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Complete Pharmacology for Medical Students

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The BEST Pharmacology for the USMLE – PowerPoint PPT presentation

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Updated: 18 December 2015
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Title: Complete Pharmacology for Medical Students


1
PHARMACOLOGY
  • IMEC INC.
  • Quick Learning
  • Technique

2
Routes of Administration
  • Enteral
  • Oral
  • Rectal
  • Sublingual
  • Parental
  • IV
  • IM
  • Sub-Cutaneous
  • Topical
  • Transdermal
  • Other
  • Inhalation-- Albuterol
  • Intrathecal- Apho B for Meningitis
  • Intranasal- desmopresson

3
Absorbtion of Drugs
  • Passive Diffusion
  • From a higher concentration to a lower
    concentration
  • Active transport
  • Is a process that may use a carrier protein or a
    simple H ion gradient to move a drug across a
    structural membrane

4
Physical Factors
  • Blood flow to absorption site
  • Total surface area for absorbtion
  • Contact time at the absorption site

5
Bioavailabilty
  • This is the fraction or percentage of a drug that
    reaches circulation in an unchanged form
  • INFLUENCED BY
  • Firstpass Hepatic Metabolism
  • Solubility of the drug
  • Chemical instability
  • Nature of the drug formulation

6
Volume of distribution
  • When accessing VD, we must take into account all
    WATER COMPARTMENTS
  • Total Body Water 42 Liters
  • Intracellular volume 28 Liters
  • Extracellular volume 14 Liters
  • Interstitial Volume 10 Liters
  • Plasma Volume 4 Liters

7
Binding of Drugs to Plasma Proteins
  • Binding of drugs to Albumin
  • Many HydroPHILIC drugs do not bind to albumin
  • NOTE many Hydrophobic drugs are by design done
    this way for absorption
  • Competition for binding
  • Class I Highly bound to Albumin
  • Class II Drug given that greatly exceed binding
    sites to Albumin

8
Volume of Distribution
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13
Binding to Plasma Protiens
  • Drug binding to plasma proteins (specifically
    Albumin) may be of great importance
  • CLASS I DRUGS are those drugs that are
    administered in a lesser amount than binding
    sites so displacement occurs
  • CLASS II DRUGS are those drugs that are given in
    a greater than binding sites scenerio
  • The importance of displacement comes into play
    with drugs such as Tolbutamide in which it is
    highly bound but only a small portion is free in
    plasma

14
P450 Metabolism
15
Isoenzyme CYP2C9/10
16
Isoenzyme CYP2D6
17
Isoenzyme CYP3A 4/5
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20
Renal Clearance
  • Cx Ux V/Px
  • This equals volume of plasma from which the
    substance is cleared completely/ per unit time

21
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22
First Order Kinetics
  • Michaelis-Menten kinetics
  • V rate of metabolism V max ( C )

  • Km
  • Rate of Drug Metabolism is directly proportional
    to concentration of the free drug

23
Zero Order Kinetics
  • V rate of metabolism V max ( C )
  • ( C )
  • The enzyme is saturated , so metabolism is
    constant
  • ASPIRIN, ETHANOL, PHENYTOIN

24
Steady State Drug Levels
  • Css Ro/KeVd
  • Where as
  • Ro Rate of infusion
  • Ke 1st Order Elimination
  • Vd Volume of Distibution

25
99
  • Therefore if we follow a drug washout with a
    continual steady state we reach 99 of the Css in
    3.3 T ½

26
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30
Dose Response Curse
  • Is a sigmoidal curve in which EC50 comes into
    play
  • The effect of and magnitude of binding is simply
  • Receptors Bound
  • Total Receptors

31
Therapeutic Index
  • Therapeutic Index TD50/ED50
  • TD 50 toxic effect in 50 of People
  • ED50 Effective dose in 50 of People
  • Warfarin has a small therapeutic index
  • Penicillin has a large therapeutic index

32
Major Receptors and Ligands
  • Ligand-gated Channels
  • NICOTINIC CHOLINERGIC
  • G-Protein Coupled Receptors
  • ADRENERGICS
  • Enzyme Linked Receptors
  • INSULIN
  • Intracellular Receptors
  • STEROIDS

33
ANTICANCER DRUGS
34
Therapeutic of Log Kill
  • This means that when diagnosed at 109 cells, if
    99 were killed it would still leave 104 cells.
  • 2nd is tumor cells are not readily eliminated
  • NoteLeukemic cells and other tumor cells find
    sanctuary in tissue that chemotherapy drugs
    cannot enter

35
Principles
  • Eradication of neo-plastic cells
  • Cell burden is reduced by surgery and/or
    radiation
  • Chemotherapy can help reduce size as is with
    surgery,
  • Radiation is used to reduce micro-metastasis
  • Cells become increasingly susceptible during
    growth phase
  • Divided into PALLATIVE and CURATIVE
    CHEMOTHERAPY

36
Acute Lymphocytic Leukemia
  • MOPP therapy
  • Methchloramine
  • Oncovirin
  • Prednisone
  • Procarbazine
  • POMP therapy
  • Prednisone
  • Oncovirin (Vincristine)
  • Methotrexate
  • Purinethol (Mercaptopurine)

37
Target Site for Chemotherapy
  • Cause a lethal cyto-toxic lesion that can arrest
    the tumors progression
  • THE ATTACK IS DIRECTED AGAINST THE METABOLIC
    SITES ESSENTIAL TO CELL REPLICATIONEXAMPLE BEING
    THE AVAILABILTY OF PURINE AN PYRIMIDINE
    PRECURSORS FOR DNA AND RNA SYNTHESIS

38
Common side effect
  • Most CHEMO drugs have a low therapeutic index
  • Severe vomitingcontrolled by cannabinoids
  • Stomatitis--
  • Alopecia
  • Myelo suppression
  • Cardiotoxicity--Doxirubicin
  • Pulomonary Fibrosis-Bleomycin
  • Megaloblastic Anemia Methothrexate
  • Countered by Leukovorin
  • TREATMENT INDUCED NEOPLASM ARE A SPECIAL PROBLEM
    AFTER AKLYLATING AGENTS

39
Cell Cycle
  • S-Phase----DNA is replicated
  • G2-Phase----Synthesis of cellular components
    required for mitosis
  • M-PhaseMitotic division
  • G0-Phase----Resting Phase
  • G1-Phase----Enzyme are synthesis for DNA synthesis

40
CELL CYCLE
41
ANTI-CANCER DRUGS
  • ANTI-METABOLITES
  • Methotrexate
  • 6-Mercaptopurine
  • 6-Thioguanine
  • 5-Flourouricil
  • Cytarabine

42
METHOTREXATE
  • Structurally related to Folic acid and is and
    antagonist of the vitamin
  • Folate is key in replicating cells for
    biosynthesis of methionine the purine
    nucleotides adenine and guanine, and pyrimidine
    nucleotides dTMP
  • It is no wonder Methotrexate adversely effects
    cell survival

43
METHOTREXATE
  • Undergoes reduction to (FH4) by intracellular
    NADPH dependant di-hydrofolate
  • AT HIGH CONCENTRATION it enters the cell by
    diffusion
  • Methotrexate has a strong affinity for
    Dihydrofolate reductase, and its inhibition can
    only be reversed by a thousand fold excess of
    natural substrate, dyhydrofolate (FH2) or
    Leukovorin
  • This leads to decreased biosynthesis of
    thymidylic acid, and methionine, purines (A G)
    and leads to depressed RNA and DNA synthesis and
    cell death

44
Methotrexate resistance
  • Resistance is characteristic of non-proliferating
    cells-The following mechanisms have been detected
  • Increased enzymeAmplification of the gene that
    codes for dihydrofolate reductase (therefore
    higher doses are required)
  • Modified enzyme----enzyme affinity for
    methotrexate is diminished
  • Less drug pumped into cellapparent changes in
    carrier mediated transport

45
MethotrexateTherapeutic applications
  • A-L-L-(Acute Lymphocytic Anemia)
  • Chorio-carcinoma
  • Burkitts lymphoma
  • Breast Cancer
  • Head and Neck Carcinoma,
  • Severe Neoplastic diseases
  • Severe Psoriasis, and Rheumatoid Arthritis
  • HIGH DOSES causes Osteogenic Carcinoma and be
    followed by Leukovorin to rescue bone marrow

46
Methotrexate Administration
  • IM
  • IV
  • Orally-well absorbed
  • Intra-thecally- because it does not cross blood
    brain barrier
  • FATE-they are converted to POLYGLUTAMATES-this is
    important because they remain in the cell
    even when there is an absence of extra-cellular
    drug

47
Methotrexate-adverse effects
  • Most frequent are stomatitis, myelosuppression,
    erythema, alopecia, nausea, vomiting and diarrhea
  • DOSES of LEUCOVORIN must be kept minimal to avoid
    interference with the anti-tumor action of the
    methotrexate
  • OTHER Adverse Effects
  • Renal Complications
  • Pulmonary Toxicity- especially in children
  • Hepatic Fibrosis
  • Neurological toxicities-especially associated
    with intra-thecal administration

48
6-Mercaptopurine
  • 6-MP is a Thiol analog of the Purine-Hypoxanthine
  • Of the purines analogs tested, only 6-MP and
    Thioguanine (6-TG) have proved beneficial in
    treating neoplastic disease
  • It works in on the hypoxanthine-guanine
    phosphoribosyl transferase (HGPRT) pathway and
    must penetrate the cell and be converted to a
    corresponding nucleotide
  • 6MP-ribose phospshate, also known as
    Thio-IMP
  • 6MP-RP, can inhibit the first step in de novo
    synthesis of AMP, and XMP (xanthinylic acid) from
    IMP(inosinic acid)
  • Resistance is associated to Lesch-Nyhan Syndrome,
    where patients lack HGPRT, or in increased
    metabolism of the drug to thio-uric acid, which
    is excreted in the urine
  • Must reduce dose of 6-MP when administering
    Allupurinol, because it is a xanthine-oxidase
    inhibitor.

49
6-Mercaptopurine-
  • IT IS USED WITH AZATHIOPRINE FOR THE TX OF
    CHROHNS DISEASE
  • Excretion of parent drug and metabolytes is by
    the Kidney
  • Adverse Effects
  • Nausea, vomiting, diarrhea
  • Mild myelotoxicity
  • THOMBOCYTOPENIA

50
6-Thioguanine
  • This purine analog is primary to
  • Acute Myelocytic Leukemia (AML)
  • Used in combination with Daunorubicin and
    Cytarabine
  • Like 6-MP is must be converted to a nucleotide
    form, which then inhibits bio-synthesis of the
    purine ring and the phosphorylation of GMP to GDP
  • Unlike 6-MP, Allopurinol does not potentiate
  • 6-TG action
  • Other toxicities are the same

51
5-Fluorouracil
  • 5-FU is a pyrimidine analog
  • The flourine interferes with the conversion of
    deoxuridylic acid to thymidylic acid
  • Thus depriving cells for DNA synthesis
  • Not for neoplastic situations
  • Used for slow growing solid tumors (e.g. colon,
    breast, ovarian, pancreatic, and gastric
    carcinoma)
  • Also effective for superficial basal cell
    carcinoma
  • 5-FU given IV, or in skin cancer topically
  • It is Metabolized to CO2, which is expired via
    respiration
  • Toxicity, nausea, vomiting, diarrhea, alopecia,
    bone marrow depression

52
Cytarabine
  • It is a pyrimidine antagonist
  • The cytotoxic locus is unknown
  • Competitively inhibits DNA polymerase
  • It works in the S-phase of the cell cycle
  • Very complex-altering CDP-to dCDP
  • Major use in AML-Acute Myelogenous Leukemia in
    combination with 6-TG and Daurorubicin
  • It does not penetrate CNS---however may be
    injected interthecally
  • Side Effects-Severe Myelo-suppression, nausea,
    vomiting, diarrhea, hepatic dysfunction

53
ANTI-BIOTICS USED IN CHEMO
  • Dactinomycin
  • Doxyrubicin
  • Daunorubicin
  • Bleomycin
  • Plicamycin
  • Mitomycin

54
Dactinomycin
  • Dactinomycin (actinomycin D) first antibiotic
    to be used in tumor chemo therapy
  • The complex interferes Primarily at DNA-dependant
    RNA polymerase
  • At high doses it may interfere with DNA
    synthesis-may cause strand breaks like
    doxyrubicin
  • Resistance is believed to be due to excision
    repair
  • DACTINOMYCIN is used with surgery and Vincristine
    for WILMS TUMOR
  • It is also used with methotrexate for the
    treatment of gestational choriocarcinoma

55
Doxorubicin (adriamycin) and Daunorubicin
  • The anthracyclines have three activities
  • INTERCALATION OF DNA
  • BINDING OF DRUG TO CELL MEMBRANE
  • GENERATION OF OXYGEN RADICAL THROUGH LIPID
    PEROXIDATIONP450 Reductase (in nuclear membrane)
    catalyzes ANTHACYCLINES to SEMIQUINONES FREE
    RADICALS
  • This may explain the cardiotoxicity of
    Doxirubicin
  • Resistance possibly decreased cytochrome p450
    reductase DNA repair
  • Doxorubicin is one of the most important and
    widely used cancer drugscarcinomas, sarcomas,
    ALL, breast cancer, lung cancer and Hodgkins
    disease
  • Daunorubicin for AML
  • BOTH MUST BE GIVEN IV-radiation increases
    cardiotoxicity

56
BLEOMYCIN
  • Is a mixture of different copper chelating
    glyco-peptides, like anthra-cycline antibiotics,
    causing scission of DNA by an oxidative process
  • Bleomycin- Fe(II), and DNA appear to go through
    oxidationthe liberation of electrons react to
    form a superoxide
  • Bleomycin is cell-cycle specificaccumulating in
    the
  • G2 phase
  • TESTICULAR CANCER in combination with Vinblastine
  • Response is 90 but even better if Cisplatin is
    added
  • Bleomycin is also used in Squamous Cell, but not
    curative
  • Pulmonary Toxicity

57
Plicamycin and mitomycin
  • Plicamycin---osteoclasts and lower plasma calcium
    concentrations in hypercalcemic patients----BONE
    TUMORS
  • Mitomycin---is employed in the treatment of a
    variety of solid tumors, but limited to
    myelosuppression

58
ALKYLATYING AGENTS
  • Mechlorethamine
  • Cyclophosphamide
  • Carmustine Lomustine

59
Mechlorethamine
  • Nitrogen Mustard
  • Alkylation of the N7 nitrogen of guanine DNA
    linkage
  • Though the alkylating reaction can occur in both
    cycling and resting phasetherefore cell cycle
    non specific
  • Resistance is due to the permeability of the drug
  • Methochlorethamine is very unstable---Part of
    MOPP therapyHodgkins and some some solid tumors

60
Cyclophosphamide
  • A nitrogen mustard that is biotransformed to the
    hydroxylated form intermediate by the cytochrome
    P-450 system.
  • Active phosphoramide with DNA is considered to be
    the cytotoxic action
  • Resistance is probably due to DNA repair and
    decreased pemeability
  • Used in Burkitt,s, some non-neoplastic disease
    entities such as nephrotic syndrome and
    intractable rheumatoid arthritis.
  • ORAL ROUTE PREFFERED
  • SE- Bone Marrow suppression and Hemorrhagic
    cystitis that can lead to a fibrotic bladder.
    Testicular atrophy and sterility
  • SE-Some altered increase in ADH secretion- (watch
    water intake-give furosemide)

61
Nitrosoureas
  • Lomustine is a methylated derivitive of
    CarmustineThe are alkylating agents
  • Alkylating mechanism inhibits DNA replication and
    eventually RNA and protein synthesis.
  • THIS CYTOTOCITY IS ONLY IN CELL DIVISION,
    THEREFORE NON-DIVIDING CELL ESCAPE NITROSUREAS
  • Resistance is probobly due to DNA repair
  • USED IN MALIGNANT GLIOMASBecause of the ability
    to penetrate the CNS
  • PHENOBARBITAL REDUCES THE CYTOTOXICITY SUGGESTING
    MIXED-FUNCTION OXIDASES ARE RESPONSIBLE FOR
    DETOXIFICATION
  • SE- Delayed hematopoeitic side effects, aplastic
    marrow and durational renal toxicity

62
Mitotic Spindle Poisons
  • The mitotic spindle consists of microtubules, and
    it is essential for the equal partitioning of DNA
  • Vincristine
  • Vinblastine

63
Vincristine and Vinblastine
  • Structurally related compounds from the
    periwinkle plant-Vinca roseatherefore referred
    to as Vinca Alkaloids
  • THEY ARE SPECIFIC TO MITOSIS DURING
    METAPHASEbinding to micro-tubular
    protein-Tubulin-and disrupting the spindle
    apparatus and causing termination of assembly
  • This in turn prevents chromosomal segregation
  • Resistance may be a P-glycoprotein (permeability)
  • ALLUPRURINOL DECREASES ACTION

64
Vincristine and Vinblastine USES
  • Vincristine
  • MOPP-the O in Oncovin, trade name for
    Vincristine
  • Acute Lymphocytic Leukememia
  • Wilms Tumors
  • Ewings soft tissue sarcoma
  • Hodgkins disease
  • Vinblastine
  • Metastatic Testicular Disease
  • Also in Hodgkins as well.
  • AE---PHLEBITIS or CELLULITIS, Nausea, vomiting,
    diarrhea, and alopecia

65
Hormones in Cancer Therapy
  • Prednisone
  • Tamoxifen
  • Estrogens
  • Leuprolide

66
Prednisone
  • Must be converted to Prednisolone
  • A potent synthetic anti-inflammatory
    corticosteroid with less mineralcorticol activity
    than cortisol
  • Use stems from treating lymphomas associated with
    Cushings syndrome (hyper-secretion of cortisol)
  • Triggers production of specific protein, still
    being elucidated
  • Prednisone is useful in ALL and treatment of
    Hodgkins and Non-Hodgkins Lymphoma

67
Tamoxifen
  • This is an estrogen antagonist, structurally
    related to synthetic estrogen
  • Tamoxifen binds to estrogen receptors, and the
    growth promoting effects of the natural hormone
    is suppressed---estrogen competes with tamoxifen
    therefore only effective in post-menopausal women
  • Resistance is associated to the number of
    receptors
  • Its clinical use is confined to the treatment of
    estrogen-dependant breast cancer an endrometrial
    cancer
  • Excreted primarily in the bile into feces
  • Orally administered
  • SE-Hot flashes, nausea,vomiting, skin rashes, and
    vaginal bleeding
  • Can lead to increased pain if tumor has mets to
    bone

68
Aromatase Inhibitors
  • Where Tamoxifen blocks Estrogens to the breast
  • AROMATASE INHIBITORS BLOCK ANDRENAL CORTEX FROM
    PRODUCTION OF ANDROGENS

69
Estrogens
  • Estrone of Diethylbestrol, are used to treat
    Prostate Cancer
  • Estrogens inhibit the growth of prostatic tissue
  • Also used in Metastatic Primary Carcinoma who are
    at least 5 years menopausal
  • Estrogen treatment can cause serious
    complications including Thrombo-emboli and
    Myocardial infarction, strokes, hyper-calcemia
  • In women loss of libido may accompany menstrual
    changes
  • In men gynacomastia may present itself

70
Trazuzamab
  • Tratuzumab binds with HER2 sites in cancer tissue
    and inhibits proliferation of cells that
    over-express the HER2 protein
  • Does not penetrate the blood-brain barrier

71
Leuprolide
  • In an analog of gonadotropin-releasing hormone
    (GnRh)
  • It inhibits the release of LH, and FSH reduces
    androgen synthesis
  • IT IS EFFECTIVE SUBCUTANEOUSLY AGAINST METASTATIC
    CARCINOMA OF THE PROSTATE
  • A depot formulation has been approved for monthly
    administration

72
ETOPOSIDE
  • Etoposide blocks cells in late synthesis (S) and
    G2 phase of the cell cycle
  • Etopiside finds its major clinical treatment in
    the treatment of
  • OAT CELL TUMORS of the lung

73
Procarbazine
  • Procarbazine is used in the treatment of
    Hodgkins disease and some other cancers.
  • Procarbazine is special in that it has a rapid
    equilibrium between plasma and CSF.
  • The major toxicity is bone marrow suppression
    therefore it can be a teratogenic agent itself.

74
INTEFERONS
75
Interferons
  • Interferons are glycoprotiens that are classified
  • Alphaprimarily leukocytes
  • Beta----connective tissue fibroblast
  • Gamma----T- lymphocytes
  • Site of action
  • Alpha and Beta receptors in close proximity and
    compete
  • Gamma interferon in a different receptor site
  • Therapeutic indications
  • a2(A) interferon is approved for hairy cell
    leukemia
  • (a) interferon has also shown to be productive
    in cytopenia
  • reduction of serious infections, and reduction
    for the need of tranfusion
  • Interferon has also been used in squamous cell
    carcinoma, melenoma, multiple myeloma

76
Interferon (cont)
  • GIVEN IM
  • Being a protein it is degraded by proteases
  • AE-Fever and chills occur
  • Dose related Leukopenia, and Thrombocytopenia
  • Fatigue, malaise, anorexia, weight loss,
    alopecia, and transient elevation of liver
    enzymes, as well as reversible nephro-toxicity

77
Cisplatin
  • Cis-daimedichloroplatinum II, (newer class of
    platinum drugs)
  • DNA and RNA synthesis at all stages but primarily
    the G1 and S stages
  • Therapeutically used with bleomycin and
    vinblastine in testicular cancer
  • And with cyclophosphamide in ovarian cancer
  • Alone in bladder cancer
  • IV administration, 90 serum bounddoes not X BBB
  • SE-Limitless-nausea, vomiting, nephotoxicity,
    hypomagnesium, hypocalcemia, HYPERSENSITIVITY
    REACTIONS

78
Procarbazine
  • Stucturally unrelated to any other cancer drug
  • Observed to be similar to Alkylating Agents,
    because a strand sission of DNA is observed and
    DNA and RNA synthesis is inhibited
  • There is also a formation of H2O2 and
    formaldehyde , so there may also be a free
    radical oxidative process
  • The reasons for resistance is not know
  • MOPP component in Hogdkins
  • ORAL or parental
  • Metabolytes excreted by the Kidney
  • AE-PYSCHIC DISTURBANCESinhibits MAO
  • Also, nausea, vomiting and diarrhea
  • Disulfuram type reactions WITH TYRAMINE

79
L-Asparaginase
  • L-aparaginase catalysizes deamination of
    asparginine to asparic acid and ammonia.
  • Some neoplastic cells require and external source
    of asparagine to support growth (LOW LEVEL OF
    ASPARGININE SYNTHATASE)
  • Thus depriving the tumor cells nutrients for
    protein synthesis-deprives growth
  • ALL (Acute Lymphocytic Leukemia) in combination
    with Vincristine and Prednisone
  • IV or IM because gastric enzymes destroy drug
  • AE-decreased Clotting factors and liver
    abnormalities, as well as pancreatitis, seizures
    and coma

80
ETOPOSIDE (VP-16)
  • Etoposide is a semi-synthetic derivative of a
    plant alkaloid
  • It blocks cells in the late S-G2 phase
  • Possibly degrades DNA-nucleoside
    transportInhibition of mitochondrial oxidation
  • Major use in OAT CELL OF LUNG and Refractory
    Testicular Carcinoma
  • IV or Oral, but enters CSF poorly
  • Excreted in urine as Gluconuride or sulfates
  • Small amount in Bile
  • Dose Limited myelosuppression is a major toxicity
  • Alopecia, Anaphylaxis, Nausea, and Vomiting

81
Myelosuppression
  • Highly
  • Vinblastine
  • Nitrosueas
  • Cyclophosphamide
  • Cytarabine
  • Doxirubicin
  • Moderate
  • Carboplatin
  • Procarbazine
  • Etoposide
  • Low
  • Bleomycin
  • Vincristine
  • Methotrexate with leucovorin

82
Immunosuppressive Drugs
83
Immunosuppressive drugs
  • These drugs are designed to help the immune
    system in response to a foreign antigen.
  • This could be to decrease cytokine production,
    disrupt cell metabolism, preventing lymphocyte
    proliferation, or effect both mono- and
    polyclonal T-cell surface molecules

84
Selective Cytokine Inhibitors
  • CYCLOSPORIN
  • SIROLIMUS
  • TACROLIMUS (FK506)
  • Remember cytokines are soluble non-specific
    proteins that bind to certain cell receptors

85
Cyclosporin
  • The drug is extracted from a soil fungus
  • CsA is used to prevent rejection of KIDNEY, HEART
    LIVER TRANSPLANTS
  • It depresses the effect of T-CELL by decreases
    the stimulus of IL-2
  • Metabolized in intestine by P450 CYP3A4
  • It can be Nephrotoxic

86
Tacrolimus
  • Is a Macrolide that is derived from soil fungus
  • Has found favor over CsA, in Transplants and can
    be given with glucocorticoids
  • Metabolized in Liver by P450 Isoenzymes
  • Also there may be difficulty with Black and
    Hispanic populations with this agent

87
Sirolimus
  • Much like Tacrolimis
  • High Fat diet decreases effect of this agent
  • Side effect is hyperlididemia

88
Imuno-suppressive Antimetabolytes
89
Aziothioprine
  • Used in Bone Marrow Suppression
  • Has been the corner stone during the last several
    decades
  • Converted to 6-mercaptopurine (6-MP)
  • Lymphocytes are primarily effected

90
Adrenocorticoids
  • The glucocorticoids that were first pharm agents
    were used in transplantation and autoimmunine
    disorders
  • Methylprednisone
  • Prednisone
  • Prednisilone
  • They are also used in in Systemic Lupus,
    Rheumatoid Arthritis and Asthma

91
Anti-inflammatory Drugs
92
Anti inflammatory Drugs
  • NSAIDS
  • ASPIRIN, SULINDIC, TOLMENTIN, IBUPROPHEN
  • PHENYLBUTAZONE , INDOMETHACIN, PIROXICAM,
    FENAMATES
  • NON-NARCOTIC ANALGESICS
  • ACETOMENIPHEN, PHENACETIN
  • DRUGS FOR ARTHRITIS
  • GOLD SALTS, CHLOROQUINE, D-PENICILLAMINE,
    METHOTREXATE
  • DRUGS FOR GOUT
  • COLCICHINE, ALLUPURINOL, PROBENICID,
    SULFINPYRAZONE

93
PROSTAGLANDINS
  • Biosynthesis of prostaglandins comes from
    Arachidonic acid by the action of phospholipase
    A2.
  • Unlike leukotrienes, which come from the HPETE
    pathway.
  • Actions include inhibition of adenyl cyclase, but
    in some tissue it does not involve cAMP.
  • PGF2a, leukotrienes and thromboxane A2 (TXA2)
    mediate certain actions that cause the increase
    in intracellular Ca
  • PROSTAGLANDINS VIA THE CYCLOOXEGENASE PATHWAY IS
    INHIBITED BY NSAID
  • ANTI-INFLAMMATORIES

94
NSAIDS-Aspirin
  • Aspirin is the prototype, yet 15 of people show
    an intolerance to aspirin
  • Aspirin is IRREVERSIBLE cyclooxygenase inhibitor.
    Therefore other NSAIDS were developed.
  • Aspirin is rapidly deacetylated by
    esterases,producing salicylate, therefore a zero
    order anti-inflammatory, anti-pyretic, and
    analgesic effects
  • Aspirin inhibits prostaglandins by via inhibiting
    cyclooxygenase therefore modulating inflammation
  • Analgesic action is thought to be Prostaglandin
    E2
  • The antipyretic influence works on PGE2 as well
  • Aspirin does cause a decrease gastric mucosal
    secretion, which in turn can exacerbate ulcers
  • Misoprostol is used in the treatment of aspirin
    induced ulcer
  • Note-Acetomeniphen has a low anti-inflammatory
    activity

95
Aspirin continued
  • Thromboxane A2 enhances platelet aggregation
  • Aspirin can irreversibility (3-7 days) inhibit
    thromboxane production
  • Resulting in platelet inhibition
  • Other NSAID can cause interstitial nephritis,
    edema, and hyper-kalemia
  • Aspirin does not cause this

96
Phenacetin
  • Phenacetin, introduced in 1887, is used
    principally as an analgesic. Typical doses of
    300mg to 500mg a day result in an analgesic
    effect. Its analgesic effects are due to its
    actions on the sensory tracts of the spinal cord.
    In addition, phenacetin has a depressant action
    of the heart, where it acts as a negative
    inotrope. It also is an antipyretic, acting on
    the brain to decrease the temperature set point.
    It is also used to treat rheumatoid arthritis
    (subacute type), intercostal neuralgia, and some
    forms of ataxia.
  • Phenacetin, and products containing phenacetin
    have been shown in an animal model to be
    carcinogenic.

97
Other Salicylates
  • Salicylic Acid- treats corns, calluses,
    epidermaphytes
  • Salicylamide- analgesic and sedative, but not
    reliable
  • Methyl Salicyates- (Oil of Wintergreen),- as a
    cutaneous counter-irritant for ligaments
  • Difluisinal- 3-4 X as potent as aspirin, but does
    not have anti-pyretic properties
  • Low dose aspirin is useful to decrease unstable
    angina in human-due to less TIA

98
Phenylbutazone
  • Has a powerful analgesic effect
  • Used for acute gout and acute rheumatoid
    arthritis when other therapies o not work
  • Absorbed completely via oral or rectal
    administration
  • Poorly tolerated-skin rashes, vomiting,
    epigastric discomfort
  • Other side effects are Vertigo, insomnia, blurred
    vision, and hematuria
  • Reduces uptake of IODINE therefore may enhance
    development of GOITER, and MYXEDEMA
  • Also agranulocytosis and aplastic anemia

99
Indomethacin
  • Antipyretic, analgesic, anti-inflammatory
    properties
  • Works better than aspirin in ankylosing
    spondilytis, osteoartritis, and acute gouty
    arthritis, postoperative opthalamic surgery, and
    antipyretic for Hodgkins Lymphomas
  • Side effects-ACUTE PANCREATITIS, hepatic failure,
    vertigo, light-headedness, and mental confusion
  • Rarely aplastic anemia, thrombocytopenia,
    neutropenia

100
Sundinlac
  • Inactive prodrug closely related to indomethacin
  • It itself had little pharmacologic activity,
    metabolism by hepatic microsomal enzymes produce
    active form of the drug.
  • Used in rheumatoid arthritis, ankalosing
    spondylitis, osteoarthritis, and acute gout

101
Ibuprofen
  • Along with naproxen and ketoprofen, has
    anti-inlammatory properties, analgesic, and
    antipyretic activities,
  • Same anti-inflammatory as aspirin
  • SE-some hypersentivity reactions and GI
    disturbances, yet they are usually better
    tolerated than aspirin

102
Piroxicam
  • Used to treat rheumatoid arthritis
  • GI disturbances in 20
  • Long ½ life like Indomethacin and Sundelic

103
Non Narcotic Analgesic
104
Acetaminophen
  • Tylenol acts by inhibiting prostaglandin
    synthesis in the CNS. This is why it still has
    analgesic and antipyretic properties but weak
    anti-inflammatory properties
  • It does not effect platelet function therefore it
    dot not increase clotting times.
  • It lacks many of the side effect of aspirin.

105
Acetaminophen continued
  • Under normal condition acetaminophen is
    conjugated in the liver to form an inactive
    glucuronylated or sulfated metabolite
  • Toxicity occurs at high doses when the
    glutathione in the liver gets depleted by the
    sulfahydryl group of hepatic proteins, forming
    covalent bonds. This hepatic necrosis is a very
    serious and potentially life threatening
    condition. Renal tubular necrosis can also occur.
    This is life threatening and can occur with doses
    greater than 10 grams.
  • Mucomyst (Acetlycystiene) is given orally to
    competatively bind the sulfa metabolites and
    hopefully stop potential necrosis

106
Slow acting-anti inflammatory agents
107
Gold Salts
  • Gold Sodium Thiomalate, Auriothioglucose,
    Auranofin
  • It is believed that they are taken up by
    macrophages and suppress phagocytic and lysosomal
    action, retarding bone articular destruction
  • Major use is in Rheumatoid Arthritis that does
    not respond to salicylates
  • They are effective primarily in rapidly
    progressive disease states
  • Auranofin is the only one given orally-otherwise
    IM
  • SE-dermititis, and oral membrane breakdown.
    Possible proteinuria, and rare agranulocytosis
    and aplastic anemia

108
Chloriquine and Hydroxychoriquine
  • These are also used in Malaria. The
    anti-inflammatory effects are unclear, but have
    been used in rheumatoid arthritis and may slow
    progression of erosive bone lesions and induce
    remission

109
D-penicillimine
  • Is an analog of the amino acid cystiene.
  • It slows the progress of destruction of bone in
    rheumatoid arthritis
  • IT IS USED AFTER SALICYLATES AND GOLD SALTS, BUT
    BEFORE CORTICOSTEROIDS
  • Penicillimine is also used as a chelating agent
    for heavy metals

110
METHOTREXATE
  • Methotrexate was recently approved by the FDA for
    treatment of patient with severe rheumatoid
    arthritis
  • Response is lightly faster than other slow acting
    agents (3-6) weeks
  • SE of Methotrexate for Arthritis is suppression
    of the White Cell Count, Some liver cirrhosis,
    and a pneumonia like syndrome

111
DRUGS for GOUT
112
Gout
  • Gout is characterized by a high level of uric
    acid in the blood
  • Hyper-uricemia results as deposition of crystals
    affects the Joints and kidneys.
  • Hyper-uricemia does not always lead to Gout
  • Sodium Urate is the result of purine metabolism
  • Decrease in pH increases Urate deposition
  • The urate deposition kindles inflammation by
    increasing lactate in the synovial fluid of the
    joint

113
Treating Acute Gout
  • The cause is hyper-uricemia , which is and
    overproduction to the patients ability to excrete
    it
  • This can be cause from a number of conditions
  • Excessive alcohol consumptions
  • A diet rich in purines
  • Kidney disease
  • TREATED WITH COLCICHINE

114
Treating Chronic Gout
  • Genenitically Related
  • Lesch-Nyhan Syndrome
  • Excessive synthesis of Uric Acid
  • Treated with Uricocursic drugs, or Allopurinol

115
Colchicine (Acute)
  • Plant Alkaloid, suppressive effect is that it
    helps in the incidence of gouty attacks
  • Colchicine does not prevent progression, but is
    suppressive to number of acute attacks.
  • Inhibits leukotrienes, Lipoxygenase pathway
  • Binds to Microtubules and inhibits cell function,
    therefore mobility of granulocytes
  • Administered orally or via IV
  • SE-Myopathy, Nausea, Vomiting, agranulocytosis,
    aplastic anemia, alopecia

116
Allopurinol (Chronic)
  • Allopurinol is a purine analog
  • Inhibit the production by inhibiting Xanthine
    Oxidase-making purines less likely to precipitate
  • Effective in hyper-uricemic primary gout
  • Short ½ life
  • Orally administered
  • SE Most common is Hypersensitivity Reaction
  • If needed more frequently, give Colcichine and
    NSAIDs as well
  • May Interfered with 6-mercaptopurine

117
Probenicid
  • General inhibitor of tubular secretion of organic
    acids
  • Blocks proximal tubular re-absorbtion of Uric Acid

118
AUTOCOIDS AND AUTOCOID ANTAGONISTS
119
Prostaglandins
  • Dinoprost
  • Dinoprostone
  • Carboprost
  • Misoprostol

120
Prostaglandins
  • Dinoprost, Dinoprostone, Carboprost
  • Acts directly on myometrium to induce
    contractions and labor
  • Administration is by intra-amnionic or
    intra-vaginal instillation from the 12th week
    through the second trimester of pregnancy
  • ABORTIFACIENTS

121
Prostaglandins
  • MISOPROSTOL
  • Inhibits secretion of HCL and Pepsin and enhances
    mucosal resistance
  • Useful in patients with gastric ulcer who
    chronically take aspirin

122
Angiotensin Antagonist
  • Captopril
  • Enalapril
  • Lisinopril
  • Saralasin

123
Angiotensins
  • Angiotensins area a group of peptides that are
    best know for there vaso-constrictor activity,
    increasing B/P
  • Baroreptors in the kidney, or do the reduction of
    Sodium in the distal tubule, release the enzyme
    renin
  • Angiotensin I is converted to Angiotesin II in
    the lungs by ACE
  • Angiotensin stimulates the synthesis and
    secretion of aldosterone in Zona Glomerulosa

124
ACE inhibitors
  • Captopril, Enalapril, Lisinopril, inhibit the
    action of ACE, decreases the conversion of
    inactive Angiotensin I to the potent
  • Angiotensin II.(VASO-CONSTRICTOR)
  • The drugs also diminishes the rate of Bradykinin
    inactivation. Bradykinin has a (VASO-DILATORY)
    effect---increasing circulation of Bradykinin
  • Therefore lowering peripheral vascular resistance

125
Captopril
  • Therapeutic uses
  • Mild to moderate hypertension
  • Refractory Hypertension
  • Congestive Heart failure-beyond the use of
    digitalis
  • Administered Orally
  • Well absorbed, but reduced by food, some hepatic
    metabolism
  • Adverse Effects/Dizziness, light-headedness
  • Rashes, fever, arthralgia, joint-pain,
    leukopenia, proteinuria

126
Enalapril
  • 10-20 times more potent than Captopril
  • Longer duration
  • Not as much Bradykinin effect
  • Increases survival in patients with congestive
    heart failure

127
Lisinopril
  • Extremely long half life
  • Less adverse effects than Captopril

128
SARALASIN
  • ANGIOTENSIN RECEPTOR BLOCKER
  • (ARB)
  • Used as an AID in the diagnosis of ANGIOTENSIN
    II-dependent hypertension

129
KININS/BRADYKININS
  • Known to be potent vasodilators
  • Kinins can cause increased capillary permeabilty
  • Kinins can be potent-pain inducing agents

130
Serotonins
  • An autocoids (5-HT), 90 which comes from the
    entero-chromaffin cell in the gastro-intestinal
    tract. Most remaining serotonin in the platelet
    of the central nervous system. Primarily the
    Hypothalamus, and Basal Ganglia

131
Serotonins
  • Serotonin acts as a neurotransmitter
  • Pain perception and abnormal disorders
  • Affective disorders (food intake, sleep, temp)
  • Participate in regulations of pituitary secretion
  • It stimulates the release of (ACTH)
  • Inhibits (LH),(FSH),(TSH)
  • Serotonin appears to be involved in pain
    sensitivity, and vessel permeability of Migraine
    headaches

132
Drugs that effect Serotonins
  • Tryptophan
  • Increases serotonin synthesis
  • Tricyclic Antidepressent
  • Inhibits receptor mediated uptake
  • MAO inhibitors
  • Inhibits Serotonin Degradation
  • Reserpine, Tetrabenzine
  • Depletes stores of Seretonin in neurons
  • Cyproheptadine
  • H-1 blocker in Carcinoid Tumors that synthesize
    excessive quantities of Seretonin

133
ERGOT ALKALOIDS
  • A complex group of compounds that can be used in
    various substance
  • ErgotamineMigraines, diminishing pulsation
  • Bromocriptinereduces circulating prolactin in
    pituitary tumors
  • Have been used in Post-Partum hemorrhage
  • Gastric absorption is variable- caffeine
    increases
  • Adverse effects- Cause hallucinations at high
    doses

134
Histamine H1 Receptor
  • Antihistamine
  • Antagonizes the actions of all histamine in the
    H1 class
  • Dyphenhydramine, clemestine fumerate,
    promethazine
  • CHOLINERGIC RECEPTORS
  • Promethazine
  • ADRENERGIC RECEPTOR

135
Histimine H1 Receptor
  • Adverse effects
  • Sedation
  • Dry Mouth
  • Drug Interaction with MAO
  • Overdoses in young Children

136
Motion Sickness
  • Scopolamine
  • Meclizine
  • Anti-histamine prevent prevents vestibular
    pathways
  • Anti-emetic effects are independent of
    anti-histamine effects

137
H2 Receptor Blockers
  • Cimetidine
  • Reduces ulcers
  • Duodenal Ulcers
  • Hypersecretion associated with multiple endocrine
    disorders, Zollinger-Ellison syndrome, systemic
    mastocytosis
  • SE- Headache
  • Reduced Sperm count

138
H2 Receptor Blockers
  • Rantidine-
  • 5-10 times as potent
  • Famotidine
  • 20-160 times as potent
  • Nizatidine
  • Little first pass metabolism-so great
    bio-avalability

139
Viagra-----Sildenafil Erectile Dysfunction
  • The molecular mechanisms of the effects of
    Sildenafil, a specific inhibitor of cyclic
    guanosine monophosphate (cGMP) phosphodiesterases
    are briefly reviewed. The second messenger cGMP
    as well as its molecular targets (with the
    exception of the photoreceptor signal
    transduction machinery) have long played an
    underdog role compared with cyclic adenosine
    monophosphate and other signalling molecules such
    as inositoltrisphosphate.
  • The same holds for guanylyl cyclase, which,
    albeit being the main effector molecule of the
    gaseous neurotransmitters carbon monoxide and
    nitric oxide (NO), has received much less
    attention relative to its activators and their
    synthases. Stimulation of the arginine --gt NO --gt
    cGMP pathway by bypassing NO-synthase is a
    well-established pharmacological principle in the
    treatment of cardiovascular disorders.

140
Viagra alternative
  • In addition, promising results have been shown in
    patients with treated prostate cancer, end-stage
    renal disease, Parkinson's disease and spina
    bifida and in multiple-organ transplant
    recipients. Postmarketing data of the use of
    sildenafil in clinical practice confirm the
    efficacy and safety found in clinical trials and
    high satisfaction with treatment

141
Anti-platelet drugs
142
Abcixmab anti-platelet
  • Binds to glycoprotein IIb/IIIa surface of
    platelet
  • Adverse situation mostly bleeding scenario
  • Thrombocytopenia, bleeding times
  • Use-percutaneous coronary interventio
  • To be used with Aspirin/Heparin

143
Abacavir Sulfate ANTIINFECT/ANTIVIRAL
  • Inhibits HIV transcriptase DNA synthesis
  • Side effects with ethanol-tell mother not to
    breast feed (class C)

144
Cholinergic Agonist
145
Bethanachol Cholinergic stimulator
  • Carbamic Esther hydrolyzed by AchE
  • Directly stimulates M 1 receptor (Gq3),
    particularly in atonic bladder of
    post-partum/post-op urinary retention
  • Treatment of esophageal reflux
  • Side effects-hyperthyroid, asthma, bradycardia

146
Pilocarpine opth/antiglaucoma
  • Muscarinic activity producing rapid miosis
  • In chronic simple glaucoma
  • Opposes effect of Atropine a muscarinic blocker
  • Pilocarpine is effective at meshwork around
    Schlemms canal
  • Contraindicated in narrow angle glaucoma, and
    asthmatics may have increased secretions
  • Note-Epi/acetazolamide/timolol also used for
    glaucoma

147
Physiostigmine revers/antAche
  • Stimulates both M receptors and Nicotinic
    receptors
  • Can be used in atonic bladder, lowering
    intraocular pressure- pilocarpine more effective
  • Can be used for overdoses of Atropine,
    phenothiazines, TCAs
  • Physio inhibits AchE, may lead to full paralysis
    due to build up of acetylcholinepossible
    convulsion

148
Endophonium
  • Used in the DIAGNOSIS of Myasthenia Gravis
  • Greatly increases muscle strength when given IV
  • Shorter Duration of action (10-20 minutes)

149
Neostigmine
revers/antAche
  • Inhibit AchE,
  • It is used to reverse Tubocurare and other
    competitive neuromuscular agents
  • Side effect-Increased Salivation, dec B/P,
    nausea, abdominal pain, diarrhea and bronchospasm
  • May be used in TREATMENT of Myasthenia Gravis
  • 2-4 hr duration

150
Isoflurophate irrever/Anticholinesterase
  • Long term treatment of glaucoma
  • Rarely used-because covalent bond to AchE

151
Pralidoxime (PAM)
  • Reactivates inhibited AchE, it was designed to
    bind tenaciously with inhibit
  • Takes a while to work, used against nerve agent
    but must give Atropine first

152
Cholinergic Antagonists
  • Antimuscarinic

153
Atropine
  • Belladonna Alkaloid, high competitor for
    Muscarinic Receptors
  • Lasts about 4 hours/ t1/2 2 hour eliminated in
    urine
  • Uses
  • Gastrointestinal-reduces motility
  • Eye-myadriasis
  • Dries secretions
  • Urinary-reduces hymotility states of bladder
  • Cardio
  • Low doses lt.05mg slows heart
  • High Doses gt 5.0mg Rapid Heart.

154
Scopolamine
  • Belladonna alkaloid longer duration than Atropine
  • Often administered via Transdermal patch behind
    ear
  • Used for motion sickness, also used in
    anesthetic amnesia for childbirth-causes short
    term Memory Loss

155
  • Ganglionic Blockers

156
Trimethaphan
  • Competes directly with Acetylcholine-metabolized
    in lung
  • Used in Emergency lowering of B/P, especially in
    situation of acute Pulmonary Edema1-2 minute
    duration
  • NICOTINIC

157
Mecamylamine
  • Produces a long nicotinic block of ganglion
  • Oral absorption is good as compared with
    Trimethaphan
  • Treatment of severe and moderately severe
    hypertension

158
Non-Depolarizing
  • (Competitive) Blockers

159
Tubocurarine
  • Competitive Blocker-blocks nicotinic receptor,
    therefore preventing acetylcholine to bind to the
    NMJ
  • 20 minute to 2 hours-first eyes, face, then hands
  • Can cause skin wheals and bronchospasm, Histamine
    release
  • Reversed by Neostigmine
  • Streptomycin an aminoglycocide, enhances block
    via synergism of competing with calcium
  • Works well with Halothane
  • Mechanical Ventilation during childrens surgery

160
Pancuronium (pavulon)
  • X 5 potency of Tubocurarine
  • Does not cause the Histamine Release

161
Gallamine
  • Blocks cardiac vagus at the M-2 site (Gi) causing
    sinus tachycardia

162
Depolarizing Agents
163
Succinylcholine SUX
  • Phase II Depolarization and flaccid paralysis
  • Muscle fasciculation within minutes, broken down
    rapidly by plasma cholinesterases
  • So a sux drip may be needed if longer paralysis
    is desired
  • Used for Intubation
  • Can cause Malignant Hypertension

164
Adrenergic Agonist
  • Direct Acting

165
Alpha 1 adrenergic
  • Vasoconstriction, Increased Peripheral
    Resistance, Increased B/P, Closure of sphincter
    of bladder
  • POST-SYNAPTIC
  • Leads to a rise in cytosolic calcium ions as well
    as activation of calcium dependent protein
    kinases. In many cells also activates IP3, and DAG

166
Alpha 2 Adrenergic
  • Presynaptic
  • In contrast to A1, this mechanism has a feedback
    inhibition that inhibits further output from
    adrenergic stimuli and serves as a local
    modulation when there is high adrenergic stimuli
  • The binding at A2 are mediated by the inhibition
    of adenylate cyclase and a fall in intracellular
    cAMP
  • It therefore inhibits norepinephrine, a classic
    is Clonidine which is Alpha

167
Catacholamines
  • Epinephrine
  • Nor-epinephrine
  • Dopamine
  • Dobutamine-synthetic
  • Isoproterenol-synthetic
  • Rapid Onset, Brief duration, not oral, do not
    penetrate BBB

168
Nor epinephrine
  • Tyrosine?Dopa via tyrosine hydroxylase (rate
    limiting)?Dopamine via MAO? Nor epinephrine at
    vesicle----Carrier system is blocked by Reserpine
  • Release at NMJ (cAMP) 2nd Messenger and adrenals
    15
  • Action Potential on Ca
  • The uptake is inhibited by Cocaine and TCAs
  • Degraded by COMT and oxidized to monoamine
    oxidase
  • Alpha and Beta
  • Excreted as VMA, metnephrine, normetnephrine

169
Nor Epinephrine
  • Vaso Constriction (ALPHA) both SYSTOLOIC AND
    DIASTOLIC INCREASE
  • No tachycardia (except)
  • Atropine may enhance tachycardia

170
Epinephrine
  • 85 synthesized from Tyrosine at Adrenal Medulla
  • Low Doses Beta effects-High doses Alpha
  • Respiratory-Bronchodilator B2
  • Hyperglycemia-increased release of Glucagon (B2),
    and decreased release of insulin (Alpha)
  • Lipolysis (B1)-Triacylglycerol to free fatty acid
    glycerol
  • Cardiovasculature
  • Positive Inotrope B1, Contraction
  • Positive Chronotrope B1, Rate
  • Broken down similar to Nor epinephrine

171
Epinephrine (continued) uses
  • Bronchospasm-used in acute setting for acute
    anaphylactic shock, and bronchoconstriction
    (subQ)
  • Glaucoma-2 vasoconstriction of ciliary body
    blood vessels
  • Anesthesia-local to vasoconstrict allowing
    anesthetic to remain at site longer

172
Epinephrine (continued) adverse
  • CNS-anxiety, fear, tension, tremor
  • Hemorrhage-marked elevation in B/P
  • Cardiac arrhythmias, particularly of receiving
    Digitalis
  • Pulmonary Edema
  • Interactions
  • Hyperthyroid
  • Cocaine exacerbation-similar to anesthetics

173
ISOPROTERENOL
  • BETA 1 and BETA 2
  • Cardiac-Intense Rate and Force Increase
  • Bronchodilation Beta 2-recommend aerosol
  • Increases CO Decreases PVR

174
Dopamine
  • Stimulates Alpha and Beta as well as Dopaminergic
    receptor
  • High Doses stimulates Alpha?Vasoconstriction
  • IONTROPE
  • Low Doses-increases blood flow to Kidneys and
    other visceragreater output--diuresis
  • Ideal for Septic Shock with low Peripheral
    Resistance
  • Also useful in Refractory CHF
  • Adverse effectNausea, some arrhythmia

175
Dobutamine
  • Synthetic CatacholB1
  • Specific for Cardiogenic situations, CHF,
    Cardiogenic Shock
  • Does not increase O2 Consumption

176
Phenylephrine
  • Alpha 1 gt Alpha 2
  • For nasal mucosal membranes
  • Mydriasis of eyes
  • USED in SVT-Supraventricular Tachycardia

177
Methoxamine
  • Alpha 1 raises arteriolar vasoconstriction----ther
    efore increasing Total Peripheral Resist TPR
  • Used clinically for Paroxymal SVT
  • It also is used to overcome hypotensions
    associated with cyclopropane-or Halothane
  • SE-headache and vomiting

178
Clonidine
  • Is an Alpha 2 Agonist
  • Used in essential hypertension to Decrease B/P
  • It can be used to minimize Opiate and
    Benzodiazepine withdrawal

179
Metaproterenol-Alupent
  • Similar to Isuprel yet not a Catachol therefore
    is resistant to methylization by COMT
  • Primary is Beta 2- Bronchodilation
  • Treatment Asthma and reduce bronchospasm

180
Terbutaline
  • B2 Agonist
  • More selective than Metaproteronol
  • Bronchodilation
  • Reduces uterine contraction in premature labor

181
Ritodrine
  • Ritodrine is B2 selective
  • Used for Uterine contractions in premature labor

182
Albuterol
  • B2 Selective Bronchodilator
  • Aerosolized
  • 2 puff Q6

183
Indirect-acting Adrenergic Agonist
184
Amphetamine
  • MethylphenidateRitalin
  • Aderall
  • CNS stimulant in the treatment of children with
    attention deficit

185
Ephedrine
  • Nasal Decongestant
  • Cardio-Increases Systolic and Diastolic Pressure
  • Muscles-Has been shown to help some in Myasthenia
    Gravis
  • CNS-Alertness

186
Metaraminol
  • Has been shown to work IN SHOCK when other drugs
    were not available

187
Adrenergic Antagonists
  • Alpha Blockers

188
Phenoxybenzamine
  • Related to Nitrogen Mustard in that is
    irreversibly and non-competitively blocks Alpha
    1, and Alpha 2
  • Last 24 hours, yet few hours delayed onset
  • Prevents Vasoconstriction of Peripheral Vessels
  • Benign Prostatic Hypertrophy (BPH), reduces
    prostate size
  • Used in Pheochomocytoma-induced hypertension
  • EPINEPHERINE REVERSAL
  • Side Effect-postural hypertension

189
Phentolamine
  • Used in the diagnosis of Pheochromocytoma and
    other clinical settings where there is a release
    of catacholamines
  • Frostbiteobject is increase blood flow in the
    digits
  • TYRAMINE INDUCED HYPERTENSION
  • Adverse effects-postural hypotension
  • Reflex tachycardia
  • Anginal Pain
  • GI-peptic ulcers

190
Prazosin and Terazosin
  • Decreases PVR by relaxing arterial and venous
    smooth muscle
  • TYRAMINE INDUCED HYPERTENSION
  • Syncope is noted on First Pass of Prazosin, so
    adjustment of 1/3 to ¼ load when hypo-tensive
    response is expected to be exaggerated

191
BETA BLOCKERS
192
Propanolol
  • Diminishes CO, negative ionotrope and
    chronotropic effect
  • O2 Consumption also diminished
  • Bronchoconstriction-blocker B2
  • Increased Na retention and plasma volume
  • Hypoglycemia-due to decreased Glucogon secretion,
    and glycogenolysis because B-blockade
  • Blocks B2 Bronchodilators

193
Propanalol (cont) Therapeutics
  • Hypertension
  • Glaucoma-decreased secretion of aqueous humor by
    ciliary bodies
  • Migraine-blocks catocholamine induced
    vasodilation
  • Hyperthyroid- blunts sympathetic stimulation
  • Angina Pectoris-reduces O2 requirements
  • MI- reduces catachol from tissues and O2
    requirements
  • Adverse effects-Bronchoconstriction-arrhythmia-sex
    ual impairment-hypoglycemia-TRIACYLGLYCEROL
    INCREASED

194
Timolol
  • Reduces Aqueous Humor in chronic and some 2ndary
    GLAUCOMA (acute is Pilocarpine)
  • Cardiac effects same as Inderal
  • SE-Same as Propanolol except more exaggerated

195
Esmolol
  • Short term(1/2 life short) management of SVT
  • Also used with Thyroid Storm
  • Attenuated Cardiovascular assoc with ECT and
    anesthesia
  • Infusion well documented up to 48hrs
  • SE-Typical Beta Blocker-
  • DO NOT USE In Sinus Bradycardia, and 2nd or 3rd
    Heart Block

196
Acebutolol, Atenolol, Metoprolol
  • Primary B1gtB2 (none less monitor lungs)
  • Considered beta 1
  • Effective in lowering blood pressure and
    increasing exercise tolerance in Angina
  • THEY ARE MORE SELECTIVE, so they are useful in
    diabetic patients receiving insulin or
    hypoglycemics

197
Pindolol and Acetbutolol
  • They are NOT TRUE Blockers-They are Partial
    Agonist
  • ISA-intrinsic sypathomimetic activity
  • Very Useful in Diabetics

198
Nadolol
  • Beta blocker with very long ½ life, mostly angina
    situations
  • Con
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