Pharmacology Exam 2

  1. The cell cycle checkpoints and cancer
    • G1: Activation of oncogenes in G1, before entering S phase, overrides G1 arrest
    • G2: Inactivation of tumor suppressor genes, which repair DNA or signal apoptosis, overrides G2 arrest and allows entry into mitotic phase
  2. Tumor cell growth fraction
    • Fraction of cells not in G0 to those in G0
    • Tells us which cells are dividing, and are, therefore, susceptible to conventional chemotherapy
    • The presence of tumor stem cells is debatable, as well as their susceptibility
  3. General classes of antineoplastic agents
    • Alkylating agents
    •   Bifunctional Alkylators: Mechlorethamine, cyclophosphamide, ifosfamide, chlorambucil
    •   Alkylators: Carmustine, lomustine, busulfan, dacarbazine, procarbazine
    • Anti-tumor antimetabolites: Methotrexate, 6-mercaptopurine, 6-thioguanine, 5-fluorouracil, capecitibine, cytosine arabinoside
    • Anti-tumor antibiotics: Daunorubicin, doxorubicin, dactinomycin D (all are anthracyclines); and bleomycin
    • Mitotic spindle poisons: Vincristine, vinblastine, paclitaxel, docetaxel
    • Topoisomerase inhibitors
    •   Topoisomerase I: Camptothecin, irinotecan, topotecan
    •   Topoisomerase II: Etoposide, teniposide, daunorubicin, doxorubicin
    • Platinum coordination complexes: Cisplatin, carboplatin
    • Anti-tumor hormones and hormone antagonists
    • "Targeted" agents
  4. General mechanisms of action of antineoplastic agents
    • DNA alkylation
    • DNA strand scisson/breakage
    • Inhibiton of S-phase metabolism
    • Interference iwht mitotic spindle funciton
    • antagonism of hormone action in hormone-dependent cancers
    • Interference with specific target proteins or enzymes upon which tumor cell survival is dependent
  5. Metabolic inhibitors
    Toxicity: Cells in the S-phase of the cell cycle
  6. Mitotic spindle poisons
    Toxicity: Cells in the M-phase of the cell cycle
  7. Normal cells that are susceptible to toxic side effects of antineoplastic agents
    • Bone marrow precursors of blood cells: Myelosuppression, cytopenias (reduction in blood cells)
    • Intestinal epithelial cells
    • Oral mucosa
    • Gonadal cells
    • Hair follicles (alopecia)
  8. Mechanism of anti-tumor alkylating agents: Bischloroethyl amines
    • Bis-chloroethylamine conjugates to DNA at guanine base to make an alkylated guanine
    • These drugs have two chloroethyl groups attached to an amine, so the other one also alkylates a guanine
    • The result is cross-linked guanine residues, and the cell dies by apoptosis
  9. Mechanism of anti-tumor alkylating agents: Nitrosoureas
    • Is great when used with other alkylating agents because of a synergistic effect and little cross-resistance
    • Cross BBB, so are useful against brain tumors
  10. Mechanism of anti-tumor antimetabolites: Methotrexate
    • Analogs of required substrates for DNA synthesis
    • Methotrexate is a folic acid analog, which blocks synthesis of DNA, RNA, and protein precursors by preventing dihydrofolatereductase (DHFR) from regenerating FH2 into FH4
    • Accumulates in cells as a polyglutamate derivative, which enhances cytotoxicity
  11. Mechanism of anti-tumor antimetabolites: Purine antagonisists
    • Inhibit de novo purine synthesis, and interfere with DNA and RNA synthesis
    • Fraudulent base incorporation: Causes mismatches and strand breaks
    • S-phase specific
    • Activated by conversin to NMPs or to NTPs via hypoxanthine-guanine phosphoribosyl transferase (HGPRT)
    • Downregulation of HGPRT enzyme levels is a common mechanism of resistance
  12. Mechanism of anti-tumor antimetabolites: Pyrimidine antagonists
    • Fluorouracil is incorporated in place of uracil, and cytarabine is incorporated for cytosine deoxyriboside
    • Fraudulent base incorporation
  13. Mechanism of anti-tumor antibiotics: Anthracyclines
    • The anthracyclines have a broad spectrum of activity
    • DNA intercalation: Makes them mutagenic and carcinogenic
    • They stop DNA topoisomerase II binding and cause DNA scission
    • Toxicity: Irreversible cardiac toxicity or pulmonary fibrosis at high doses
  14. Mitotic spindle poisons: Vinca alkaloids
    • Bind to microtubles and prevent polymerization
    • OR
    • Enhance tubulin polymerization (block disassembly)
  15. Topoisomerase "inhibitors"
    • Prevent religation of single-strand break by binding DNA topoisomerase I
    • OR
    • Interfere with religation of double-strand break made by topoisomerase II
  16. Mechanism of platinum coordination complexes
    • Platinum2+ crosslinks base pairs
    • It is not cell cycle specific
  17. Anti-tumor hormones and antagonists
    • Used in hormone-dependent cancers, such as prostate (androgen-dependent; most common cancer in males), breast (most common cancer in females), or endometrial cancer
    • Breast and prostate cancer cause second-most deaths in each sex behind lung cancer
    • Tamoxifen and raloxifene target the estrogen receptor
    • Letrozole, anastrozole, and exemestane target inhibition of aromatase
    • Leuprolide, flutamide, and GnRH receptor antagonists are anti-androgen agents
  18. Estrogen
    • Binds to cellular receptors in estrogen-responsive tissues and stimulates a program of gene transcription
    • Promotes development and proliferation of estrogen-responsive tumors (breast and uterine cancers)
  19. Targeted agents
    • Oncogene addiction: Tumor cell proliferation/survival apparently depends upon activated oncogenes
    • Kinase inhibitors: Small molecule inhibitors of oncogenic protein kinases
    • "Humanized"/chimeric antibodies: Target tumor cell-specific cell surface receptors
    • Recombinant monoclonal antibodies are engineered with antigen recognition elements of a mouse and structural portions of a human (Fc)
    • Conjugated toxins may be a new targeted agent
  20. Types of chemotherapy based upon when they are given
    • Induction: First round
    • Adjuvant: Post-surgical
    • Neoadjuvant: Pre-surgical
    • Salvage: Second- and third-line therapy
  21. Phases of clinical trials
    • I: Looking for toxicity in humans; give 0.1 of the LD10 of mice
    • II: Looking for effect upon a particular type of cancer
    • III: Double-blind study; looking to see if better than current therapy
    • IV: After the FDA approves the drug
  22. Unique toxicities of chemotherapeutic agents
    • Vincristine: Peripheral neuropathy; SIADH (syndrome of inappropriate antidiuretic hormone secretion)
    • Paclitaxel: Neuropathy
    • Bleomycin: Pulmonary fibrosis, fever, anaphylaxis
    • Methotrexate: Renal and hepatic dysfunction
    • 5-fluorouracil: Severe diarrhea
    • Cytosine arabinoside: Cerebellar dysfunction and fever
    • Cyclophosphamide: Hemorrhagic cystitis and SIADH-like syndrome
    • Busulfan: Pulmonary fibrosis
    • Cisplatin and carboplatin: Renal failure
    • Anthracyclines: Cardiomyopathy
    • Alkylating agents: Secondary cancers, due to their mutagenic nature
    • Irinotecan: Diarrhea; this is because it induces muscarinic agonist effects by inhibiting acetylcholinesterase
  23. What to do about myelosuppression in chemotherapy
    • Schedule surgery at the same time as beginning chemo or after the first round
    • Leucovorin is a "rescuer" of the immune system by folinic acid; helps bone marrow recover
  24. Opioid receptors
    • Mu
    • Delta
    • Kappa
    • All are G-protein-coupled
  25. Opioids as analgesic drugs
    • They produce pain relief without loss of consciousness
    • Their effects are mediated by opioid receptors
    • Endogenous opioid peptides also act at these receptors
    • They induce analgesia by desensitizing pain fiber sensitiztion, but produce a variety of side effects
  26. Main side effects of opioids
    • Sedation
    • Constipation
    • Respiratory depression
    • Nausea and vomiting
    • Cardinal signs of opioid agonist intoxication: Respiratory depression, constriction of the pupils (miosis), stuporous/comatose state; rescue with naloxone
    • Euphoria (psych addiction)
    • Antitussive (anti-cough)
    • inhibit release of sex hormones (impotence or osteoporosis)
    • Miosis (constriction of pupils)
    • Itching (histamine release and non-histamine-mediated itching
    • Cardiovascular effects (orthostatic hypotension, bradycardia, vasodilation)
    • GI effects (smooth muscle spasm)
    • Myoclonus/seizures (high doses of opioids)
  27. Other classes of drugs used for analgesia
    • Opioids
    • NSAIDs
    • Antidepressants
    • Anticonvulsants
    • Alpha2 receptor agonists
  28. Narcotics versus opioids
    • Narcotics refers to illegal substances and includes opium and its synthetic substitutes, such as morphine, fentanyl, and codeine
    • Opioids and narcotics are the same thing medically
  29. Types of pain receptors, endogenous peptides that target them, and fibers that carry pain
    • Remember that there are mechano, thermo, chemo, and silent pain receptors
    • Endomorphins: Mu
    • Endorphins: Mu and delta
    • Enkephalins: Delta
    • Dynorphins: Kappa
    • They are carried by A delta and C fibers
    • They signal tissue damage or potential tissue damage
  30. Clinical pain changes subsequent sensation of pain how?
    • It sensitizes the body more to pain, allowing a smaller stimulus to produce a greater response to pain
    • Opioids activate mu receptors, to produce pain relief and unwanted side effects
  31. Two components of pain and how opioids change them
    • 1: Sensory discriminative component
    • 2: Motivational-affective component
    • Opioids are more effective against the motivational-affective component, so we can still know the injury
  32. Mechanisms of opioid actions
    • Inhibit neurotransmission by blocking Ca2+ influx and increasing K+ efflux
    • In other words, reduces depolarization by blocking Ca2+, or causes hyperpolarization by blocking K+ efflux
  33. Opiate tolerance
    • Develops to most opioids, but not to ocular or GI effects of opioids (will still have smooth muscle spasms and miosis)
    • There is no maximum dose of morphine for malignant pain management becaus of tolerance to respiratory depression
  34. Opiate withdrawal
    • Results from abrupt cessation or dose reduction of drug, or administration of an opioid antagonist
    • Sighns: Restlessness, perspiration, abdominal cramps, hot and cold flashes, insomnia, nausea, vomiting, diarrhea, tahypnea, hypertension, hypotension, tachycardia
  35. Physical dependence of opiates
    Presence of withdrawal symptoms precipitated following cessation of the drug or administration of an opioid antagonist
  36. Psychological dependence of opiates
    • Impaired control over drug use for the reinforcement it provides; related to the mesolimbic dopamine system
    • Feels like having a "need"
  37. Addiction
    • Impaired control over drug use/psychological dependence
    • Compulsive use
    • Continued use despite physiologic, psychosocial and/or economic harm
    • Craving
    • Basically, it's psychological dependence gone wild
  38. Morphine
    • Mu opioid receptor agonist
    • This action on mu influences the motivational-affective component of pain
    • Morphine produces its analgesic effects largely in the brain
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    • Onset of action: 10-15 minutes
    • Peak effects: 30 minutes
    • Clinical duration: 4 hours
    • This is because only 20% of morphine is in uncharged form, which crosses BBB better than charged; results in slow onset of action
    • Metabolism: Glucuronidation in the kidney; this results in a little active metabolite (M-6-glucuronide), that is 10x more potent than morphine; and a lot of an inactive metabolite (M-3-glucuronide)
    • Liver disease can change the pharmacokinetics little, but renal disease/failure can greatly influence the effects of morphine
    • MS Contin or Morphine SR: Extended release forms
    • Dosage is 3-5 times higher by PO because of poor oral bioavailability than IV
    • Other ways of administering: Intrathecal (subarachnoid) or epidural for chronic or acute pain, respectively to target the spinal mu receptors in the dorsal horn
  39. Serotonin syndrome
    • 1: Neuromuscular hyperactivity, tremor, clonus, myoclonus, hyperreflexia, and pyramidal rigidity
    • 2: Autonomic hyperactivity, diaphoresis, fever, tachycardia, and tachypnea
    • 3: Altered mental status, agitation, excitement, and confusion
    • Death can happen when taking serotonin SRIs or MAO inhibitors with meperidine or methadone
    • SSRIs and MAOIs combined cause this
  40. Drugs that are both opioid agonists and antagonists
    • Their effects vary at the opioid receptor that they target
    • Pentazocine, butorphanol, and nalbuphine are kappa agonists and mu partial agonists/antagonists
    • Used for management of acute, short-term pain; not chronic pain; also used for side effects
    • These could put patients into withdrawal
    • Buprenorphine: A partial mu agonist and kappa agonist; difficult to reverse mu agonist effect, and difficult to provide analgesia; has utility for drug abuse and addiction
  41. Volatile anesthetics
    • Gases or volatile liquids that produce anetsthesia, amnesia, and muscle relaxation as well as suppressing hemodynamic responses
    • May also impact the sympathetic nervous system, airways (depresses respiration), heart (decreases heart rate, CO, and systemic vascular resistance to drop BP), liver, and kidneys
    • Used for maintenance of anesthesia, but a few are used for induction
    • In general, they are potent (only 1-10% of inhaled air needed), have little tissue metabolism, are insoluble in blood, and are not flammable
    • Facilitate inhibitory neurotransmission at GABA and Glycine receptors; excitatory Glutamate transmission is also reduced
  42. Partial pressures of volatile anesthetics
    They roughly equilibrate: alveoli, arteries, and brain
  43. MAC
    • minimum alveolar concentration
    • At a steady state, the alveolar concentration is in equilibrium to the brain
    • One MAC is the concentration of an inhaled anesthatic that prevents skeletal muscle movement in response to a noxious stimulus in 50% of patients
    • We use MAC to determine our doses: 1.3 MACs
  44. Stages of anesthesia
    • Premedication: Sedation/anxiolysis before induction (anxiolytic/antianxiety agents administered) by use of a benzodiazepine with or without an opioid
    • Induction: Initiation of unconsciousness
    • Maintenance: During surgery
    • Emergence: Regaining consciousness
    • Recovery: Stabilization
  45. Blood:gas partition coefficient
    • Tells us how much of the gas is soluble in blood
    • We want low solubility: Fast onset and offset; stays as gas; this lets the whole system be close to equilibrium
  46. MAC-sparing
    • This happens when drugs affect NE, ACh, and Histamine receptors in the brain, causing a decreased amount of anesthetics to be used
    • EEG is used to measure depth of anesthesia
  47. Malignant hyperthermia
    • A rare life-threatening condition that is triggered by exposure to volatile anesthetics and succinylcholine
    • In genetically susceptible individuals, anesthetics trigger increases in skeletal muscle metabolism, which overwhelms the body's capacity to supply O2, remove CO2, and regulate body temperature
    • Dantrolene treats malignant hyperthermia
  48. Depressive disorder
    • Characteried by a diminished interest to pleasurable activities, feelings of worthlessness or inappropriate guild, decrease in appetite and libido, insomnia, and recurrent thoughts of death and suicide
    • Treatable in over 80% of people with illness
    • Types: Major depression dysthymia, and bipolar disorder
  49. Major depression
    • At least one episode of serious mood depression lasting longer than two weeks
    • May be totally disabling, interfering with work, sleeping, and eating
    • May progress to psychosis
    • 40-60% of all unipolar depressive disorders
    • Subtypes: Atypical, reactive, seasonal
  50. Dysthymia
    • Less severe than major depression
    • Involves long-term chronic depressive symptoms (2 or more years)
  51. Bipolar disorder
    • AKA manic-depressive disorder
    • Characterized by cycling mood changes
    • Mania: Enthusiasm, rapid thoughts and speech patterns, extreme self-confidence, and impaired judgement
    • 25% of all depressive disorders
  52. Amine hypothesis of depression and mania
    • Low levels of biogenic amines (serotonin and norepinephrine) correlate with depression
    • High levels correlate with mania
    • Serotonin: Found in the rostral raphe nuclei (and much others); the major metabolite of serotonin is 5-hydroxyindoleacetic acid (5-HIAA), which is how we measure serotonin in the brain
    • Norepinephrine: Decreased levels in patients with depression; found in the lateral tegmental nuclei
  53. Main classes for treatment of depressive disorders
    • Major depression
    • Tricyclic antidepressants (TCAs)
    • Seective serotonin reuptake inhibitors (SSRIs)
    • Serotonin-norepinephrine reuptake inhibitors (SNRIs)
    • Atypical antidepressants
    • Monoamine oxidase inhibitors (MAOIs)
    • Bipolar Disorder
    • Lithium salts
    • Certain antidepressants
    • Certain antipsychoitics
    • Certain anticonvulsants
  54. Tricyclic antidepressants
    • Nonspecific blockers of monoamine reuptake
    • Affect both NE and Serotonin synapses
    • Also block muscarininc, adrenergic, and histamine receptors, causing a lot of side effects
    • Therapeutic effect takes longer than 2 weeks
    • High binding to plasma proteins
    • Side Effects
    • Antimuscarinic: Dry mouth, blurred vision, urinary retention, constipation, aggrevation of glaucoma and epilepsy
    • Cardiouvascular: Increased levels of NE results in tachycardia
    • Orthostatic hypotension: Due to blockage of alpha1 adrenergic receptors
    • Sedation: Due to blockage of H1 receptors
    • Metabolic-endocrine: Weight gain (due to antihistamine), sexual dysfunction
    • Neurologic: Seizures
    • Psychiatric: Induction of mania in patients with bipolar disorder; delirium in elderly
  55. NET
    • Norepinephrine transporter
    • It is structurally similar to the 5-HT reuptake protein, so it is difficult to selectively block one type of transporter
    • TCAs block these
  56. SSRIs
    • Most widely-prescribed in US
    • Less of an anticholinergic agent than TCAs, so fewer side effects
    • Different SSRIs have different side effect profiles, but the same efficacy
    • Cause neurogenesis after 2 weeks because they raise levels of BDNF (brain-derived neurotrophic factor)
    • High first-pass liver metabolism, but also block a lot of liver enzymes (potential for drug interactions)
    • High binding to plasma proteins
    • Side effects: Much safer than TCAs (no cardiac toxicity); nausea, anxiety, sleep distruptance, anorexia, sexual dysfunction, induction of mania in bipolar patients
    • Drug interactions: Blocks liver enzymes, so do not take with TCAs, neuroleptic drugs, antiarrhythmics, some beta-adrenergic antagonists
  57. SNRIs
    • Serotonin-norepinephrine reuptake inhibitors
    • Used for patients refractory to SSRIs
    • Metabolized by liver
    • Eliminated by kidney
    • Side effects: Nausea, anxiety, insomnia, sexual dysfunction, increase in BP and HR at high doses
    • Much safer than TCAs
  58. Atypical antidepressants
    • Used with TCAs in patients that don't respond to a single agent
    • no significant cardiotoxic effects
    • Side effects: Headache, nausea, tinnitus, insomnia, nervousness
  59. Types of monoamine oxidase
    • Type A: Not very specific; deaminates NE, 5-HT, and dopamine
    • Type B: More specific for dopamine
  60. MAOIs
    • Third-line drugs for depression in patients who do not respond to SSRIs and TCAs
    • Severe and unpredictable side effects
    • CNS effects, cardiovascular effects, constipation
    • Drug interactions: Serotonin syndrome is possible when given with SSRIs
    • Cheese effect: Cheese has higher levels of tyramine, which causes release of large amounts of catecholamines, leading to hypertension, cardiac arrhythmias, stroke, headache, and nausea
    • Must be on restricted diet!
  61. Amphetamines
    • Used to treat narcolepsy, ADHD
    • Increase release of dopamine and norepinephrine in the brain by inhibiting MAO, increasing DA/NE release by vesicular monoamine transporter (VMAT)
    • All are schedule II controlled substances
    • Side effects: Euphoria, anxiety, vertigo, insomnia, confusion, arrhythmias, hypertension, nausea, diarrhea, potential for addiction
    • Overdose: paranoia, psychoses, suicidal/homicidal impulses
  62. General treatment of ADHD and narcolepsy
    • Stimulants
    • They also modulate monoamine levels
  63. ADHD
    • Main traits: Inattention, hyperactivity, impulsivity
    • Treated with stimulants or atomoxetine
  64. Narcolepsy
    • Sleepiness, abnormalities of dreaming sleep, loss of muscle control or paralysis by strong emotions
    • Treated with amphetamines or modafinil
  65. Basic classes of sedative-hypnotics/antianxiety agents
    • 1: Benzodiazepines
    • 2: Barbiturates
    • 3: Non-benzodiazepines that interact with benzodiazepine receptors4:
    • 4: Non-benzodiazepines that do not interact with benzodiazepine receptors
    • Interact with various sites on GABAa receptors to enhance CL- influx into neurons
    • Enchance the inhibitory activity of neurons in the limbic system
    • Benzodiazepenes and barbiturates have similar toxicities, produce tolerance and dependence, and cross-tolerance with other CNS depressants
    • Abuse potential with benzodiazepines is lower than barbiturates, and benzodiazepines have a much higher therapeutic index (safer)
    • Barbiturates make complex drug-drug interactions with CYP enzymes
    • Barbs + BZs can make additive CNS toxicities; ethanol also has additive effect
  66. Parts of the brain affected by anxiety disorders
    • Amygdala: Regulates the heartbeat and other visceral functions; processes fear emotions
    • Hippocampus: Establishment of long-term memory in regions of cerebral cortex
  67. Therapeutic uses of benzodiazepines (remember, they all end in "-pam" or "-lam")
    • Sedative-hypotic
    • Anxiolytic
    • Muscle relaxant
    • Anticonvulsant
    • Preoperative medication
    • Withdrawal from chronic use of ethanol and other CNS depressants
    • Diazepam, alprazolam, chlordiazepoxide
    • NOT: Anesthetics or analgesics
  68. Central effects of benzodiazepines
    • Bind to GABAa receptors in the limbic system; enhance inhibition of neurons
    • GABAa receptors are pentamers with multible binding sites: GABA site, barbiturate site, and benzodiazepine site all hyperpolarize neuron; picrotoxin site blocks the Cl- channel and reduces inhibition
    • Benzodiazepenes increase the frequency of GABA channel opening in the presence of GABA
  69. Metabolism of benzodiazepenes
    • All have active metabolites made in the liver
    • All are conjugated to glucuronide to make inactive metabolites (in the liver)
    • Excreted by kidneys
  70. Withrdawal of benzodiazepenes
    • Ths means physical dependence is occuring
    • mild: anxiety, insomnia, irritability, bad dreams, tremors, anorexia
    • Severe: Agitation, depression, panic, paranoia, muscle twitches, convulsions
  71. Actions of GABA and other agents at GABAa receptor
    • Agonists: GABA
    • Antagonists: Bicuculline; reduces inhibition of neuronal activity and produces convulsions
    • Antagonists: Picrotoxin; reduces inhibition of neuronal activity and produces convulsions
    • Inverse agonists: Beta-carbolines
    • Antagonist: Flumazenil; blocks effects of both agonists and inverse agonists; no effects by itself
  72. Non-benzodiazepines that act on BZ-receptors
    • Act on BZ-binding site on GABAa receptor
    • Metabolized by liver to make inactive metabolites
    • No respiratory and cardiovascular effects under normal conditions
    • IV administration makes marked CV and respiratory depressant effects
    • Includes: Zolpidem and zaleplon
  73. Barbiturates
    • Disadvantages: Respiratory depression, cardiovascular depression, influence liver enzymes
    • They bind to GABAa receptors to increase chloride conductance and hyperpolarize the neuron
    • They increase the duration that Cl- channels are open in the presence of GABA
    • Metabolism: Liver; dealkylated, conjugated by glucuronidation
    • Excreted by kidneys
    • Side effects: Drowsiness, confusion, diminished motor skills, impaired judgment
    • Contraindications: Pain (increases sensitivity), pulmonary insufficiency (cause respiratory depression)
    • Drug interactions: Enhance CNS depressive effects of antipsychotics, antihistamines, and ethanol
    • Enhances metabolism of many drugs by incuding liver enzymes
    • Acute toxicity: 10x hypnotic dose causes circulatory collapse, renal failure, respiratory depression, coma, hypotension, hypothermia
    • Treatment: Support respiration and blood pression; gastric lavage to get rid of drugs
  74. Barbiturates and tolerance
    • Create their own self-tolerance by inducing liver CYP enzymes within a few days
    • Decreased CNS response with chronic exposure
    • There is also a cross-tolerance to other CNS depressants
    • Dependence: Develops with continued use
    • Withdrawal symptoms: Anxiety, insomnia, dizzinness, nausea, vomiting, hyperthermia, tremors, delirium, convulsions, death
  75. Miscellaneous antianxiety drugs
    Include propranolol (beta-adrenergic blocker) for stage fright or buspirone (partial agonist for serotonin receptor) since no additive depression with ethanol
  76. Seizures
    Produced by abnormal, excessive synchronized electrical activity in a group of neurons that can spread to other parts of teh brain
  77. Epilepsy
    • Primary: Idiopathic; no specific cause is evident; patients are often treated chronically with antiepileptic drugs for life
    • Secondary: Symptomatic; caused by illness; antiepileptic drugs are given until the primary cause of the seizures is corrected
    • Generalized
    • Usually have immediate loss of consciousness; may be convulsive or non-convulsive
    • Spread throughout both hemispheres of the brain
    • Tonic-clonic (grand mal): Most common; most dramatic; tonic phase where sudden loss of consciousness, falling, rigid extension of trunk and limbs; clonic phase with rhythmic contraction of arms and legs
    • Absense (petit mal): Breif, abrupt loss of consciousness; patient often unaware of attacks
    • Myoclonic: Short episodes of muscle contractions that may occur for several minutes; rare; often a result of permanent neurologic damage from hypoxia, uremia, encephalitis, or drug poisoning
    • Febrile: During illness in young children accompanied by fever
    • Status epilepticus: Medical emergency; repeated seizures without recovery between them; consciousness is not regained between seizures; can lead to cardiovascular collapse and permanent brain damage
    • Partial (focal)
    • Simple complex: No impairment of consciousness; jerking, tingling, sweating, or psychic disturbance
    • Partial complex: Impaired consciousness; dreamy disaffective state, may spread throughout the entire cortex progressing to secondarily generalized seizure
  78. Antiepileptic drugs and side effects
    • Phenytoin
    • Carbamazepine
    • Lamotrigine
    • Valproic acid
    • Ethosuximide
    • Phenobarbital, primidone
    • Diazepam, lorazepam
    • Gabapentin
    • Levetiracetam
    • Side effects: Drowsiness, ataxia, nausea/vomiting, skin rash, metabolic changes, gingival hyperplasia (phenytoin), hepatotoxicity (valproic acid, carbamazepine), megaloblastic anemia (phenytoin, primidone), thrombocytopenia (valproic acid, pregabalin), teratogenic effects (phenytoin, carbamazepine, valproic acid, phenobarbital)
  79. General mechanism of antiepileptics
    • Inhibit electrical activity via inhibition of ion conductance (Na or Ca)
    • OR
    • Facilitate inhibitory neurotransmission (GABA)
  80. What drugs are useful for what types of seizures?
    • Tonic-clonic, simple partial, complex partial: Phenytoin, carbamazepine, lamotrigine, and phenobarbital
    • Absence, myoclonic: Best respond to a unique single drug or two
  81. Is status epilepticus treatment the same as other seizures?
    No, you start treating the patient immediately with a rapid-acting antiepileptic, such as diazepam (a benzodiazepine), combined with CV and respiratory support; follow up with long-acting drugs such as phenytoin
  82. Mechanism of carbamazepine, phenytoin, lamotrigine, valproic acid
    • Inhibit voltage-gated Na channels to prolong the refractory period and reduce sustained firing
    • Antiepileptic
  83. Mechanism of ethosuximide, valproic acid
    • Inhibit voltage-gated Ca channels to inhibit rhythmic activity
    • Antiepileptic
  84. Mechanism of barbiturates (phenobarbital, primidone), benzodiazepenes (diazepam, lorazepam, clonazepam), valproic acid, gabapentin
    • Enhance inhibitory GABAergic neurotransmission by allowing more calcium to flow through the GABA channel, hyperpolarizing the target cell
    • Antiepileptic
  85. Schizophrenia
    • Psychosis: Broad terminology for distuurbances of perception, impaired cognitive function (includes schizophrenia, dementias, and bipolar disorder)
    • - Schizophrenia is a life-long, progressive illness; affects males more than females
    • - Thought to arise from an increase in dopaminergic neurotransmission in the brain by an increased number of dopamine receptors
    • - 5-HT2a receptors are also activated excessively by increased 5-HT release, causing inhibition of glutamatergic neurotransmission and of nerve firing
    • - Positive symptoms: Delusions, hallucinations, mood disturbances, confusion; exaggerations of normal function
    • - Negative symptoms: Social withdrawal, reduced speech and thought, inability to experience pleasure; loss of normal function
  86. General treatment of schizophrenia
    • Typical antipsychotics: Relatively selective antagonists of D2 dopamine receptors; however, they have a higher potential for producing extrapyramidal side effects
    • Atypical antipsychotics: Selective antagonists of 5-HT and/or D2 dopamine receptors or partial agonists of D2 dopamine receptors; however, they have a low potential for producing extrapyramidal side effects
    • There is no clear evidence that they have any greater therapeutic efficacy than typical antipsychotics
    • Side effects: Weight gain, metabolic side effects (glucose intolerance and type-2 diabetes)
  87. Typical antipsychotics
    • Phenothiazines
    • Chlorpromazine
    • Fluphenazine
    • Thioxanthenes
    • Thiothixene
    • Butyrophenones
    • Haloperidol
    • These are all relatively selective antagonists for dopamine receptors (more selective for D2 vs D1 type dopamine receptors)
    • Take 4-8 weeks to work!
    • Haloperidol/fluphenzine are most potent, followed by thiothixene, then chlorpromazine
    • Metabolized to inactive metabolites by liver
    • Side effects: Infertility and impotence can result from pituitary D2 receptor block; haloperidol is big cause of this!
    • CNS side effects: Parkinsonian effects, dystonias (neck or facial spasms), akathisia (severe restlessness and strong desire to move) all from striatal dopamine receptor block; after several months to years, tardive dyskinesias (involuntary oral-facial movements) arise due to dopamine receptor upregulation (supersensitivity)
    • Interactions and adverse effects: Decreased drug elimination by inhibition of liver enzymes, but increased enzyme for its own elimination
  88. Neuroleptic malignant syndrome (NMS)
    • Instability and collapse of the autonomic nervous system results in excessive sweating and salivary secretion, unstable blood pressure, and cardiovascular instability
    • Fever, muscle stiffness, delirium, and stupor
    • Manifested in patients with Parkinson's disease who stop/reduce the dose of dopaminergics
    • Caused by a sudden, marked decrease in dopamine activity
    • Treatment: Immediately stop neuroleptics and treat hyperthermia; supportive care; bromocriptine (dopamine agonist) or dantrolene (to reduce muscle rigidity)
  89. Atypical antipsychotics
    • Synthetic benzodiazepine derivatives
    • Clozapine
    • Olanzapine
    • Quetiapine
    • Others
    • Risperidone
    • Paliperidone
    • Selective antagonists for serotonin/dopamine receptors
    • Dopamine Partial agonists: Competitive partial agonists for dopamine receptors (more selective for D2 receptors); also antagonize serotonin receptors
    • Aripiprazole
    • Metabolized by liver; produce inactive metabolites except for risperidone
    • Side effects: Can have cholinergic muscarinic receptor blockage (hyperthermia, tachycardia, constipation, confusion), alpha-adrenergic receptor block (vasodilation, orthostatic hypotension, tachycardia, sexual dysfunction), pituitary D2 block (minimal), 5-HT block (weight gain and sedation), and H1 histamine receptor block (sedation and weight gain); glucose intolerance, lipid abnormalities
    • Apiprazole is only one to not cause weight gain and metabolic adverse effects
    • Lower risk of extrapyramidal symptoms and neuroleptic malignant syndrome, Parkinsonian effects, dystonias and tardive dyskinesias than typical antipsychotics
    • Adverse effects only seen with overdose
    • Definitely change drug eliminations by inhibiting and inducing different liver enzymes
  90. Dopamine hypothesis for schizophrenia
    • Symptoms are due in part to an increase in the activity of dopaminergic neurons
    • Drugs that enhance dopamine transmission can induce and enhance schizophrenic symptoms, such as drugs for Parkinsons
    • D2 receptors are increased in the brains of schizophrenics
  91. Dopamine pathways in the brain
    • Affected by typical antipsychotics
    • Made in substantia nigra
    • Used in nigrostriatal, mesolimbic, mesolimbocortical, and tuberohypophyseal
  92. Types of dopamine receptors and their effects
    • D1, D5: Alpha-s subunit of G protein; enhances ATP to cAMP
    • D2, D3, D4: Alpha-i/o subunit of G protein; enhances inhibition of ATP to cAMP
    • For antipsychotic therapy, we do not want to block D1, because it is found on the presynaptic side and would result in increased amounts of NT available
    • We want to block D2 receptors because they are overstimulated by excess dopamine (or the presence of more receptors)
    • By blocking D2, we allow loss of inhibition of glutamatergic transmission, resulting in excitation of the neuron
  93. Antipsychotic effects are produced through agonism/antagonism of what receptors?
    • Competitive antagonism of postsynaptic D2 dopamine or 5-HT2a serotonin receptors
    • Reduced activation of D2 dopamine receptors by competitive partial agonists
    • All in the striatal and negrostriatal neuronal circuitry
  94. Parkinson's disease
    • Degeneration of nigrostriatal dopamine neurons, consequently resulting in disorders of the basal ganglia
    • Results in net decrease in the excitatory input to the cortex, resulting in disruption of muscle control
    • Presence of Lewy bodies made of alpha-synuclein in surviving neurons
    • Treatment: Dopamine synthesis, decreasing dopamine catabolism, providing drugs with dopamine agonist activity, and suppressing activity of the cholinergic system
  95. Parkinsonism
    Disorders that resemble Parkinson's disease but have a known cause and variable rates of progression and responses to drug therapy (traumatic brain injury, antipsychotic drugs, encephalitis lethargica, multiple small strokes)
  96. Drug therapy for Parkinson's disease
    • Increase dopamine synthesis
    • L-DOPA/carbodopa
    • Entacapone
    • Amantadine
    • Decrease dopamine catabolism
    • Selegiline (MAOb, which is specific for dopamine, inhibitor)
    • Rasagiline (MAOb inhibitor)
    • Dopamine receptor agonists
    • Bromocriptine
    • Ropinirole
    • Prmipexole
    • Apomorphine
    • Antagonists of muscarinic cholinergic receptors
    • Benztropine
    • Trihexyphenidyl
  97. Alzheimer's disease
    • Degeneration of cholinergic neurons in the cortex and hippocampus
    • Degeneration of basal forebrain cholinergic neurons
    • Presence of amyloid senile plaques and neurofibrillary tangles
    • Treatments: Inhibiting acetylcholinesterase or blocking NMDA receptors
    • Way more common in women over age 65
    • Mutations in APP gene (PS1 and PS2) or APOE4 are risk factors for familial
  98. Amyotrophic lateral sclerosis
    Neurodegenerative disease involving muscle weakness and atrophy due to degeneration of motor neurons in the spinal cord and cerebral cortex
  99. Factors in selective neurodegeneration
    • Genetics and environment
    • Excitotoxicity: Excessive glutamate release produces excitation-induced excessive influx of Ca2+ into neurons causing excitotoxicity
    • Energy metabolism: Drug-induced or aging-associated decline in energy metabolism (eventually leads to increase in Ca2+ influx)
    • Free radicals
  100. Drug therapy for Alzheimer's disease
    • Acetylcholinesterase inhibitors
    • Donepezil
    • Galantamine
    • Rivastigmine
    • Tacrine
    • NMDA receptor inhibitor
    • Memantine
  101. Classes of diuretics
    • Carbonic anhydrase inhibitors: Act in the proximal tubule
    • Inhibitors of the Na/K/2Cl symporter: Act in the loop of Henle
    • Inhitibors of the Na/Cl symporter: Act in the distal tubule
    • Competitive inhibitors of aldosterone: Act in the collecting tubules
    • Osmotic agents: Act by increasing renal blood flow and washing out the medullary salt gradient
  102. Antidiuretics
    Act by stimulating water reabsorption in the distal and collecting tubules
  103. Gout treatment
    • Uricosuric agents are used
    • Alter renal handling of uric acid, inhibit production of uric acid, and alter its movement around the body
  104. Single nephron glomerular filtration rate (SNGFR)
    SNGFR = Koeffecient (change in pressure - difference in osmotic pressure)
  105. What all is absorbed in the proximal tubule?
    • 65% of Na, H20, and bicarbonate
    • Most K+
    • Urine is isoosmotic with blood
    • Oranic acids and bases are actively moved into urine by the driving force of Na/K ATPase on basolateral surface of membranes
  106. What all is absorbed in the loop of Henle?
    • Water is reabsorbed in the descending limb (90% collectively)
    • No NaCl is absorbed in descending limb, but it is actively transported out in ascending
    • Makes the medullary gradient
    • The ascending limb is the diluting limb
    • The macula is found at the distal end of the ascending thick limb, which senses the osmolality of urine and causes tubuloglomerular feedback (TGF) to slow the pressure and reduce GFR if too high of osmolarity of NaCl
    • This causes sodium diuresis to be self-limiting
  107. What all is absorbed in the distal convoluted tubule?
    • Actively transports out NaCl but not water
    • Fluid is hypotonic urine even when you are dehydrated; it is the diluting segment of the nephron
  108. What all happens in the collecting tubule?
    • Water is allowed out only if ADH is present
    • Urea out of the distal collecting duct into the medullary sat gradient
  109. Diuretic, aquaretic, natriuretic, saluretic, kaliuretic definitions
    • Diuretic: Increases solute excretion to increase the volume of urine
    • Aquaretic: Increases excretion of water but not of solutes (dilutes urine)
    • Natriuretic: Increases excretion of sodium
    • Saluretic: Increases the excretion of sodium and chloride ions
    • Kaliuretic: Increases excretion of potassium
  110. Carbonic anhydrase inhibitors
    • Work on the proximal tubule, which is a major site of bicarbonate reabsorption and acidification
    • Net process is to drive sodium bicarbonate out of the urine
    • CA turns bicarbonate into CO2 and H2O, which allows it to go across the endothelium and back into the interstitial space
    • This cannot happen with these inhibitors, and bicarbonate is trapped in the tubule lumen
    • This also results in a decreased ability to reabsorb sodium, because a sodium/carbonic acid symporter exists on the basolateral side of the cell to move both into the interstitial space
    • Effects on excretion
    • Na: Up
    • K: Up Up
    • H: Down
    • Ca
    • Mg
    • Cl
    • HCO3-: Up Up
    • H2PO4: Up Up
    • Potassium wasting
  111. Potassium wasters
    • When high amounts of sodium are delivered to the distal tubule, we get decreased potassium reabsoprtion
    • Kypokalemia is a potential side effect
  112. Osmotic diuretics
    • Work on the loop of Henle
    • Act on tissues by drawing water into the blood
    • Act on kidney by increasing renal blood flow and washing out the medullary salt gradient
    • Water efflux is also inhibited by the osmotic gradient in the proxial convoluted tubule
    • Potassium wasting
    • Good for renal failure, tubular necrosis, glaucoma
    • Effects on excretion
    • Na: Up Up
    • K: Up
    • H
    • Ca: Up
    • Mg: Up Up
    • Cl: Up
    • HCO3-: Up
    • H2PO4: Up
    • Uric acid: Up
  113. Loop diuretics
    • Inhibit Na/K/2Cl symporter in the ascending thick limb of loop of Henle
    • Enter the urine via organic ion transporters in proximal tubules
    • Potassium wasters
    • Diminish the medullary ion gradient by preventing transport of ions from thick ascending limb tubule
    • Urine flow is increased and urine is more concentrated because salts are not removed
    • Effects on Excretion
    • Na: Up Up
    • K: Up Up
    • H: Up
    • Ca: Up Up
    • Mg: Up Up (this movement of Ca/Mg is due to a changed electrochemical gradient, making tubule more positive)
    • Cl: Up Up
    • HCO3-: Up
    • H2PO4: Up
    • Uric acid: Up This is an acute effect due to increased flow; with chronic use, actually reduce hypertension and get decreased flow
  114. Thiazide diuretics
    • Block Na/Cl symporter, but not K+, in the distal convoluted tubule
    • Potassium wasters
    • Enter the urine via organic ion transporters in proximal tubules
    • Get energy from the basolateral Na/K ATPase
    • They are not that effective because 90% of Na has already been reabsorbed before the distal convoluted tubule, but they do act distal to the macula and are not limited by TGF
    • The medullary salt concentration is NOT affected, so water retention during dehydration is preserved
    • Effects on excretion
    • Na: Up
    • K: Up Up
    • H: Up
    • Ca: Down This is because a Na/Ca antiporter exists on the basolateral membrane that works better since there is a sodium gradient
    • Mg: Up
    • Cl: Up
    • HCO3-: Up
    • H2PO4: Up
    • Uric acid: Up acutely, down chronically
  115. Inhibitors of renal Na+ channels
    • Block luminal Na channel in the late distal tubule and collecting duct
    • Stops drive of positive ions into lumen by electrochemical gradient
    • Cause small increases in NaCl excretion but are generally used for their ability to block K+ excretion in combination with other diuretics
    • Potassium sparing
    • Effects on Excretion
    • Na: Up
    • K: Down
    • H: Down
    • Ca: Down
    • Mg: Down
    • Cl: Up
    • HCO3-
    • H2PO4
    • Uric acid
  116. Mineralocorticoid antagonists
    • Mineralocorticoids act in the distal convoluted tubule and collecting duct to retain salt and water, while increasing the excretion of potassium and protons
    • Potassium sparing
    • Effects on Excretion
    • Na: Up
    • K: Down
    • H: Down
    • Ca: Down
    • Mg: Down
    • Cl: Up
    • HCO3-
    • H2PO4
    • Uric acid
  117. Antidiuretic hormone
    • Increases deposition of Na/K ATPase in basolateral membrane
    • Increases prevalence of renal Na channel to lumenal membrane
    • Induces retention of salts that may precipitate dehydration
    • It does all of this through aldosterone-induced proteins (AIPs) in response to dehydration
  118. Antidiuretic drugs and effects on V receptors
    • Vasopressin (ADH) binds V1 and V2 receptors
    • Desmopressin binds V2 and a little V1
    • V1: Reduces medullary blood flow, thus increasing medullary salt gradient and reabsorption of water
    • V2: Stimulates ater reabsorption in distal tubule and collecting duct by stiulating production of aquaporins in the epithelium
  119. Diabetes insipidus
    • Pituitary isn't making enough vasopressin; lots of urination and volume depletion
    • Nephrogenic diabetes insipidus: Nephrons don't respond to vasopressin
    • Distinguish these from diabetes mellitus by fluid deprivation; DI will still cause high urine volume, but DM will not
  120. Gout
    • Painful inflammatory response to the presence of urate crystals formed in tissues and joints
    • Precipitated by high serum urate
    • Allopurinol and colchicine reduce uric acid/inflammation
    • Uricosuric agents increase renal excretion of uric acid
  121. Local anesthetics classes and side effects
    • Amides: Have an "I" before the -caine
    • Bupivacaine
    • Lidocaine
    • Mepivacaine
    • Prilocaine
    • Ropivacaine
    • Esters: No "I" before -caine
    • Benzocaine
    • Cocaine
    • Procaine
    • Tetracaine
    • Remember, they block both autonomic nerves as well as sensory and motor nerves, but our pain fivers are A-delta and C
    • Signs of toxicity: Numbness of tongue, lightheadedness, visual and auditory disturbances, unconsciousness, convulsions, coma, and death
    • Toxicity is big possibility because must give such a large dose; be sure not to hit a vessel!
    • Treatment of toxicity: Intralipid by IV injection; pulls off local anesthetics from channels
  122. Allergic reactions to local anesthetics
    • Rare, but esters are the most likely
    • Epinephrine/preservatives/other drugs are often culprit
    • Epinephrine is used to vasoconstrict and reduce the plasma levels of the local anesthetic; also prolongs the duration of the local anesthetic
  123. Epinephrine concentration in a local anesthetic
  124. Lidocaine solution concentration
  125. Potency of local anesthetics
    • The more lipid-soluble, the more potent
    • Tetracaine and bupivacaine are super high potent
    • This is because they block Na channels intracellularly in a charged form
  126. How to figure out how much local anesthetic crosses the axonal membrane?
    • pKa = the pH where LA = LA+
    • pH = pKa + log LA/LA+ (for weak bases, which is what local anesthetics are)
  127. Bier block
    • IV is placed in distal vein
    • Useful for surgery that is less than 2 hours on an extremity
    • Useful for treatment of chronic pain
  128. Peripheral nerve blockade
    Electrical stimulation locates the nerve, then we can give our local anesthetic
  129. Neuraxial anesthesia
    • Epidural or spinal
    • Dextrose 8.5% increases the baricity, to help stay at a lower level
Card Set
Pharmacology Exam 2
CCOM Pharm Exam 2 flashcards. Separate set contains drugs.