CYP3 and CYP2c play
    a significant role, that related to the
    metabolism of many drugs. 30-50 of drugs are
    metabolised by CYPA4 which is the member of CYP3.

134
  • Cytochrome P-450 transformation (oxidation)

135
  • Cytochrome P-450 transformation
    (reduction)

136
  • Phase II reactions are conjugation reaction
  • To combine a glucuronic acid, sulfuric acid,
    or glycine with the drug to make it more polar,
    the high polar drugs can then be excreted by
    kidney.

137
  • Excretion of Drugs
  • Drugs are excreted from the body in variety
    of ways. Excretion can occur by kidneys into
    urine. That is most important routes for the drug
    excretion. Some drugs in the blood pass into the
    glomerulor filtrate. Drugs can excreted in free
    forms (water-soluble substances). Non-ionized
    lipid- soluble drugs may be reabsorbed by tubule.
    Some drug may transported into the lumen of the
    tubule by either of two transport mechanism. One
    transport mechanism deal with acidic molecules,
    the other with basic molecules.

138
  • Competition between drugs that share the same
    transport mechanism may occur, in which case the
    excretion of these drugs will be reduced.
    Probenecid is a drug that was designed to compete
    with penicillin for excretion and therefore
    increase the duration of action of penicillin.
    Toxicity with acid drug can be treated by
    alkalifying which makes the urine more alkaline,
    this ionizes substance and renders it less prone
    to re-absorption. In contrast, basic drugs is
    same reason for their toxicity.

139
  • Renal disease will affect the excretion of
    certain drugs which may prolong the effect of
    these drugs. Such as cardiac glycosides
    administration.

140
  • Modify the urine of pH to treat toxicity.

141
  • Drugs are also excreted from the body by the
    bile, faeces and by the lungs into exhaled air.
    Drugs may leave the body through breast milk and
    sweat.

142
  • The excretion of the drugs from bile posses
    three transport channels, i.e. acid, base and
    neutrality channels. Some drugs conjugated are
    excreted into bile and subsequently released into
    the intestines where they are hydrolysted back to
    parent compound and reabsorbed ( hepatoenteral
    circulation). This effect of circulation
    prolongs the action of drugs, but in
    hepatocholangiostomy, the stay time of drugs in
    plasma which is excreted by bile may be shorten.

143
  • The change course of drug concentration with
    time (time- concentration relationship)

144
  • The relationship is described by
    time-Concentration curve

145
The ascending limb of curve is considered to be a
general reflection of the rate of drug
absorption. The peak concentration (Cmax) express
same speed between absorbing and eliminating
course. The time to reach the peak concentration
of the drug is Tpeak. The descending limb of the
concentration- time curve is a general indication
of the rate elimination of the drug from the
body. The time of over-effect concentration is
effective period. The concentration in blood by
one-half is called elimination half life.

146
  • The area under the concentration-time curve
    AUC
  • It described the relative dose of drug that
    enter the circulation. AUC is an indication of
    bioavailability.

147
  • Bioavailability is the amount and speed of
    drug that is absorbed after administration by
    route X compare with the amount and speed of drug
    that is absorbed after intravenous (IV)
    administration. X is any route of drug
    administration other than IV.

148
  • F A / D 100
  • D Dose of drug A dose of entering circulation
  • Absolute FAUC ( oral) / AUC ( iv) 100
  • Relative FAUC (test) / AUC (standard) 100
  • Standard drug compared with test drug to get the
    rate of absorption.

149
  • The bioavailability of different drugs is
    assessed by an evaluation of parameters
  • The peak concentration The time to reach the
    peak concentration The area under the
    concentration-time curve
  • The extent to which the bioavailability of one
    preparation form differs from that of another
    must be evaluated.

150
  • Bioavailability of three form preparations

151
  • Drug elimination kinetics is the eliminating
    course of plasma or blood concentration of drug
    with its distribution, metabolism and excretion.
    It is expressed by mathematics equation
  • dc / dt -kCn
  • C plasma concentration(dose/volume) A dose
    of plasma volume k rate constant

152
  • First-order kinetics drug disappear from
    plasma by process that are concentration
    dependent. The higher of drug concentration is,
    the more the drug elimination in unit time is.
    The elimination is in percentage course
  • n1 dc / dt keC1 CtC0e-ket
  • lnCt ln C0 ket
  • to convert from nature log to base 10 log
    units
  • Log Ct log C0 ke / 2.303t
  • t log C0 / Ct 2.303/ke

153
  • When Ct 1/2C0
  • t ½ log2 2.303/ke 0.301 2.303/ke
    0.693/ke the half life is 0.693/ke. The half
    life is the period of the required for the
    concentration of drug to decrease by one half .
  • The half life is constant and related to ke
    for drugs in first order kinetics, and not
    related with plasma concentration ( C).
  • Ke the fraction change in drug
    concentration per unit of time
  • Ke 0.5 h -1, t1/2 1.39h

154
  • AtA0e-0.693nA0(1/2)n When n5, At 3 .
  • after 5 half life of a drug, the drug are
    almost eliminated

155
  • When a drug is given at dosing interval that
    is equal to its elimination half life, the steady
    state will be achieved in 5 half life.

156
  • C L(plasma clearance) is defined as the sum of
    clearance of all the organs (liver, kidney and so
    on). It is the volume of fluid cleared of a drug
    per unit time. CL of drug is different from the
    elimination rate which is rate of removal of drug
    in weight per unit time, but they are related as
    shown in the equation CL ke VD

157
  • VD (apparent volume of distribution) is
    defined as the volume of fluid into which a drug
    appears to distribute with concentration equal to
    that of plasma, or the volume of fluid necessary
    to dissolve the drug and yield the same
    concentration as that found in plasma
  • VD dose administration / initial apparent
  • plasma concentration

158
  • The volume of distribution is hypothetical
    apparent volume, but not a real volume. It gives
    a rough accounting of where a drug goes in the
    body, if you have a feel for the various body
    fluid compartments and their size. In addition,
    it can be used to calculate the dose of drug
    needed to achieve a desired plasma concentration.

159
  • Such as, some drugs have a volume of
    distribution that exceeds body weight, in which
    case tissue binding is occurring
  • (bone, fat, nucleic acid and so on)

160
Calculation of Vd
Vd A / C0
161
  • CL ke VD 0.693 / t1/2 VD
  • CL A / AUC
  • When patient suffer from the damage of kidney
    or liver, the CL is decreased for drugs. The
    dose should be adjusted

162
  • Zero order kinetics drugs that saturate
    routs of elimination disappear from plasma in
    non-concentration-dependent manner. Many drugs
    will show zero-order kinetics at high dose of
    toxic concentration.

163
  • dC/dt -KC0 -K, Ct C0-Kt, when slope
    -K, Ct / C01/2, t t1/2
  • t1/2C0C0- k t1/2, t1/20.5 C0 /k
  • So, for drugs with zero-order kinetics, a
    constant amount of drug is lost per unit time.
    The half life is not constant for zero-order
    reaction, but depend on the concentration. Drugs
    is eliminated at same speed, such as at alcohol
    toxicity state.

164
  • In clinic, the treatment need in a
    therapeutic level of drug. For a drug displaying
    first-order kinetics, at first, the plasma level
    will be low and infusion rate will be greater
    than elimination rate, so, the drug will
    accumulate until the amount administered per unit
    time is equal to the amount eliminated per unit
    time

165
  • Css RE / CL RA / CL Dm / t/ CL
  • Dm / t / KeVD
  • Dm maintenance doses, t interval time
  • The time needed to reach steady state depends
    on the t1/2 , Ke, VD and CL , but not the speed
    of administration. The speed of administration
    determines the level of Css.

166
  • Intravenous infusion of drug get the steady
    state of plasma smoothly. With repeated dosing
    the concentration fluctuates between Cmax and
    Cmin. The longer the interval time is , the
    bigger the fluctuation is.

167

Time-concentration curve of intravenous infusion
168
  • If the Cmax is desired higher or lower, the
    rate of administration is adjusted, but after the
    5 half lives, the new Css is achieved.

169
  • Sometime, the patient can not wait for the
    therapeutic effect to occur. In this condition,
    a loading dose is used. Load dose is a single
    large dose of a drug that is used to raise the
    plasma concentration to a therapeutic level more
    quickly than usually occur through repeated
    smaller dose

170
  • Ass Dm Ass e-ket, D1 Ass Dm /
    (1-e-ket)
  • Ass loading dose
  • At beginning, the 1.44 times of infusion
    dose which is dosage of first half life time,
    should be intravenous injected , and it may reach
    the Css at once.
  • When interval time is t1/2, the double dose
    should be given at first time
  • Except t1/2 is much longer or shorter, zero
    order kinetics, half dose at half life interval
    and double dose at first time are necessary to
    get a desired effect and less side effects

171
  • Compartment model
  • One compartment model The body is a single
    compartment . With this single compartment, a
    drug is absorbed, immediately distribute (e.g. by
    intravenous injection). This situation expresses
    itself graphically as a straight line when the
    log plasma concentration is plotted against the
    time after IV dose

172
the log plasma concentration is plotted against
the time after IV dose
with the one-compartment model
173
  • Two compartment model
  • The distribution of drug between the
    peripheral compartment. (Such as , muscle , skin
    and fat depots) and central compartment (such as
    brain, heart, liver and kidney). Because of the
    rich blood volume of central compartment organs,
    the drug firstly enter the central compartment,
    then enter the peripheral compartment.

174
  • C Ae at Be ßt
  • An early, rapid, a-phase , which represent
    the redistribution of the drug to the peripheral
    compartment and a modest component of
    elimination. An later, slow, ß phase, which is
    combination of elimination and return of drug
    form to peripheral compartment to the central
    compartment in which the drug distribution
    rapidly.

175
Time-concentration curve of two compartment
176
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