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2012-03-23 02:06:57
pharm final

pharm final signal transduction
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  1. DRUGS ACTING ON nicotinic type I receptors = autonomic ganglia
    • agonists = ACh and nicotine
    • (enhance Na conductance)

    antagonists (ganglionic blocking drugs) = trimethaphan, hexamethonium

    nicotinic type II receptors = skeletal muscle
    motor endplate
    • agonists = ACh, nicotine, succinylcholine =
    • enhance Na conductance

    antagonists = d-tubocurarine (d-tc), pancuronium, Mg++ = the -curiums and -roniums
  3. DRUGS ACTING ON sodium channels of cardiac fast fibers = atria, ventricles
    class IA drugs = procainamide, quinidine

    class IB drugs = lidocaine - only affects ventricles

    class III drugs = amiodarone, dronedarone
    • the antiepileptic drugs
    • phenytoin,
    • carbamazepine,
    • valproate
    • lamotrigine

    inhibit the spread of electrical signals by prolonging the state of inactivation of the sodium channel

  5. Na+ channels in sensory nerve fibers = the cationic form of local anesthetic drugs

    the antiepileptic drugs phenytoin, carbamazepine,
    valproate & lamotrigine inhibit the spread of electrical signals by prolonging the
    state of inactivation of the sodium channel
    • cocaine,
    • procaine,
    • lidocaine

    • blocks Na+ conductance by binding to a site
    • in the channel on the axoplasmic side (inside cell)
  6. Sodium channels coupled to 5-HT3 receptors in CTZ = induce nausea/emesis, blocked by
  7. Ca++ channel blockers
    • nifedipine, diltiazem & verapamil = block
    • L-type channels in heart and vascular smooth muscle (VSM)
  8. Ca++ channels in SM of GI tract blocked by
    Al, Fe, diltiazem and verapamil
  9. Ca++
    channels in SM of uterus blocked by
  10. T-type Ca++ channels in CNS blocked
  11. Glutamate stimulation of NMDA receptors coupled
    to Ca++ channels BLOCKED BY
    • Ketamine and phencyclidine (“angel dust”) block
    • NMDA receptors and prevent the

    • excitatory effects of glutamate to cause “dissociative” anesthesia and hallucinations. Felbamate prevents seizures by blocking NMDA
    • receptors.
  12. Opiate receptors (m, k and d) are coupled via
    G-proteins to voltage-gated CA++ channels. Stimulation CAUSES ...
    • suppresses Ca++ entry and thus
    • decrease NT release.
  13. Internal Ca++ channels of SR blocked by
    • dantrolene which prevents the release of “trigger”
    • Ca++ = DOC for tx of neuroleptic
    • malignant syndrome and anesthesia-induced
    • malignant hyperthermia (hyperpyrexia);
  14. WHAT DRUG prevents spasticity caused by neuro diseases, but causes generalized muscle weakness bx it
    relaxes all skeletal muscle, not just the spastic muscle.
  15. Muscarinic receptors at the SA node - coupled to
    a K-channel via a G-protein agonists
    • ACh,
    • pilocarpine,
    • AChase inhibitors (indirect through increased ACh)

    • antagonists =
    • atropine et al.,
    • pancuronium,
    • quinidine,
    • TCA’s,
    • older antihistamines like diphenhydramine
  16. K-COUPLED 5-HT1A-receptors in the CNS
    buspirone is a partial agonist = antianxiety
  17. K AGONISTS ON Vascular smooth muscle - arterial vasodilators
    hydralazine, minoxidil, diazoxide)

    • activate
    • ATP-modulated K-channels = hyperpolarization = relaxation = vasodilation
  18. K-COUPLED Fast cardiac fibers - antiarrhythmic drugs
    • Class IA =
    • procainamide
    • quinidine

    • slow K+ conductance and thus prolong repolarization
    • (APD & ERP increased); only quinidine actually widens the QRS and ­ the Q-T interval

    • Class IB =
    • lidocaine accelerates repolarization (APD decreased)

    • Amiodarone and sotalol
    • – delay ventricular repolarization via block of K+ channels; APD, ERP and Q-T interval increase. The prolongation of repolarization can cause torsades de pointes = polymorphic ventricular tachycardia

    • Adenosine
    • --opens potassium channels in the AV node to hyperpolarize and stop all AV conduction
  19. K-COUPLED pancreatic b-islet cells
    • tolbutamide,
    • chlorpropamide,
    • glypizide,
    • repaglinide, etc

    • close K+-channels causing the cell to depolarize; depolarization opens voltage-sensitive
    • Ca++ channels; Ca++ flows in to activate PLC which
    • increases IP3 which release more Ca++ from the SR; increased free intracellular Ca++ causes insulin secretion

    • Diazoxide
    • --opens ATP-regulated K+-channels to prevent depolarization and thus inhibit insulin secretion. Used to decreases insulin release from insulinomas.

    • Thiazides and furosemide
    • --also inhibit insulin secretion, but the MOA is unknown
  20. GABAB-receptors coupled to K+-channels
    in the CNS
    • agonist = baclofen
    • --enhances GABA-mediated K+ conductance to hyperpolarize presynaptic Ia fiber terminals and thus reduce the release of the excitatory NT glutamate onto
    • a-motor neurons.

    • Baclofen used to tx spasticity ass w cerebral palsy, multiple sclerosis and stroke. Baclofen is as effective as
    • BZ’s, but causes less sedation.

    Baclofen also causes less of a decrease in muscle strength than does dantrolene.
  21. Stimulation of pre- or postsynaptic a2-adrenoceptors enhances K+ conductance
    to hyperpolarize cells in the CNS
    • - in the medulla
    • --clonidine hyperpolarizes to inhibit peripheral sympathetic outflow

    • - in the spinal cord
    • --tizanidine stimulates presynaptic a2-adrenoceptors on Ia fiber terminals to prevent the release of glutamate
    • onto a-motor neurons.

    Tizanidine also hyperpolarizes a-motor neurons via stimulation of a2-adrenoceptors.

    These two actions decrease spasticity.
  22. Opiate receptors (m, k and d) are coupled via G-proteins to K+ channels. STIM CAUSES ...
  23. D2-receptors in the anterior
    • dopamine,
    • bromocriptine
    • pergolide

    • hyperpolarize cells to prevent prolactin release
    • (NB: in other parts of the brain DA inhibits adenyl cyclase or calcium conductance)
  24. Effect of GABA enhanced by
    • ethanol,
    • propofol,
    • volatile anesthetic agents,
    • BZ’s

    (increased frequency of channel opening) and barbiturates (increased duration of channel opening)

    • Valproate increases [GABA] by increasing glutamic acid dehydrogenase and inhibiting
    • GABA transaminase

    Gabapentin releases GABA from its neurons.
  25. STIM OF GABAA-receptors
  26. Glycine receptors on Renshaw cells (spinal

    inhibits a-motor neurons; strychnine blocks glycine receptors in the spinal cord = no a-motor neuron inhibition = convulsions
  27. BETA 1&2
    • Cyclic AMP (CAMP) - receptors coupled to adenyl
    • cyclase via a G-protein

    • b1-adrenoceptors
    • --heart =­ INC heart rate, contractility & impulse
    • conduction; DEC APD and ERP adipocyte = lipolysis = increased plasma free fatty acids
    • --renal JG cells = increased renin release

    • b2-adrenoceptors
    • --lungs = (bronchial SM) = relaxation = bronchodilation = increased FEV1
    • --vascular smooth muscle = relaxation = vasodilation of arteries and veins
    • --uterus = relaxation (inhibition of parturition)
    • --liver = glycogenolysis via protein kinase activation of phosphorylase a
    • --mast cell = decreased free intracellular calcium inhibits degranulation
    • Cyclic AMP (CAMP) - receptors coupled to adenyl
    • cyclase via a G-protein

    • vasodilation in the kidney, blocked by D1-,
    • D2-receptor blockers like haloperidol
  29. H2-histamine receptors
    • Cyclic AMP (CAMP) - receptors coupled to adenyl
    • cyclase via a G-protein

    • --relaxation of VSM (direct and through NO) causes
    • vasodilation
    • --increased gastric acid secretion from oxynitic cells
  30. PGI2 (prostacyclin) and PGE receptors
    Cyclic AMP (CAMP) - receptors coupled to adenylcyclase via a G-protein

    • --relaxation of vascular smooth muscle =
    • vasodilation
    • --decreased platelet aggregation
  31. V2-AVP receptors (renal collecting
    duct) = AVP (ADH)
    increases water reabsorption

    • This cyclase inhibited by:
    • PGE’s,
    • atrial natriuretic factor,
    • lithium and
    • demeclocycline

    • Antidiuretic effect of AVP potentiated by: chlopropramide
    • carbamazepine.
  32. m, k and d opiate receptors ACTION ON ADENYL CYCLASE
    ACTH, FSH, LH, glucagon, PTH
  34. phosphodiesterase inhibitors
    • theophylline, aminophylline
    • = bronchodilation = tx of neonatal apnea

    • papaverine
    • = relaxation of s.m. in the corpus cavernosa = penile erection

    • dipyridamole
    • = decreased platelet aggregation when used with aspirin

    amrinone and milrinone = increased cardiac dp/dt (tx of terminal CHF)
  35. Signal transduction via cyclic GMP (CGMP)
    THINK antianginal drugs!

    • Nitric oxide (NO)
    • --produced tonically by the vascular endothelial cells.

    nitrate vasodilators (nitroglycerin) and Na nitroprusside are converted to NO which activates guanyl cyclase: CGMP relaxes arterial/venous VSM (a kinase dephosphorylates the MLC’s) and inhibits platelet aggregation.

    Atrial natriuretic factor (ANF) also dec BP by activation of guanyl cyclase and ­ [CGMP].

    Sildenafil causes erection by inhibiting the type V PDEase which degrades CGMP.
    • releases Ca++ from the SR; Ca++
    • binds to calmodulin which then

    • activates enzymes (E’s) = smooth muscle
    • contraction or increased secretion

    • 1. muscarinic receptors = sphincter muscle of iris, SM of bronchioles, bronchial glands, SM of GI tract and gall bladder, detrusor muscle of urinary bladder, pancreatic
    • acini and a-islet cells (glucagon); salivary glands, lacrimal glands, nasopharyngeal glands

    • 2. a1-adrenoceptors = radial
    • muscle of eye, vascular SM, internal sphincter (trigone)
    • of the GU tract, SM of urethra/prostate, pilomotor muscles, salivary glands

    3. Ang II receptors -=VSM

    4. TXA2 receptors = VSM

    5. V1-AVP receptors = VSM

    • 6. H1-histamine receptors = vascular
    • endothelial cells, SM of bronchioles and GI tract

    7. 5-HT2-receptors = VSM

    8. PGE receptors = SM of uterus and GI tract

    • 9. Li+ inhibits the recycling of PIP2
    • and thus interrupts the IP3 signaling pathway
  37. Cardiac glycosides= digoxin & digitoxin
    Depolarization allows Ca++ to move into the cell via L-type (voltage-sensitive) Ca++ channels.

    • Some of the Ca++ is pumped into the SR. Additional Ca++ is extruded by a Na+- Ca++ antiporter which uses the high outside/low inside Na+ gradient to move Ca++
    • out against its concentration gradient.

    • This outside/inside Na+- gradient is maintained
    • by the membrane Na+- K+ ATPase.

    Digoxin partially blocks the Na+- K+ ATPase; the outside/inside Na gradient is decreased; less Ca++ is extruded via Na+- Ca++ exchange;

    this excess Ca++ in the cell is stored in the SR; the next depolariaztion results in a greater release of Ca++ from the SR
  38. Gastric H+-K+ ATPase
    (proton pump) - inhibited by
  39. Na+: K+:2Cl-
    symporter in ascending limb of Henle’s loop is blocked by
    • furosemide
    • and
    • ethacrynic acid.
  40. Na+: Cl- symporter in
    renal DT - inhibited by
    thiazide diuretic drugs
  41. Na+ channels in principal cells of
    LDT/CD - blocked by
    amiloride and triamterene
  42. H+ ion secretion in renal PT and DT -DEC by
    acetazolamide bx it inhibits CA
  43. H+ ion secretion from LDT/CD - blocked by
    amiloride and triamterene
  44. Changes in DNA transcription
    • INC b-receptors &
    • mitochondrial E’s for oxidative phosphorylation (ATP)
  45. Changes in DNA transcription
    INC basolateral ATPase, Na+ channels and E’s for oxidative phosphorylation (ATP) in the LDT/CD;

    • increased deposition of fibrillar collagen in the
    • extracellular matrix of the heart
  46. Changes in DNA transcription
    • cortisone, hydrocortisone, prednisone, prednisolone,
    • etc.

    - increases gene transcription for lipocortin (inhibits PLA2), IKB (the inhibitor of nuclear factor kappa-B (NFKB) and enzymes (E's) for gluconeogenesis

    • - DEC transcription of genes for COX-2; IL-1 &
    • IL-6 in monocytes & macrophages; gene for NFKB, and E’s for glycogen storage (except glycogen synthetase)
  47. Changes in DNA transcription
    • block the ATP binding site of the IKK kinase.
    • This prevents the phosphorylation and subsequent dissociation of the inhibitory IKB from NFKB:

    this action prevents the increased expression of the genes which code for many inflammatory mediators.
  48. Changes in DNA transcription
    decreased transcription of genes for TNFb, IFNg, IL-2 & IL-2 receptors in helper T-cells
  49. Changes in DNA transcription
    • increased erythropoesis and hepatic synthesis of
    • C1-esterase inhibitor of complement.

    Tx hereditary angioedema (peripheral edema, abdominal pain and potentially fatal laryngeal edema) with an androgen (e.g., stanozolol)
  50. Changes in DNA transcription
    increased hepatic protein synthesis = transcortin (CBG), thyroxine- binding globulin (TBG), angiotensinogen (renin substrate), transferrin, fibrinogen and clotting factors 2, 7, 9 and 10.
  51. Changes in DNA transcription
    Paclitaxel & docetaxel
    • cause the phosphorylation of the antiapoptosis
    • gene Bcl-2.

    Phosphorylation turns the gene off and allows normal programmed cell death.
  52. Changes in DNA transcription
    The Philadelphia chromosome
    • contains a translocation which codes for the
    • fusion

    • protein
    • Bcr-Abl, a tyrosine kinase which is essential for the proliferation and

    • survival
    • of the abnormal leukocytes causing chronic myelogenous leukemia.

    • Imatinib
    • blocks the binding of ATP site of the tyrosine kinase. Inhibition of this

    • tyrosine
    • kinase inhibits cell proliferation and causes cell death through apoptosis.
  53. Changes in DNA transcription
    Proteasome 26S
    causes proteolysis of the IKB inhibitor of NFKB. NFKB then

    • upregulates
    • DNA transcription and cell survival and inhibits apoptosis. Bortezomib

    • inibits
    • the 26S proteasome, so NFKB is not released. The end result is

    • enhancement
    • of apoptosis and the death of multiple myeloma cells.
  54. Changes in DNA transcription
    • blocks the epidermal growth factor receptor
    • (EGFR) coded by the

    • HER2/neu
    • (ErbB-2) gene in breast cancers (about 30% of cancers are HER2/neu

  55. Changes in DNA transcription
    • 60-75% of colorectal cancers express the
    • epidermal growth factor receptor HER1

    • (ErbB1)
    • which mediates cell proliferation, survival and angiogenesis. Cetuximab

    • blocks
    • the HER1 EGFR.
  56. Plasma pseudocholinesterase deficiency
    the NEURO MUSC BLOCK caused by succinylcholine last

    • hours
    • instead of minutes.
    • produce excitation and anxiety instead
    • of sedation in older patients.
  58. Idiosyncratic drug reactions
    older antihistamines
    • (e.g. diphenhydramine) cause excitation
    • instead of sedation

    • in
    • very young children and older patients.
  59. Idiosyncratic drug reactions
    Aspirin and other NSAID's
    • precipitate an anaphylactic-like
    • reactions (a.k.a. aspirin

    • hypersensitivity)
    • in patients with nasal polyps. Blockade
    • of PG synthesis by the

    • NSAID
    • shunts all the arachidonic acid to leukotriene synthesis ® LT's cause

    • rhinoconjunctivitis,
    • angioedema and urticaria.
  60. Idiosyncratic drug reactions
    Glucose-6-phosphate dehydrogenase (G6PD) deficiency
    • hemolytic anemia is produced by
    • primaquine,
    • isoniazid,
    • sulfonamides,
    • nitrofurantoin
    • or eating fava beans.

    G6PD is the enzyme in the pentose phosphate pathway which creates NADPH.

    • NADPH
    • maintains glutathione: glutathione inactivates free radicals which cause

    • oxidative
    • damage to RBC membranes.
  61. Idiosyncratic drug reactions
    SHIP drugs exhibit toxicity in slow acetylators
    sulfapyridine (contained in the drug sulfasalazine) hemolytic and aplastic anemia, hepatic damage.

    hydralazine = SLE-like syndrome

    • isoniazid = hepatic damage, peripheral
    • neuropathy - tx neuropathy w pyridoxal phosphate (a.k.a., pyridoxine, vitamin B6)

    procainamide = SLE-like syndrome
  62. Idiosyncratic drug reactions
    Malignant hyperthermia (hyperpyrexia)
    • a gene defect prevents Ca++ from being sequestered
    • correctly in the sarcoplasmic reticulum (SR) of skeletal muscle.

    • - anesthesia with a volatile anesthetic agent
    • (e.g., halothane) plus the administration of
    • succinylcholine causes the massive release of Ca++ = masseter muscle spasm

    • - S/S = ­ INC BP, HR, & muscle contraction w
    • hyperthermia, lactic acidosis andVcardiac dysrhythmias

    - tx w dantrolene sodium which prevents the release of Ca++ from the SR
  63. Idiosyncratic drug reactions
    Neuroleptic malignant syndrome
    etiology NOT related to malignant hyperthermia = produced by rapid blockade of central DA receptors with the typical antipsychotic drugs like haloperidol

    - S/S = resembles severe Parkinson's dx w catatonia = EPS, stupor, hyperthermia, INC CPK, myoglobinuria, ARF

    - Tx w dantrolene sodium + bromocriptine (a D2-receptor agonist)

    Cpo =
    estimated plasma concentration at zero time
    • Cpo = (Xo F)/Vd

    Cl =
    clearance (ml/min or L/h)
    Cl = rateout /Cp

    = loading dose (depends only on the Vd)
    XL = (Cp x Vd)/F
    at Cpss: ratein = rateout
  68. k = fractional rate of elimination (%/h or h-1)

    k IF GIVEN t1/2?
    k = 0.7/ t1/2
  69. mcg/ml = mg/L
  70. t1/2 ~ Vd/Cl
  71. 4 x t1/2 = Cpss
  72. Favorite inducers of CYP450
    phenobarbital, phenytoin, carbamazepine, nicotine and chronic EtOH consumption.

  73. Favorite inhibitors of CYP450
    erythromycin, cimetidine and ketoconazole.

    The time is ripe for them to ask about grapefruit juice as an inhibitor of CYP450: the question will probably involve decreased clearance of a calcium channel blocker.

    The question may not ask about the Cp; rather, the effect of the drug will be decreased (induction of CYP450) or increased (inhibition of CYP450)
  74. The renal clearance of acidic drugs (e.g., aspirin)
    can be increased by
    • making the urine
    • alkaline by the administration of sodium bicarbonate or a carbonic anhydrase inhibitor
    • such as acetazolamide. The lower the pKa
    • of the acidic drug, the greater the
    • increase in renal clearance when the urine is made alkaline.

    • The renal clearance of a basic drugs
    • (e.g., amphetamine) can be increased by

    • making
    • the urine acidic by the administration of ammonium chloride. The higher the

    • pKa
    • of the basic drug, the greater the increase in renal clearance when the urine
    • is

    • made
    • acidic.
  75. Only free drug exerts a pharmacological effect, and decreased plasma protein concentration
    (e.g., albumin) increases the fraction of free drug in plasma.