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Pharm > Block 3 > Flashcards

Block 3 Flashcards

1
Q

Propofol

A

USE: maintaine and induce anesthesia for OUTpatient

KINETICS: shorter half life than thiopental (3.5 hrs)–rapid mental return post surgery

**antiemetic

-GABA A receptor activator

SE: pain on injection; excitation; cns (decrease cerebral blood flow, decrease intracranial pressure); cv (SEVERE decrease BP); respiratory depression; abuse liability

CONTRAINDICATION: patients intolerent of decrease in BP

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2
Q

Etomidate

A

USE: induce anesthesia in HYPOTN risk patients

-GABA A receptor activator

SE: pain on injection; myoclonus; cns (reduce cerebral blood flow, reduce intracranial pressure); cv (less effects than thiopental); respiratory depression (less than thiopental); NAUSEA/VOM; INCREASE POST SURG MORTALITY

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3
Q

Ketamine

A

USE: dissociative anesthesia; children undergoing short/painful procedure

Iv, intramusc, oral or rectal

-NMDA receptor antagonist

SE: nystagmus; salivation; lacrimation; spontaneous limb movements; increased muscle tone; INCREASE INTRACRANIAL PRESSURE; EMERGENCE DELIRIUM; increase BP

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4
Q

Dissociative anesthesia

A
  • profound analgesia
  • unresponsive to commands (eyes may still be open)
  • amnesia
  • bronchodilation
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5
Q

Midazolam

A

USE: conscious sedation; anti anxiety; amnesia for MINOR surgery; tooth extraction

  • effects reversed by FLUMAZENIL
  • GABA A receptor activator
  • short acting

***Anti anxiety for PRE SURGERY

SE: reperatory depression/arrest esp w/ IV

CONTRAINDICATIONS: neuromusc dz; parkinson’s; bipolar

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6
Q

Isoflurane

A

USE: induce and maintain anesthesia

**co admin w/ NO to reduce isoflurane dose

-mod blood:gas partition coeff

SE: bronchodilation, AIRWAY IRRITANT; DECREASE TIDAL VOL; INCR RR; cv (increase HR, arrhythmias); INCREASE INTRACRANIAL PRESSURE

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7
Q

Desflurane

A

USE: for OUTpatient surgery; skeletal musc relaxant; NOT for induction

-V low blood:gas partition coeff (v rapid induction/recovery)

SE: cough/bronchospasm; incr bp and HR; resp irritant

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8
Q

Sevoflurane

A

USE: induction and maintenance of anesthesia; INpatient and OUTpatient; children and adults

NOT a respiratory irritant

  • v low blood:gas partition coeff
  • 5% metab to fluroide ion in liver –>damage

SE: cv (similar to isoflurane but not as much incr in HR); less respiratory depression; NOT irritant

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9
Q

Nitrous Oxide

A

USE: OUTpatient dentistry –> sedation and analgesia; adjunct w/other inhaled anesthetics allows for decreased dose

  • weak anesthetic
  • v insoluble in blood; rapid induction/recovery
  • it dilutes O2 when discontinued thus put patient on 100% O2 during emergence

SE: decreases myocardial fx; abuse liability

CONTRAINDICATION: pneumothorax (bc can exchange w/N in any air containing cavity)

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10
Q

Cocaine

A

USE: topical anesthesia for upper respiratory tract….lol yeah that’s what it’s used for

  • ester
  • blocks NE uptake into presyn nerves
  • potent vasoconstrictor

SE: toxicity, potential for abuse

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11
Q

Procaine

A

USE: infiltration anesthesia

  • low potency
  • slow onset
  • short DOA

-ester

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12
Q

Tetracaine

A

USE: spinal anesthesia; topical/opthalamic prep; NOT for peripheral nerve block

  • long acting
  • more potent
  • longer DOA

-ester

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13
Q

Benzocaine

A

USE: apply to wounds/ulcerated surface = long period of relief (for BURNS)

  • low solubility in water
  • ester
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14
Q

Lidocaine

A

USE: wide range

  • faster, more intese, longer than procaine
  • use w/epinepherine to decrease rate of absorption and decrease toxicity
  • intermediate DOA
  • amide
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15
Q

Bupivacaine

A

USE: prolonged anesthesia; local anesthetic

**provide more sensory than motor block

SE: more CARDIOTOXIC

  • amide
  • long acting
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16
Q

Ropivacaine

A

USE: epi and regional anesthesia

**more motor sparing than Bupivacaine

SE: LESS cardiotoxic than Bupivacaine

  • amide
  • long acting
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17
Q

Sodium thiopental

A

USE: induce anesthesia for INpatient

KINETICS: doa (10min); long half life (12hrs) so hangover effect
-GABA A receptor activator

-can admin rectally in pediatric patients

SE: cns (decrease cerebral blood flow, decrease intracranial pressure); cv (vasodilation-decrease preload); respiratory depression

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18
Q

Antidepressants

A

All antidepressants affect the functioning of brain biogenic amine (NE, DA, 5HT) systems; some show selectivity toward a particular amine

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19
Q

Localization of NE neurons

A

Locus coeruleus, and innervate nearly every part of CNS

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20
Q

Localization of DA neurons

A

Substantia nigra (project to striatum) and the ventral tegmental area of midbrain (project to prefrontal cortex and parts of limbic system).

Dopamine Pathways in the brain include: Nigrostriatal, Tubero-infundibular, mesolimbic, and mesocortical

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21
Q

Localization of 5HT neurons

A

Two groups of raphe nuclei and project to most of the brain

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22
Q

GABA Localization

A

Substantia nigra, globus pallidus, hippocampus limbic structures (amygdala, hypothalamus, spinal cord)

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23
Q

Classes of Affective Disorders

A
  1. Depressive Disorders: Disruptive mood dysregulation disorder, major depressive disorder, persistent depressive disorder, premenstrual dysphoric disorder
  2. Bipolar/Related Disorders: Bipolar I, Bipolar II, Cyclothymic Disorder
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24
Q

Selective Serotonin Reuptake Inhibitor (SSRI)

A

Most commonly used anti-depressant. Both long and short half live compounds are available. Less risk of acute toxicity and overdose.

Tx: Major depressive disorder, OCD, panic disorder, social phobia, PTSD, generalized anxiety disorder, PMS

SE: N/V, insomnia, nervousness, sexual dysfunction.

Black box warning in teens.

SSRI discontinuation syndrome (within 1-7 days of stopping SSRI) - more common in short acting drugs. Leads to: dizziness, light-headedness, vertigo, anxiety, fatigue, headache, tremor, visual disturbance

Drug interactions: In presence of MAO inhibitors, can lead to hyperthermia, muscle rigidity, CV collapse. FDA requires warnings about associations of SSRIs and SNRIs with neuroleptic malignant syndrome.

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25
Q

Sertraline (Zoloft)

A

SSRI. Similar in action to Fluoxetine, with less effects on drug metabolism.

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26
Q

Fluoxetine (Prozac/Sarafem)

A

First SSRI on market; has effects on drug metabolism. Active metabolite with long half-life. Available as sustained release.

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27
Q

Tricyclic Antidepressants

A

First highly effective drugs for treatment of depression. Now used secondarily to SSRIs and other nerve compounds.

MOA: blockade of transmitter uptake (NE and 5HT), will affect receptors and second messengers.

Rapidly absorbed after parenteral or oral administration. Relatively high concentrations are found in brain and heart.

Long-half life.

Tx: major depression, replaced by SSRIs as primary treatment.

SE: elevation of mood in depressed patients after about 2 to 3 weeks, decreases REM and increases stage 4 sleep, prominent anticholinergic effects, sedation, cardiac abnormalities.

Overdoses: acute toxicity - hyperprexia, hyper or hypotension, seizures, coma and cardiac conduction defects

Drug intxns: Guanethidine, Sympathomimetic drugs (particularly indirect acting ones), and effects on absorption and metabolism of other drugs.

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28
Q

Amitriptyline

A

Tricyclic antidepressant. Require demethylation to become active metabolites which are used as drugs themselves.

Long plasma half-life: 8-1000 hours

Tx; Major depression, and chronic pain.

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29
Q

Atypical Antidepressants

A

Drugs without typical tricyclic structure or SSTRI action. May or may not block catecholamine uptake.

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30
Q

Bupropion

A

Atypical antidepressant: blocks NE and DA uptake

Also approved for nicotine withdrawal and seasonal affective disorder.

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31
Q

Mirtazapine

A

Atypical antidepressant: blocks presynaptic alpha-2 receptors in the brain.

Increases appetite.

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32
Q

Serotonin and NE reuptake inhibitor (SNRI)

A

Block both serotonin and NE uptake.

Side effect profiles are similar to SSRIs.

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33
Q

Duloxetine

A

SNRI. 12-18 hour half-life.

Tx: Same as SSRI, and also: fibromyalgia, diabetic neuropathy, back pain, and osteoarthiritis pain.

Use in caution in patients with liver disease.

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34
Q

Monoamine Oxidase (MAO) Inhibitor

A

Block the oxidative deamination of naturally occurring biogenic amines, such as NE, DA, and 5HT and ingested amines.

MAO is found in mitochondrial fraction of neurons – also in liver, lung and other organs.
MAO-A and B exist, but antidepressant action is likely due to inhibition of MAO-A.

Antidepressant action takes about 2 weeks.

Tx: major depression, not first drug of choice though.

Produces mood elevation in depressed patients - may progress to hypomania, especially in bipolar patients.

SE: Acute toxicity can produce agitation, hallucinations, hyperprexia, convulsions, and changes in blood pressure.

Drug intxn: Tyramine from food - can produce hypertensive crisis.

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35
Q

Phenelzine

A

MAO IRREVERSIBLE INHIBITOR.

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36
Q

Antipsychotic drugs

A

All differ in potency, but basically same mechanism.
Actions of drugs:
-Extrapyramidal: result of dopamine receptor blockage - Dystonias Parkinsonism, Akathisia, and long term tx can lead to tardive dyskinesia, oral-facial dyskinesias, and choreoathetoid movements
-Neuroendocrine effects due to dopamine receptor blockade
-Orthostatic hypotension due to alpha adrenergic receptor blockade
-Cardiac effects (from Thioridazine)
-Weight gain: diabetes related events are more common with atypicals, particularly olanzapine, risperidone, clozapine, and quetiapine.
-Neuroleptic malignant syndrome: fever, mutism, Eps, possible death

Tx: acute psychotic episodes, chronic schizophrenia, manic episodes, augmentation of antidepressant action (Olanzapine, Quetiapine), Tourettes syndrome, Antiemesis (NOT Thioridazine)

SE: Sedation–more pronounced after large doses of low potency agents

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37
Q

Dopamine Receptors - Target of Antipsychotic Drug Action

A

All antipsychotics interact with dopamine systems. Multiple receptors for dopamine in the brain.

D1 type (D1 and D5) - activate adenylyl cyclase

D2 type (D2, D4, D4) - inhibit adenylyl cyclase

Autoreceptors

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38
Q

Chlorpromazine

A

Phenothiazine antipsychotic drug- has an aliphatic side chain. Low to medium potency, and had pronounced anticholinergic actions.

Sedative.

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39
Q

Thioridazine

A

Phenothiazine antipsychotic drug - has a piperidine side chain. Low potency with fewer extrapyramidal actions. Anticholinergic effects as well.

Sedative.

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40
Q

Fluphenazine

A

Phenothiazine antipsychotic drug - has a piperazine side chain. High potency with LESS anticholinergic effects, but MORE extrapyramidal reactions.

Less sedative than other phenothiazine antipsychotic.

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41
Q

Haloperidol

A

Butyrophenone derivative - not chemically related to phenothiazines but is pharmacologically similar to the high potency piperazine derivatives.

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42
Q

Clozapine

A

Atypical antipsychotic drugs (DA + 5HT actions). Less extrapyramidal symptoms. Has more effects on the negative symptoms.

May cause serious agranulocytosis or other blood dyscrasias in small percentage of patients. Weight gain.

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43
Q

ATYPICAL Antipsychotics

A

DA + D-HT2 Receptors

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44
Q

Olanzapine

A

Atypical antipsychotic agents - related to Clozapine. More potent as a 5-HT2 antagonist. Few extrapyramidal symptoms.

No agranulocytosis (as compared to Clozapine). Weight gain and diabetes risk.

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45
Q

Risperidone

A

Atypical antipsychotic agents - combined DA and 5HT receptor antagonist. Has a low incidence of extrapyramidal side effects.

PALIPERIDONE (Invega) is the active metabolite of Risperidone. Both are available as intramuscular depot preparations.

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46
Q

Quetiapine

A

Atypical antipsychotic agent- structurally similar to Clozapine with effects on D2 and 5HT2 receptors.

Has some abuse potential.

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47
Q

Aripiprazole

A

Atypical Antipsychotic agent- D2 partial agonist - approved as adjunct in the treatment of depression.

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48
Q

Major Depressive Disorder

A

Affective disorders, in the “depressive disorder” subtype. Pharmacotherapy is treatment of choice for major depressive disorders.

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49
Q

Psychosis

A

A general germ for major mental disorders characterized by derangement of the personality and loss of contact with reality as evidenced by delusions and hallucinations. There are several causes: schizophrenia, organic brain disorders and drug induced states. Prototype: Schizophrenia.

DSM-5 criteria (at least 2 symptoms during one month, at least one core positive symptom)

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50
Q

Schizophrenia

A

Unknown etiology, many theories: Dopamine Hypothesis.

Tx: drug tx is most common therapy, but it is NOT curative.

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51
Q

Mesocortical Pathway

A

One of the dopamine pathways in the brain.

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52
Q

Mesolimbic pathway

A

One of the dopamine pathways in the brain.

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53
Q

Pain Systems

A

Ascending pathway: Nociceptors - A-delta and C fibers terminate in dorsal horn of spinal cord and transmit somatic and visceral pain – uses glutamate and substance P. Ascend via spinal thalamic pathway from dorsal horn to thalamus - then to limbic nuclei and somatosensory and association cortex.

Descending pathway: Originates in PAG of midbrain and nuclei of rostro-ventral medulla - projects to dorsal horn and release NE, 5HT, and enkephalin. Inhibit the activity of ascending pain pathways.

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54
Q

Major families of opioid peptides

A
  1. Endorphins, precursor: proopiomelanocortin
  2. Enkephalins, precursor: proenkephalin
  3. Dynorphins, precursor: prodynorphin
    Encoded by three distinct genes
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55
Q

Opioid receptors

A

Three major classes - all belong to GPCRs, homology amongst all three is 65%. All are coupled negatively to adenylyl cyclase by Gi: activation of receptor by agonist decreases adenylyl cyclase activity, thus decreasing cAMP, leads to more K+ efflux and cellular hyperpolarization. Decrease in Ca2+ influx and lower intracellular concentrations of free calcium. Overall: DECREASE in neuronal release of neurotransmitters.

1. Mu 
2. Kappa
3. Delta
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56
Q

Mu receptors

A

Endogenous ligands: enkephalins, B-endorphin
Drug: morphine, fentanyl, methadone, meperidine, heroin, codeine, oxycodone, buprenorphine, hydromorphone
Antagonist: naloxone, naltrexone

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57
Q

Kappa receptors

A

Endogenous ligands: dynorphins

Drug ligands: Nalbuphine, butorphanol, pentazocine, salvinorin A

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58
Q

Delta receptors

A

Endogenous ligands: enkephalins

Drugs ligands: NONE

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59
Q

Agonists

A

Effects:
• Analgesia (most opioid agonists are equally efficacious in alleviating pain, except codeine and propoxyphene which are less so) - both perception and appreciation of pain are decreases.
• Cough suppression (may not be mediated by opioid receptors).
• Antidiarrheal effect and constipation - effects are both central and peripheral - delay in gastric emptying, spasmodic increases in intestinal tone and decreases propulsive movments. Via mu receptors on GI nerves.
• Euphoria - rush and high
• Sedation
• Respiratory depression - most serious side effect. Via decrease in sensitivity of chemoreceptors in brainstem to CO2. Effect is at least additive with other CNS-depressing drugs.
• Nausea- stimulation of chemoreceptor trigger zone in area postrema.
• Endocrine- decreased release of LH-mu receptor. ADH secretion is increased by mu stimulation and decreased by Kappa stimulation.
• Pupillary constriction (miosis) - due to stimulation of Edinger-Westphal nucleus of oculomotor nerve. Tolerance does not develop to this effect.
• Peripheral vasodilation, reduced peripheral resistance, inhibition of baroreceptor reflexes - orthostatic hypotension/fainting when supine patient assumes head-up position. Due to release of histamine from mast cells leads to vasodilation. Blunting of vasoconstriction in response to increase P(CO2)

All opioid agonists produce tolerance and physical dependence – the abuse/addition liability varies.
All tx: moderate to severe pain.

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60
Q

Morphine

A

Opioid agonist: Mu receptor - prototype strong analgesic, found in opium poppy. Chemically it’s a phenathrene.
Oral to parenteral conversion ratio: approximately 3 to 1. Available in injectable, oral, oral sustained release, and suppository forms.
Extensive first-pass metabolism, low oral potency (about 1/3) and bioavailability.

Duration: 4-5 hours

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61
Q

Methadone

A

Opioid agonist: Mu receptor
Chemically, Phenylheptylamine.
Equipotent with morphine, has good oral bioavailability. Longer duration of action. Used in tx: opioid abuse and chronic pain.

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62
Q

Meperidine

A

Opioid agonist: Mu receptor
Chemically, a phenylpiperidine.
Shorter duration of analgesia than morphine. Forms a TOXIC METABOLITE (normeperidine) that can accumulate with frequent use.
Interacts with MAO inhibitors.

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63
Q

Fentanyl

A

Opioid agonist: Mu receptor, structurally related to MEPERIDINE. 100 x as potent as morphine. Short acting: 1-1.5 hours. Available in injectable form and transdermal patches. Also available as buccal soluble film for breakthrough pain.

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64
Q

Heroin

A

Opioid agonist: Mu receptor. DIACETYL MORPHINE. More lipophilic than morphine. Converted to 6-mono-acetyl morphine and morphine. High abuse potential.
Activated by metabolism.

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65
Q

Codeine

A

Opioid agonist: Mu receptor.
Tx: mild to moderate pain - morphine like efficacy is not possible at any dose of codeine.
Activated by metabolism, and some metabolized to morphine.
Often used in combo with NSAIDs or acetaminophen.
Cough suppression

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66
Q

Oxycodone

A

Opioid agonist: Mu receptor
Tx: moderate to severe pain
Often used in combo with NSAIDs or acetaminophen.
Available as sustained release oral prep- MAJOR abuse problem

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67
Q

Hydrocodone

A

Opioid agonist: Mu receptor
Tx: moderate to severe pain
Often used in combo with NSAIDs or acetaminophen.
Cough suppression
Also available as sustained release oral prep - MAJOR abuse problem

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68
Q

Hydromorphone

A

Other opioid receptor agonist; 2-3x as potent as morphine.

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69
Q

B-Endorphin

A

Endogenous Opioid

Works at Mu receptor
Precursor: proopiomelanocortin

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70
Q

Dynorphin

A

Endogenous Opioid

Works at Kappa receptor
Precursor: prodynorphin

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71
Q

Enkephalin

A

Endogenous Opioid

Works at Delta receptor
Precursor: proenkephalin

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72
Q

Nalbuphine

A

Mu antagonist and Kappa agonist. Similar in efficacy and potency to morphine. Much lower abuse potential. Can precipitate withdrawal in opioid dependent patients. Available only in injectable form.

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73
Q

Buprenorphine

A

Partial mu agonist. Used to treat moderate to severe pain - now available as a patch. Oral buprenorphine combined with NALOXONE to treat opioid dependence.

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74
Q

Naloxone

A

High affinity opioid antagonist f or mu receptors (significantly less for kappa and delta). Much greater activity parenterally than orally. Short duration of action: 1-2 hours. Used to treat opioid overdoses. Can be combined with opioids to decrease parenteral abuse liability.

Extensive first-pass metabolism, low oral potency (about 1/3) and bioavailability.

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75
Q

Naltrexone

A

Opioid antagonist - orally active with long half-life. Can be used to tx: alcoholism and opiate addition.
Also available with a sustained release preparation of morphine.

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76
Q

Dextromethorphan

A

Dexo Isomer of Levorphanol (which is an opioid agonist).
AKA Robitussin
Antitussive- Cough suppression. NOT analgesic. Also an NMDA antagonist.

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77
Q

Tramadol

A

Weak mu receptor agonist - also blocks NE and 5HT uptake. Used to tx: mild to moderate pain. Available for oral use including a sustained release preparation.

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78
Q

Suboxone

A

Pharmacological tx for opioid abuse

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79
Q

Lithium

A
  • Monovalent cation, lightest of alkali metals, blocks manic behavior and treats bipolar depression and mania
  • Blocks IP2->IP, and IP->inositol; this causes depletion of PIP2, and therefore IP3 and DAG
  • Oral admin, readily absorbed
  • Eliminated in urine 95%, extensive tubular reabsorption, t1/2=18-24hrs
  • Na levels affect lithium excretion (more Na excretion, more Li in body), so Thiazide diuretics alter levels
  • Narrow therapeutic window (.6-1.2)
  • Interacts with ACE inhibitors and ang II blockers
  • Toxicity: fatigue, muscular weakness, tremor, GI, goiter, slurred speech/ataxia (OD), SERIOUS at about 2-3 times above therapeutic levels (impaired consciousness, rigidity/hyperactive deep reflexes, coma)
  • Contraindications: pregnant women and while breastfeeding
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80
Q

Valproic Acid

A
  • Carboxylic acid with antiseizure activity (alternative to Lithium)
  • Blocks repetitive neuronal firing, may reduce T-type Ca channels, increases GABA concentration
  • Oral admin, well absorbed
  • Bound to plasma protein – competes with phenytoin; inhibits metabolism of phenobarbital, phenytoin, and carbamazepine
  • Distributes in ECF
  • Toxicity: Sedation, GI upset, weight gain, hair loss, idiosyncratic hepatotoxicity, teratogenicity (spinal bifida)
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81
Q

Divalproex

A
  • Carboxylic acid with antiseizure activity (alternative to Lithium – sometimes used first line in Bipolar)
  • Blocks repetitive neuronal firing, may reduce T-type Ca channels, increases GABA concentration
  • Oral admin, well absorbed
  • Bound to plasma protein – competes with phenytoin; inhibits metabolism of phenobarbital, phenytoin, and carbamazepine
  • Distributes in ECF
  • Toxicity: Sedation, GI upset, weight gain, hair loss, idiosyncratic hepatotoxicity, teratogenicity (spinal bifida)
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82
Q

Carbamazepine

A
  • Mainstay of antiseizure therapy; indicated for bipolar I, acute manic/mixed episodes
  • Blocks Na channels at therapeutic concentration; does not appear to interact with GABA
  • Unpredictable absorption, hepatic enzyme induction, toxicity is dose-related
  • Toxicity: diplopia, ataxia, GI upset, drowsiness, rare blood dyscrasias (not dose related), teratogenic (spinal bifida – less risk than with valproic acid)
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83
Q

Alprazolam

A
  • Anxiolytic – panic disorder, sleep disorders, seizure treatment
  • GABA enhancement, forebrain depression
  • Tolerance (cross-tolerance), dependence (w/drawal – anxiety, insomnia, irritability, headache, hyperacusis, hallucinations, seizures), and abuse (tx – gradual dose reduction, switch to longer acting drugs)
  • Short duration
  • Active metabolite: alpha-hydroxy metabolites (can have much longer half-lives)
  • Decrease of anxiety (limbic), sedation, hypnosis, anterograde amnesia (IV), anticonvulsant (raises seizure threshold), CV and respiratory actions minimal
  • Pharmacokinetics related to liphophilicity – determines rate of entry into CNS
  • Drug interactions: additive CNS depression with most other depressants, and with drugs that affect hepatic metabolism (like Cimetidine!)
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84
Q

Buspirone

A
  • Anxiolytic – an azaspirodecanedione cmpd neither chemically nor pharmacologically related to benzos
  • Partial agonist at 5-HT1A receptors (high affinity) – inhibits adenylate cyclase, opens K channels
  • Also binds to dopamine D2 receptors
  • Little sedation, no dependence, delayed onset
  • T1/2: 2-11 hours
  • Less sedating than benzos, and no cross-tolerance with benzos
  • Does not potentiate other sedative-hypnotics and depressants, nor suppress their symptoms
  • Used in tx of generalized anxiety syndrome – therapeutic effect may take 1-2 weeks to occur
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85
Q

Flurazepam

A
  • Primarily used as hypnotic
  • Tolerance (cross-tolerance), dependence (w/drawal – anxiety, insomnia, irritability, headache, hyperacusis, hallucinations, seizures), and abuse (tx – gradual dose reduction, switch to longer acting drugs)
  • Decrease of anxiety (limbic), sedation, hypnosis, anterograde amnesia (IV), anticonvulsant (raises seizure threshold), CV and respiratory actions minimal
  • Pharmacokinetics related to liphophilicity – determines rate of entry into CNS
  • Drug interactions: additive CNS depression with most other depressants, and with drugs that affect hepatic metabolism (like Cimetidine!)
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86
Q

Diazepam

A
  • Anxiolytic, sedative (IV), muscle relaxant (partly mediated in SC – can be used in pt’s with muscle spasm of almost any origin, including local trauma)
  • GABA enhancement, broad CNS depression
  • Tolerance (cross-tolerance), dependence (w/drawal – anxiety, insomnia, irritability, headache, hyperacusis, hallucinations, seizures), and abuse (tx – gradual dose reduction, switch to longer acting drugs)
  • Most rapidly absorbed, long duration
  • Active metabolite: Desmethyldiazepam (can have much longer half-lives)
  • Decrease of anxiety (limbic), sedation, hypnosis, anterograde amnesia (IV), anticonvulsant (raises seizure threshold), CV and respiratory actions minimal, muscle relaxant
  • Pharmacokinetics related to liphophilicity – determines rate of entry into CNS
  • Drug interactions: additive CNS depression with most other depressants, and with drugs that affect hepatic metabolism (like Cimetidine!)
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87
Q

Flumazenil

A
  • Benzodiazepine - anxiolytic
  • Tolerance (cross-tolerance), dependence (w/drawal – anxiety, insomnia, irritability, headache, hyperacusis, hallucinations, seizures), and abuse (tx – gradual dose reduction, switch to longer acting drugs)
  • Decrease of anxiety (limbic), sedation, hypnosis, anterograde amnesia (IV), anticonvulsant (raises seizure threshold), CV and respiratory actions minimal
  • Pharmacokinetics related to liphophilicity – determines rate of entry into CNS
  • Drug interactions: additive CNS depression with most other depressants, and with drugs that affect hepatic metabolism (like Cimetidine!)
88
Q

Lorazepam

A
  • Anxiolytic
  • Tolerance (cross-tolerance), dependence (w/drawal – anxiety, insomnia, irritability, headache, hyperacusis, hallucinations, seizures), and abuse (tx – gradual dose reduction, switch to longer acting drugs)
  • Less liphophilic, absorption/onset slower, longer DOA
  • No active metabolite
  • Decrease of anxiety (limbic), sedation, hypnosis, anterograde amnesia (IV), anticonvulsant (raises seizure threshold), CV and respiratory actions minimal
  • Pharmacokinetics related to liphophilicity – determines rate of entry into CNS
  • Drug interactions: additive CNS depression with most other depressants, and with drugs that affect hepatic metabolism (like Cimetidine!)
89
Q

Zolpidem

A

-Insomnia tx (Ambien!!)
Imidazopyridine derivative binds to benzodiazepine receptors, less disruption of sleep architecture (stage 3 & 4 sleep preserved, minor effects on REM)
-Binds to Omega-1 BDZ receptor
-Antagonized by Flumazenil
-Relative lack of muscle relaxant or anxiolytic effects
-Longer acting cmpd available
-Dose reduction to prevent daytime drowsiness required

90
Q

Baclofen

A
  • GABA mimetic agent that works at GABA-B receptors
  • Results in hyperpolarization, and thus presynaptic inhibition, which can result in decreases release of excitatory transmitters such as glutamate
  • At least as effective as diazepam, and produces much less sedation
91
Q

Tizanidine

A
  • Alpha2 adrenergic agonist related to clonidine; may enhance presynaptic and postsynaptic inhibition
  • May have similar efficacy to diazepam and baclofen in relieving muscle spasm
  • Side effects include drowsiness, hypotension, dry mouth, and asthenia
92
Q

Bipolar disease

A
  • Bipolar I: at least one manic episode
  • Bipolar II: one or more hypomanic episode, and one or more episodes of major depression
  • Cyclothymic: mild bipolar I
  • Tx: lithium, antiseizure agents, atypical antipsychotics
93
Q

GABA receptor-chloride ion channel complex

A

-Have sites where benzodiazepines and barbiturates act at

94
Q

Benzodiazepines

A
  • Primary drugs used for tx of anxiety and insomnia
  • Act at sites on the GABA-receptor chloride ion channel complex: benzo receptor is found on GABA receptor-Cl channel complex, enhances action of GABA, increases frequency of GABA-induced openings
95
Q

Hypnotics

A
  • All benzodiazepines have hypnotic actions, but the ones that are primarily used are:
  • Flurazepam
  • Temazepam
  • Triazolam
  • Quazepam
  • Estazolam
96
Q

Barbiturates

A
  • Used to be used as sedative hypnotics – not really used any more (secobarbital); anticonvulsant (phenobarbital), induction of anesthesia (thiopental)
  • Effects: general CNS depression (sedation, hypnotic, anesthesia), anticonvulsant, respiratory depression
  • Tolerance – both metabolic and pharmacodynamics
  • Physical dependence – can get withdrawal symptoms such as anxiety, agitation, insomnia, tremor, life threatening seizures
  • Acute poisoning: stupor, coma, respiratory depression
  • Drug interactions: additive with other CNS depressants, drugs that affect microsomal drug metabolism
97
Q

Alcohol

A
  • NOT very potent

- standard dose = 14g –> BAC 0.03

98
Q

Ethanol

A
  • dose dependent cns depressant
  • absorbed in sm intestine
  • distributes to total body water; freely membrane permeable
  • metabolism: significant 1st pass in liver; 90-98% ingested is metab to acetaldehyde (2 different pathways: Alcohol dehydrogenase path, microsomal ethanol oxidizing sys–see other notecards)
  • excretion: 2-10% as ethanol through lungs and urine
99
Q

Alcohol dehydrogenase pathway

A

-primary pathway for ethanol oxidation to acetaldehyde

**amt of NAD+ available is rate limiting

  • primarily in the liver
  • zero order elimination kinetics
100
Q

Microsomal ethanol oxidizing system

A

-high Km (contributes little to the metabolism of ethanol to acetaldehyde at concentrations below 100mg/dl)

**induced in alcoholics (CYP2E1)–this cyp450 influences the metabolism of other drugs

101
Q

Aldehyde dehydrogenase

A
  • oxidizes aldehyde to acetate

- inhibited by disulfiram

102
Q

Drugs used for management of alcohol withdrawal syn

A
  • benzodiazepines–Diazepam
  • chlordiazepoxide

**gradual reduction of dose to taper off

103
Q

Naltrexone

A

USE: reduces urge to drink

MECH: opioid receptor antagonist

*best together w/ psychosocial therapy

104
Q

Acamprosate

A

USE: decreases drinking frequency and reduces relapse

MECH: GABA mimetic

SE: generally well tolerated; diarrhea

105
Q

Disulfiram

A

USE: aversion therapy of alcohol

MECH: inhibition of aldehyde dehydrogenase (causes buildup of acetaldehyde when consume alcohol, very uncomfortable)

  • causes acetaldehyde syn
  • not very effective
106
Q

Caffeine

A

USE: increase alertness, sustained attn; decrease fatigue and drowsiness; tx headaches

MECH: 1.competitive antagonist of adenosine receptors (blocks their usual postsyn IPSPs and inhibition of glutamate release; thus causes DISINHIBITION=cns stim)

         2. inhib of phosphodiesterase --> increased cAMP
         3. induces release of calcium from intracell stores

SE: -nervousness, restlessness, tremors; high doses–>stim medullary respiratory, vasomotor and vagal centers

   - stim myocardium; dialates coronary blood vessels, CONSTRICTS cerebral blood vessels
   - increases gastric secretion
   - modest bronchodilator
   - tolerance development to stim effects
   - physical dependence
107
Q

Cocaine

A
  • weak base (unprotonated form is unionized; this form predominates at alkaline pH)
  • used in 2 forms: cocaine hydrochloride (water soluble); cocaine free base (lipid soluble, volatile)
    - free base made by extracting cocaine base from alkaline solution into ether
  • ABSORBED through most mucous membranes, incl lungs
  • IV or smoked faster effect than transmural or oral
  • METAB by serum and liver esterases
  • v short half life (50 min)
  • *to test for use: look for metabolites in urine

MECH: potent inhib of NE, dopa, 5HT reuptake

 - ax on dopamine syn in ventral striatum = central reinforcing effects
 - increases tyrosine and tryptophan hydroxylase

EFFECTS: vasoconstriction, tachycardia; increased alertness; euphoria/elation

WITHDRAWAL is mild

OVERDOSE seizures, cardiovasc effects

**fetal affects more significant than alcohol (low birth weights, learning/emotional problems, attachment disorder)

108
Q

Amphetamine

A

-weak base
-longer DOA than cocaine (4-6 hrs)
METAB: predominantly deaminated to benzoic acid; also excreted unchanged as amphetamine (excretion increased in acid urine)

MECH: releases NE, dopa, 5HT

 - blocks NT uptake
 - direct partial agonist of alpha adrenergic receptors
 - MAOI at high doses

EFFECTS: wakefulness, alertness, decreased fatigue (more done/more errors); enhances athletic/intellectual performance; increases self confidence; elevates mood; increased motor and speech ax; respiratory stim; decrease appetite

USE: narcolepsy, ADHD

109
Q

Methamphetamine

A
  • better cns bioavail
  • more cns effect
  • higher abuse liability

**refer to amphetamine card for effects, metabolism, etc.

110
Q

Methylphenidate

A

-not actually an amphetamine bt structurally/mechanistically v similar

USE: ADHD

**refer to amphetamine card for effects, metabolism, etc

111
Q

Side Effects of Amphetamine and methylphenidate

A
  • insomnia
  • abdominal pain
  • anorexia/weight loss
  • supression of growth
  • fever
112
Q

Toxicity of amphetamine and methylphenidate

A
  • acute toxicity –> increased HR, vasoconstriction; dizziness, restlessness, tremor
  • psychosis (excessive dopa)
  • neurotoxicity – abuse can lead to permanant inellectual problems
  • very high abuse liability
113
Q

Nicotine

A

MECH: agonist of nicotinic cholinergic receptors (sympathetic activation=release of epi; parasymp activation = PREDOMINANT and has GI effects incl nausea, increased motility)

EFFECTS: **cns stimulant

 - increased alertness; activates dopa signalling in nucleus accumbens thus reinforcing; muscle relaxant
 - lungs to brain in 7 sec
 - tolerance occurs throughout the day

WITHDRAWAL Sxs: irritability, impatience, hostility, anxiety, depression, difficulty concentrating, increased appetite, weight gain

114
Q

Bupropion

A

USE: reduces craving and nicotine withdrawl sxs

MECH: unknown

SE: dry mouth, insomnia

115
Q

Varenicline (chantix)

A

USE: reduce craving and withdrawal of nicotine

MECH: partial agonist of cns nicotinic receptors –> reduces the effects of the full agonist nicotine

SE: nausea, insomnia, headache, constipation

**increases throught of suicide and depression

116
Q

Fidaxomicin

A

MECH: inhibitor of rna polymerase thus inhibits rna synthesis

USE: C. Diff inf (3rd line to metronidazole, vancomycin)

-oral, poorly absorbed

SE: GI upset, GI bleeding

117
Q

Metronidazole

A

MECH: anaerobes reduce nitro group and the product produced disrupts dna; it inhibits nucleic acid syn

USE: anaerobes; C. Diff (mild to mod cases); combination tx for H. Pylori; Gardnerella vaginalis

SE: nausea, vomiting, anorexia/weight loss, diarrhea, transient leukopenia, neutropenia, thrombophlebitis post IV infusion, bacterial and fungal superinfections (candida)

118
Q

Aminoglycosides

A
  • gentamicin
  • tobramycin
  • amikacin
119
Q

Gentamicin

A

MECH: transported into bacteria by energy requiring AEROBIC process; binds to several ribosomal sits to stop initiation, premature release of ribosome from mRNA, causes mRNA misreading

Cmax/MIC

USE: gram NEG aerobes; enterobacteriaceae, pseudomonas, klebsiells

  • only for serious infections
  • use with cell wall inhibitors for gram POS

IV, IM or topically

SE: nephrotoxicity, ototoxicity

120
Q

Tobramycin

A

MECH: transported into bacteria by energy requiring AEROBIC process; binds to several ribosomal sits to stop initiation, premature release of ribosome from mRNA, causes mRNA misreading

Cmax/MIC

USE: gram NEG aerobes; enterobacteriaceae, pseudomonas, klebsiells

  • only for serious infections
  • use with cell wall inhibitors for gram POS

IV, IM or topically

SE: nephrotoxicity, ototoxicity

121
Q

Amikacin

A

MECH: transported into bacteria by energy requiring AEROBIC process; binds to several ribosomal sits to stop initiation, premature release of ribosome from mRNA, causes mRNA misreading

Cmax/MIC

USE: gram NEG aerobes; enterobacteriaceae, pseudomonas, klebsiells

  • only for serious infections
  • use with cell wall inhibitors for gram POS
  • *can also be used for some gentamicin and tobramycin resistant strains

IV, IM or topically

SE: nephrotoxicity, ototoxicity

122
Q

Tetracyclines

A
  • minocycline

- doxycycline

123
Q

Minocycline

A

MECH: transported into cells; bind 30s ribosomal subunits –> prevent attachment of aminoacyl tRNA to acceptor site

USE: rickettsia, chlamydia, mycoplasma, lyme dz, alternative for syphilis and gonorrhea
-oral

SE: GI disturbances; pseudomembranous enterocolitis; candida superinfection in colon; photosenstivity; teeth discoloration; bone deposition
*calcium binds to tetracyclines inhibiting their absorption

CONTRAINDICATIONS: children, pregnancy

124
Q

Doxycycline

A

MECH: transported into cells; bind 30s ribosomal subunits –> prevent attachment of aminoacyl tRNA to acceptor site

USE: rickettsia, chlamydia, mycoplasma, lyme dz, alternative for syphilis and gonorrhea
-oral

SE: GI disturbances; pseudomembranous enterocolitis; candida superinfection in colon; photosenstivity; teeth discoloration; bone deposition
*calcium binds to tetracyclines inhibiting their absorption (antacids and calcium and magnesium containing foods decrease their absorption)

CONTRAINDICATIONS: children, pregnancy

125
Q

Tigecycline

A

MECH: binds 30s ribosomal subunit, blocks tRNA entry

USE: skin infetions; complicated intra abdominal inf; community acquired pneumonia
-IV only

SE: nausea, vomiting; enterocolitis; calcium binding (similar to tetracycline issue)
**higher death rates

126
Q

Chloramphenicol

A

MECH: interferes w/ binding of aminoacyl tRNA to 50s subunit, inhibits peptide bond formation

USE: broad spectrum; alternate tx for meningitis; brain abscesses
**v serious SE thus last resort

SE: bone marrow depression can progress to fatal aplastic anemia; grey baby syn; optic neuritis, blindness; GI effects; enterocolitis

127
Q

Macrolides

A
  • erythromycin
  • clarithromycin
  • azithromycin
128
Q

Erythromycin

A

MECH: bind 50s ribosomalsubunit to block protein syn via blocking translocation step

USE: gram POS; alternate in beta lactam allergic pts; chlamydia; legionella; bordatella; campylobacter

SE: nausea, vomiting; inhib CYP3A4 metabolism; increased risk of arrhythmias, cardiac arrest

129
Q

Clarithromycin

A

MECH: bind 50s ribosomal subunit which blocks protein syn via blocking translocation step

USE: alternate to erythromycin; pharyngitis, respiratory inf; H. Pylori; tx atypical mycobacterial inf

SE: fewer GI issues than erythro; cardiovascular risk

130
Q

Azithromycin

A

MECH: bind 50s ribosomal subunit which blocks protein syn via blocking translocation step

USE: respiratory inf; off label for GI pathogens; chlamydia; gonorrhea w/ceftriaxone

SE: fewer GI issues than erythro; few drug interax; cardiovasc risk (lower than erythro)

131
Q

Clindamycin

A

MECH: binds 50s ribosomal subunit which blocks translocation along ribosomes

USE: gram POS and ANAEROBES; B fragilis

  • *original cause of C Diff colitis
  • supresses bacterial production (strep causing necrotizing faciitis)

SE: antibiotic assoc enterocolitis; GI irritation, diarrhea; hepatotoxicity

132
Q

Linezolid

A

MECH: binds 50s ribosomal subunit which interferes w/ formation of 70s initiation complex

USE: vancomycin resistant enterococcus faecium; staph aureus MRSA, MSSA; strep A and B; strep pneumo

SE: non selective inhib of MAO (avoid foods w/tyramine); diarrhea, headache, nausea/vom; enterocolitis; superinfections; bone marrow suppression

CONTRAINDICATION: SSRIs, tricyclics, triptans, buspirinone

133
Q

Sulfamethoxazole

A

MECH: inhib folate syn; inhib of dihydropteroate syn

USE: UTI w/ trimethoprim

SE: hypersensitivity; serum sickness; GI disturbances; renal damage from crystalluria; inhib CYP2C9

134
Q

Silver sulfadiazine

A

MECH: inhib folate syn; inhib dihydropteroate syn

USE: topically for burns

SE: hypersesitivity; serum sickness; GI disturbances; renal damage from crystalluria; inhib CYP2C9

135
Q

Trimethoprim

A

MECH: inhib folate syn; inhib dihydrofolate reductase

USE: used w/ sulfamethoxazole: UTI, upper resp inf, ear inf, pneumocystis jiroveci

NOT for anaerobes

SE: nausea, vomiting, diarrhea; rashes; eosinophilia, neutropenia; bone marrow supression

136
Q

Selection of appropriate drug?

A
  1. Selective toxicity
  2. Type of organism
  3. Anatomical location of organism
  4. Host status
137
Q

Bactericidal vs Bacteriostatic?

A

Bactericidal kills the bacteria, whereas bacteriostatic stops the active growth of the bacteria but they are still viable
-cidal drugs are good for: immunosuppressed pt’s, or when infection is in meningitis, endocarditis, deep bone infections, artificial device implants

138
Q

Time-dependent killing

A
  • Best clinical effect when remain 4x above MIC for >50% of the time
  • Betalactams (penicillins, cephalosporins, etc)
139
Q

Concentration-dependent killing

A
  • Maximize the peak concentration (usually about 8x higher than MIC)
  • Aminoglycosides (gentamicin, tobramycin)
  • Still have effects even when conc
140
Q

Killing dependent on concentration x time

A
  • AUC dependent killing
  • AUC24/MIC (expressed in hours – generally want >125)
  • Quinolones (also Cmax)
141
Q

Beta-lactams

A
  • Large group of drugs
  • Bactericidal (-static under some conditions)
  • Activity maximal on actively growing bacteria (premedication with certain drugs can disrupt this)
  • Mech: inhibit transpeptidases (PBPs), which catalayze cell wall crosslinks – competitive, irreversible
  • Resistance: most prevalent is beta-lactamase, an enzyme that cleaves beta-lactam; altered PBP (eg methicillin resistance of staph); beta-lactam can’t reach PBP (problem with many G-)
  • Time-dependent killers
142
Q

Penicillins

A
  • Low penetration into CSF (increases during meningitis)
  • Some orally, others require IV/IM; generally well-distributed
  • Short t1/2 (30min-few hours); Procaine and benzathine penicillin are slow-release IM forms that can increase t1/2
  • Renal elimination – anion transport
  • Names end with “-cillin”: amoxicillin, ampicillin, penicillin G, penicillin V, piperacillin, ticarcillin, oxacillin
  • Adverse reactions: allergic (can be VERY severe – predict with PRE-PEN; anaphylaxis, serum sickness, rash), fever, diarrhea, enterocolitis, elevated liver enzymes, hemolytic anemia, seizures (esp when infusing directly into CSF)
143
Q

Penicillin G & V

A
  • V is more acid stable than G (V can survive stomach acid!)
  • V: oral
  • G: IM/IV
  • For G+ and G- cocci (non beta-lactamase producing)
  • GRAM+: Streptococcus – many, 1st line against strep throat (NOT staph and NOT bacterioides)
  • GRAM-: Neisseria meningiditis meningitis, syphilis (treponema pallidum) – IM
  • Also good activity against Bacillus anthracis, listeria, actinomyces
144
Q

Oxacillin

A
  • IV, IM
  • For beta-lactamase producing staphylococci (MSSA)
  • Reasonable activity against most streptococci
145
Q

Ampicillin, Amoxicillin

A
  • Various beta-lactamase negative G+ (Listeria, Streptococcus, etc)
  • Some G- (Haemophilus, Neisseria, Escherichia, Salmonella)
  • Alternate for Lyme disease
  • AMPicillin is IV or oral, good for meningitis (bc can be given IV asap), GI infections – beta lactamase negative shigella (bc it stays in GI tract)
  • AMOxicillin is oral; high dose amoxicillin is choice for otitis media in kids..pathogen is changing!
146
Q

Ticarcillin

A
  • By injection
  • Broad G- activity, extended to include Pseudomonas aeruginosa, some Enterobacter and Proteus
  • Often used with beta-lactamase inhibitor
  • Some anaerobes (when combined with beta-lactamase inhibitor)
147
Q

Piperacillin

A
  • Broad G- spectrum including some Pseudomonas and Klebsiella, including those that are ticarcillin-resistant
  • Often used with beta-lactamase inhibitor
148
Q

Clavulanic acid, Tazobactam

A
  • Beta-lactamase inhibitors: beta-lactam analogs that binds irreversibly to beta-lactamase
  • Limit hydrolytic cleavage of beta-lactams by some types of beta-lactamases
  • Not all beta-lactam resistance is due to beta-lactamase
149
Q

Cephalosporins

A
  • Well distributed to most areas, only some reach the CSF
  • Some oral, majority require injection
  • Short t1/2 (one exception)
  • Mechanism is similar to other beta-lactams, and resistance mechanisms are comparable to those of penicillins
  • FIRST GEN: cefazolin, cephalexin
  • SECOND GEN: cefuroxime, cefoxitin
  • THIRD GEN: ceftriaxone, ceftazimide
  • FOURTH GEN: cefepine
  • None of the Cephalosporins good for: Penicillin-resistant strep pneumo, MRSA, Listeria, Actinobacter, Campylobacter, Legionella, C diff
  • Renal clearance (anion secretion)
  • Adverse reactions: allergic reaction (cross reaction depends on if allergic to core or to side groups; shared side chains associated with increased allergic cross reaction – amoxicillin/ampicillin share side chains with 1st and 2nd gen, but NOT with 3rd gen), nausea, vomiting, diarrhea, enterocolitis, hepatocellular damage
150
Q

First generation Cephalosporins

A
  • Mostly effective against GRAM+ (MSSA, Streptococcus) – best for Staph
  • Limited GRAM- activity (limited UTI use)
  • Uncomplicated outpatient skin infections, surgical prophylaxis for skin flora
  • Cefazolim: IV/IM, best GRAM+ activity of 1st gen, longer t1/2 (2 hours)
  • Cephalexin: oral, skin, bone/joint, UTI, respiratory, otitis media, t1/2=50min
151
Q

Second generation Cephalosporins

A
  • Increased GRAM- activity, including Haemophilus influenza
  • Less active against staphylococci
  • some are for anaerobes, some tolerant of GRAM- beta-lactamases
  • Cefuroxime: only second gen to penetrate CSF; good tolerance to many G- beta-lactamases; not great against E coli
  • Cefoxitin: also good for some anaerobes (including Bacteroides), good tolerance to many G- beta-lactamases
152
Q

Third generation Cephalosporins

A
  • More active against G-
  • Good for: Klebsiella, Enterobacter, Proteus
  • Some effective against Pseudomonas aeruginosa (eg Ceftazidine)
  • Less effective against staphylococci
  • Ceftriaxone: G- infections; therapy of choice for gonorrhea (last standing – use in combo), empiric therapy for meningitis; LONG t1/2= 6-9 hours
  • Ceftazidime: effective against many strains of Pseudomonas aeruginosa; also G- activity but amongst the poorest 3rd gen MICs for G+
153
Q

Fourth generation Cephalosporins

A
  • Cefepime: IV, t1/2=2 hours; spectrum similar to ceftazidime except more resistant to type I beta-lactamases
  • More G- coverage, somewhat better G+
  • Empirical treatment of serious inpatient infections where both G+ and G- are possible
  • Penetrates CSF, but not approved for meningitis
154
Q

Imipenem

A
  • IV, well distributed
  • Broad spectrum – serious drug for serious infections
  • Not degraded by most beta-lactamases, including ESBLs!
  • NOT effective against methicillin-resistant staph, some pseudomonads
  • Given with cilastatin, a renal peptidase inhibitor (because it’s susceptible to hydrolysis by renal dipeptidases)
  • Uses: mixed/ill defined infection – such as intra-abdominal, or those not responsive to other drugs (incl those with ESBLs)
  • Adverse effects: hypersensitivity, cross-allergies with penicillins/cephalosporins, seizures, dizziness, confusion, nausea, vomiting, diarrhea, pseudomembranous colitis, superinfection
  • Resistance: associated with loss of an outer membrane protein that facilitates drug entry, or with certain zinc-dependent beta-lactamases (carbapenemases)
155
Q

Aztreonam

A
  • Completely synthetic beta-lactam, a monobactam
  • Used against G- aerobic rods (some Enterobacteriaceae, Haemophilus, some Pseudomonas aeruginosa)
  • NOT useful against G+ and anaerobes
  • NOT degraded by several beta-lactamases (susceptible to some)
  • Can be used with those with known hypersensitivities to penicillins (no allergic cross reaction with other beta-lactams)
  • IM or IV, well distributed, incl CSF (but NOT indicated for meningitis)
  • Adverse effects: seizures, cramps, nausea, enterocolitis, anaphylaxis, transient EKG changes (PVCs, bigeminy)
156
Q

Vancomycin

A
  • Glycopeptide antibiotic, NOT beta-lactam
  • Bactericidal
  • Inhibits cell wall synthesis: binds to free carboxyl end (D-Ala-D-Ala) of pentapeptide, interfering with transpeptidation (cross-linking) and transglycosylation
  • Gram+ ONLY (MRSA, hemolytic Streptococcus, S pneumonia (incl penicillin-resistant), Enterococcus, Clostridium difficile enterocolitis)
  • Empirical meningitis treatment: vancomycin + ceftriaxone
  • IV for systemic infections; oral form for enterocolitis by C diff (not absorbed)
  • Primarily used in serious infections
  • Adverse effect: “red man” syndrome, nephrotoxicity (esp in patients also getting aminoglycosides), phlebitis, ototoxicity (usually only with aminoglycosides)
157
Q

Fosfomycin

A
  • Inhibits synthesis of peptidoglycan building blocks by inactivating enolpyruvyl transferase, an early-stage cell wall synth enzyme (VERY early in process); deprives cell wall of precursors
  • Use: uncomplicated UTIs by E coli, Enterococcus (costly!)
  • Toxicity: Headache, diarrhea, nausea, vaginitis
158
Q

Bacitracin

A
  • Polypeptide, not a beta-lactam
  • Interferes with lipid carrier that exports early wall components through the cell membrane
  • Topical use only! Very nephrotoxic
  • Use: Gram+ cocci and bacilli – Staph, Strep, some activity against Neisseria and Haemophilus, ineffective against Enterobacteriaceae and Pseudomonas
  • RARE internal use for difficult staph infections
  • Toxicity: allergic dermatitis (may be comtaminants from bacillus)
159
Q

Polymyxin B

A
  • Act as cationic detergents that bind LPS in outer membrane of G-
  • Uses: Topical for Pseudomonas and other GRAM-; rare IM or intrathecal use for SERIOUS G- infections (Pseudomonas)
  • Toxicity: systemic use potential for serious nephrotoxicity and neurotoxicity; few problems topically
160
Q

Daptomycin

A
  • Cyclic lipopeptide
  • Binds to bacterial cytoplasmic membrane, causing rapid membrane depolarization (stops essential metabolic and catabolic steps)
  • Bactericidal (and rapid)
  • Uses: complicated skin and skin structure infections (Staph aureus – MRSA, MSSA, Streptococcus, Enterococcus – only vanco resistant), also for Staphylococcus bacteremia
  • NOT for pneumonia – inactivated by lung surfactant
  • Toxicity: nausea, diarrhea, GI flora alterations, muscle pain/weakness (monitor CPK levels)
161
Q

Quinolones

A
  • Inhibits alpha (and possibly beta) subunit of DNA gyrase, thereby interfering with control of bacterial DNA winding (replication and repair)
  • Bactericidal, killing dependent on AUC/MIC (want to be >40; allows for more frequent doses, more drugs/dose, longer half life)
  • Resistant: altered DNA gyrase (fluorinated quinolones still effective); combination of decreased permeability and alterned DNA gyrase
  • Use: Nonfluorinated compounds - Enterobacteriaceae in urinary tract
  • Fluroinated quinolones: Norfloxacin, Ciprofloxacin, Moxifloxacin [in other notecards]
  • *Cannot be exchanged with one another**
  • Toxicity (none high incidence): Nausea, vomiting, abdominal pain, enterocolitis, dizziness, headache, restlessness, depression, rare seizures (contraindicated in those with seizure disorders), rashes (some potentially fatal), EKG irregularities, arrhythmias (prolonged QT interval), peripheral neuropathy (can be permanent), arthrophy and tendon rupture (higher in >60yo)
  • Contraindications: seizure disorders, pregnancy category C, children (possible cartilage damage)
  • Some IV, some oral
  • Fluorinated quinolones are well-distributed
162
Q

Norfloxacin

A
  • Fluorinated quinolone
  • UTIs (although advise AGAINST quinolones for routine UTIs for resistance)
  • Limited use at other sites
163
Q

Ciprofloxacin

A
  • Fluorinated quinolone
  • UTIs and infections diarrhea, bone and joint infections, Chlamydia
  • There are better quinolones for respiratory and gram+ infections (moxifloxacin!)
164
Q

Moxifloxacin

A
  • Fluorinated quinolone
  • Better Gram+ activity than many quinolones, and targets some G-
  • Respiratory infections (NOT for Strep throat) – community-acquired pneumonia, bacterial bronchitis
165
Q

Nitrofurantoin

A
  • Nitroreductase enzyme converts them to reactive compounds (incl free radicals) which can damage DNA
  • Use: G+ and G-; for lower UTIs
  • Toxicity: nausea, vomiting, diarrhea, peripheral neuropathy, hypersensitivity, fever, chills, acute and chronic pulmonary reactions (pulmonary fibrosis in elderly), acute and chronic liver damage, granulocytopenia, leukopenia, megaloblastic anemia, acute hemolytic anemia in those with glucose-6-P dehydrogenase deficiency
166
Q

Rifampin

A
  • Inhibits bacterial RNA synthesis by binding RNA polymerase beta
  • Bactericidal
  • Use: primarily treatment of pulmonary TB, but also prophylaxis of meningococcal meningitis and Haemophilus influenza meningitis (can penetrate mucus, block organisms from setting up long term infection)
  • Toxicity: serious hepatotoxicity with long term therapy, strong induction of hepatic enzymes (CYP 3A, 2C9, 1A, 2A, 2B), orange color (urine, saliva, tears, sweat) with long-term therapy
167
Q

Isoniazid (INH)

A

TB Drug Nicotinic acid derivative.

Use: most important PRIMARY TB DRUG - all patients with INH sensitive strains should receive INH if possible. Always given in combo with other agents.

May also be effective against some strains of M bovis and M kansasii.

For prophylaxis, it can be used alone (6-9 months). For latent TB (infected, but no active disease), CDC recommends INH (9 months) or INH+ Rifapentine (3 months)

MOA: Bactercidal for actively growing bacilli, bacteriostatic for “resting cells.” INHIBITS synthesis of mycolic acids, which are improtant branched hydroxy fatty acids of mycobacterial cell walls; specifically - isoniazid is a prodrug which is activated by the catalase-peroxidase (KatG protein) of the tubercle bacillus; the activated drugs target is the enoyl-acyl carrier protein reductase (InhA protein) which is essential for fatty acid elongated; may also interfere with DNA synthesis

Resistant strains (~1 in 10^6) often result from mutations in KatG or InhA

Oral or parenteral admin. Aluminum containing antacids interfere with absorption.

Rapidly absorbed, readily distributed in tissue fluids, some into CSF, and penetrates into caseous lesions. intracellular and extracellular levels are similar.

N-acetylation is under genetic control: slow acetylators have a half-life 2-5 hours, whereas as ‘rapid acetylators’ have half-life of 70 min.

Metabolites and unchanged drug are excreted in urine mainly.

Side effects: Neurotoxicity, especially peripheral neuritis (due to relative B6 deficiency, this improves significantly with B6 admin and is more prevalent in malnourished or alcoholics).

Hepatotoxicity - subclinical injury in 10-20%; potentially fatal- highly correlated with increased age, monitor hepatic function, use with great caution in those with pre-existing hepatic disease; probably caused by acetylhydrazine, a metabolite of INH.

Infrequent: allergic skin rashes, lupus like syndrome, optic neuritis, fever, blood dyscrasias, elevated blood sugar, arthritic symptoms.

Inhibits metabolism of phenytoin (causes phenytoin toxicity), and may also precipitate convulsion in those with seizure disorders.

168
Q

Rifampin

A

TB Drug Card- Macrocyclic.
Very effective when used with INH or other agents – never used alone.

Inhibits bacterial DNA-dependent RNA polymerase, thereby suppressing RNA synthesis. BACTERICIDAL for intra and extracellular microorganisms.

ALSO LEPROSY:
Widely used in combination therapy - like with DAPSONE for leprosy. This is a very ACTIVE BACTERICIDAL ANTILEPROMATOUS drug.

1 in 10^7 have spontaneous mutations in RNA polymerase.

ORAL admin.
Readily absorbed, distributes to all tissues and body fluids; only limited penetration into CSF. Metabolized in liver by deacetylation, mostly excreted in bile.

Hepatotoxicity - may be severe in alcoholics, elderly, existing hepatic damage.
Potent inducer of multiple CYPs thereby increasing metabolism of other drugs (oral contraceptives, digoxin, quinidine, flucoanazole, methadone, warfarin, sulfonylureas, and many others)

Red/orange color to urine, feces, saliva, sputum, tears, and sweat.
Rash, fever, n/v, diarrhea, pseudomembranous enterocolitis.
Flu like syndrome when given less than 2x/week.

169
Q

Ethambutol

A

TB Drug- Semisynthetic.
Use: in conjunction with other drugs (INH, etc). May also be effective against some strains of M bovis, M marinum, M kansasii, M fortiuitum, M avium intracellulare

Interferes with arabinosyl transferase, blocking cell wall synthesis. May also affect RNA synthesis/stabilization.
Tuberculostatic.

Spontaneous resistance occurs with frequency of 1 in 10^6

ORAL admin. Well absorbed, distributed throughout the body, and adequate levels in CSF.
Metabolized to an ALDEHYDE and a dicarboxylic acid derivative. 2/3 excreted UNCHANGED in urine. Half-life is about 3-4 hours.

Generally well tolerated! NOT HEPATOTOXIC.

Optic neuritis- results in decrease of visual acuity and loss of ability to differentiate from red and green (5-15% incidence)

May increase serum uric acid in about 50% of patients

Rash, joint pain, GI upset, headache, disorientation, hypersensitivity, pulmonary infiltrates

170
Q

Pyrazinamide (PZA)

A

TB Drug-Nicotinamide analog.
Use: in combination therapy. Important component in multi-drug therapy.

Blocks mycolic acid synthesis by inhibiting fatty acid synthase I. BACTERICIDAL- sometimes bacteriostatic.

1 in 10^7 develop by spontaneous resistance.

ORAL admin.
Well absorbed, widely distributed, including the CSF. Unchanged drug and metabolites primarily excreted in urine.

Hepatic damage - up to 15% incidence; may be severe/potentially fatal (especially when combined with Rifampin)

N/v/drug fever and hyperuricemia

171
Q

Streptomycin

A

TB Drug Aminoglycoside: see antibacterial handout as well.

Use: first effective agent available for TB, is now LEAST used of the “first line” TB agents.

Usually reserved for the MOST SERIOUS forms of TB (disseminated cases)

BACTERICIDAL. Binds to several ribosomal sites, usually at 30S/50S interfaces - restricts polysome formation (stops initiations) and causes mRNA misreading

1 in 10^7 cells develop spontaneous resistance.

PARENTERAL (IM) admin.
Distributed mainly in the ECF. Does NOT penetrate into cells or CNS (lipid-insoluble) and will not kill intracellular microbes.
Most excreted unchanged in the urine.

Ototoxicity - affects both balance and hearing. Also nephrotoxic.

172
Q

Second Line TB Drugs (not bolded, but good to know?)

A

Used as part of drug combinations when resistance to primary drugs occur or in case of failure of clinical response. Expert guidance needed to deal with effects.

None of these need to be memorized:
• Quinolones, cycloserine, ethionamide, aminosalicylic acid, kanamycin, capreomycin, viomycin, thioacetazone, bedaquiline

173
Q

Rifabutin

A

Atypical mycobacterial drug-
Rifampin analog for single-agent prophylaxis of M avium intracellulare (MAC) in AID patients - recommended for those with low CD4 counts (,100/mm3). Good for multi-drug treatment of MAC or other mycobacteria.

May be substituted for Rifampin in some of the combination treatment regiments.

ORAL admin. ~20% absorption, widley distributed, and the metabolites are excreted in the urine.

Similar to Rifampin but less frequent - most common are nausea and rash. Drug interactions similar to rifampin: but less potent CYP inducer.
At higher doses, may also cause headache, myalgia, polyarthralgia/arthritis, uveitis (ocular inflammation)

174
Q

Clarithromycin

A

Atypical mycobacterial drug-

Macrolide antibacterial - see antibiotics lecture.
Part of multi-drug regimen for treatment of M avium intracellular in AID patients.

Also used for MAC prophylaxis, and combination therapy for M celatum.
Synergistic or additive IN VITRO with Rifabutin or Clofazimine.

Bactericidal - even for intracellular forms.

175
Q

Dapsone

A

Leprosy Drug- 4,4, diaminodiphenysulfone
Used in combination theraoy with other (Rifampin) for Leprosy– WHO recommend therapy with multiple drugs for all leprosy patients. Its also used as prophylaxis for leprosy patients.

Prophylaxis and treatment of Pneumocystis Jiroveci (carinii) in AIDS patients. 
Acne vulgaris (topical)
Dermatitis Herpetiformis (Oral)

Same as sulfonamides - structural analog of para-aminobenzoic acid (PABA) and inhibits synthesis of folic acid. Bacteriostatic.

ORAL admin. Completely absorbed from GI tract. Widely distributed to body fluids and tissues; especially concentration in infected skin. Metabolized by the same enzyme which acetylates INH – thus it is affected by the slow/fast acetylator polymorphisms. Metabolites are excreted in the urine.

Hemolytic anemia and methemoglobinemia

Allergic reactions, drug fever, n/v, vertigo, tinnitus, blurred vision, peripheral neuropathy, and hepatitis

176
Q

Clofazimine

A

Leprosy Drug
Phenazine dye.
Used for combination chemotherapy - often for sulfone-resistant leprosy. Also in combination therapy for MAC in AIDs patients.

Poorly understood but binds to mycobacterial DNA interfering with reproduction and growth.

ORAL admin. 
Variable absorption (45-60%) from GI tracts. Widely distributed in the body with a long retention time. Highly lipophilic, deposited in fatty tissue, skin, cells of the RES, and the distal small intestine; slowly released from these sits so serum half-life can be up to 2 months. No significant metabolism, primarily biliary excretion.

Generally well-tolerated, bright red color; may cause red-brown pigmentation of the skin, sputum, urine, and sweat. GI intolerance.

177
Q

Amphotericin B

A

Systemic Antifungal Drug
Effective BROAD SPECTRUM agent for most serious systemic mycoses.

Effective against: Candida, histoplasma, cryptococcus, coccidoides, rhodotorula, blastomyces, paracoccidoides, sphorthrix, cladosporium, phialophora, torulopsis. Variable effectiveness against: Aspergillus, Mucor, Rhizopus, Fusarium.

FUNGISTATIC at serum levels - only drug available for many infections. Due to its severe side effects, its used only for proven or highly suspected systemic infections.

Prevents relapse of Histoplasma or Cryptococcus in AIDS patients.

Very LIPOPHILIC - binds ergosterol in fungal membranes producing membrane instability/leakage. Fungi that lack, or have decreased levels of ergosterol ARE RESISTANT.

IV for 6-12 weeks as amphotericin deoxycholate. May be given intrathetcally, locally, or intraperitoneally. NOT absorbed in GI tract. ORAL admin only effective on fungi in GI lumen. Anywhere between a cumulative total of 200 mg and 3-4 g amphotericin will be administered. In addition to daily dose, TOTAL CUMULATIVE DOSE IS very important to track for renal toxicity.

Liposomal amphotericin now available: 20 to 50x more costly than standard amphotericin. Easier to administer and there are fewer side effects.

Negligible oral absorption - distribution aver IV dose is UNKNOWN. Detectable in serum 7 weeks after dose stopped - strong tisue binding causes terminal elimination phase with half-life of more than 15 days.
Poor and limited pentration into the CSF- intrathecal admin necessary for some meningitis (like Coccidioides). Principal method of elimination is unknown.

TOPICAL formulation - good tx for cutaneous or mucosal Candida. Not effective against dermatophytes.

Side effects: Fever, n/v, headache, chills, azotemia (high BUN)

Hypotension, hypokalemia, tachypnea

90% will show NONPERMANENT nephrotoxicity – enahnces toxicity of other renally excreted drugs (like flucytosine) - lower GFR; electrolyte imbalance – all together can lead to permanent renal damage related to the total drug dose– that’s why you need to monitor hepatic and renal function regularly. Liposomal amphotericin may be less nephrotoxic.
Reversible hypochromic, normocytic anemia. Thrombophlebitis can occur with IV admin.

178
Q

Fluccytosine

A

Systemic Antifungal Drug

Use: serious infections due to candida, cryptococcus, torulopsis, chromomycosis.
Septicemia, endocarditis, meninigitis, urinary and pulmonary infection.
Used in CONJUCTION (synergistic) with AMPHOTERICIN, or with “-conazole” drugs – meaning the Imidazoles and Triazoles.

Fungi contain a cytosine deaminase not found humans which converts 5-FC to 5-FU– metabolites of 5-FU then block nucleic acid synthesis; resistance usually occurs in mutants which lack cytosine deaminase completely.

ORAL capsules - well absorbed and distributed, including the CSF. When given with amphotericin B it permits reducion of amphotericin dose (acts synergistically against Cryptococcus).

90% is excreted unchanged in the urine!

Side effects: n/v/d/enterocolitis, and rash
Leukopenia, thrombocytopenia (potentially fatal)
Reversible elevated heaptic enzymes occurs in 5% of patients.
May accumulate to renal failure or renal insufficiency. Use extreme caution in patients with renal insufficiency or bone marrow depression– monitor hepatic function and hematopoietic system during therapy.

179
Q

Class: Imidazoles and Triazoles

A

Systemic Antifungal Drug Class
Inhibit sterol 14-alpha sterol demehtylase (a fungal cytochrome P450) –this blocks the conversion of lanosterol to ergosterol – this deprives the membranes of ergosterol leading to unstable fungal membranes. FUNGISTATIC.

Available oral or IV.

Side effects: N/v, rash, diarrhea, headahe
Hepatotoxicity, usually mild - but some fatalities.
Discontinue if signs of liver dysfunction appear.

Inhibits metabolism of several drugs (warfarin, cisapride, androgens, terfenadine, sulfonylurea oral hypoglycemic agents, cyclosporine, phenytoin, celecoxib, fentanyl, methadone, diltiazem, verapamil, others).

Menstrual irregularities.
Anaphylaxis (uncommon) even after first dose.

180
Q

Fluconazole

A

SYSTEMIC ANTIFUNGAL DRUG - IMIDAZOLE AND TRIAZOLE CLASS

Used for cyrptocccus meningitis, candida (oropharyngeal, esophageal, vaginal, and systemic), covers most candida albicans, and NOT candida krusei (intrinsically resistant), coccidiodes meningitis.

Treatment for Candida vaginal infection - single oral dose. Candida in urinary tract and oropharynx.

Oral is common dosage for fluconazole, but also available as IV. CNS penetration is very good.
Excreted unchanged in urine.

All Imidazole and Triazole side effects, plus UNIQUE:
Low incidence of hepatotoxicity.

Eosinophilia, thrombocytopenia in AIDS patients.

181
Q

Itraconazole

A

SYSTEMIC ANTIFUNGAL DRUG - IMIDAZOLE AND TRIAZOLE CLASS

Used for blastomyces (pulmonary and extrapulmonary), histoplasma (pulmonary, disseminated but non-meningeal), Candida (esophageal and oropharyngeal, not for invasive disease), covers more C glabrata strains, some C krusei. Also labeled for refractory Aspergillus. Successful use in other countries for: cyrptococcus, sporothrix, and coccidiodes

**Key tx for oropharyngeal and esophageal Candida.

Oral Admin (not topical)
NO CNS penetration.
Metabolized by the liver.

All Imidazole and Triazole side effects, plus UNIQUE:
Contraindicated with several drugs that inhibit CYP3A4 - cisapride, quinidine, oral midazolam, triazolam, lovastatin, others.

Weakness, dizziness, vertigo, impotence, hypokalemia

Negative ionotropic effects: not for patients with LVD - left ventricular dysfunction

182
Q

Voriconazole

A

SYSTEMIC ANTIFUNGAL DRUG - IMIDAZOLE AND TRIAZOLE CLASS

FDA approved for INVASIVE ASPERGILLUS (fungicidal), Fusarium, Scedosporium.
FDA approved also for Candida at several sites - extended spectrum includes glabrata and krusei

Not well-documented CNS penetrations, but clinical outcomes suggest some entry.
Metabolized by the liver.

All Imidazole and Triazole side effects, plus UNIQUE:
Visual disturbances, photosensitive rash, and contraindicated in ST JOHNS WORT (a P450 inducer).

183
Q

Caspofungin

A

Systemic Antifungal Drug
Used for INVASIVE ASPERGILLUS in patients intolerant of/refractory to other drugs. Candida, esophageal and systemic (peritoneal, pleural, blood) not for bladder!
Broad Candida coverage including: albicans, glabrata, krusei, parapsilosis, tropicalis

Inhibits fungal cell wall synthesis by non-competitively blocking synthesis of beta (1,3) D glucan - eventually leads to CELL LYSIS

IV infusion. Slow metabolism, spontaneous degradation. Complex pharmacokinetics, fecal and renal elimination. Does not inhibit or induce CYP P450s.

Generally well-tolerated. Fever, n/v, rash. Phlebitis at injection site. Possibly, pulmonary edema.

184
Q

Miconazole

A

Treatment of Superficial Mycoses - treatment of candida infections

Also used for topical treatment of common skin and hair dermatophytic infections.

Same mechanism as Fluconazole. TOPICAL USE - creams/suppositories for vaginal Candida.

Toxicity includes burning, itching and irritation

185
Q

Clotrimazole

A

Treatment of Superficial Mycoses - treatment of candida infections

Tx for: oropharyngeal or vaginal Candida. Also, topical preparation can be used for common skin and hair dermatophytic infections.
Use TOPICAL (vaginal tablets, topical creams/solutions) for vaginal Candida.
For oropharyngeal Candida, use oral troches (lozenge).

Similar mechanism as Fluconazole.

Topical toxicity is allergic/irritation reactions.

Oral form toxicity: abnormal liver function tests (15%), and n/v (5%)

186
Q

Natamycin

A

OPHTHALMIC FUNGAL INFECTIONS Tx

For fungal eye infections, i.e. conjunctivitis, keratitis, blepharitis. Especially those caused by: Fusarium, Cephalosporium, Aspergillus. Prep: 5% ophthalmic suspension.
Used in conjunction with appropriate surgical measure.

Mechanism if very similar to amphotericin B.

Toxicity: conjunctival chemosis (swelling, edema) and hyperemia; allergic in nature

187
Q

Tolnaftate

A

TX for Topical Hair/Skin - Dermatophytic Infeciton

1% cream or solution- also as foot spray/powder - for tx of dermatophytes (NOT candida).

No significant absorption.
MOA: inhibit fungal ergosterol synthesis.

Few toxic reactions.

188
Q

Dermatophytic Infection - Topical for Hair/Skin

A

Tx for: Trichophyton, Epidermophyton, Microsporum
I.e. ringworm, athlete’s foot, etc.
This is a large array of proprietary and prescription drugs.

Miconazole

Clotrimazole

Tolnaftate

Terbinafine

189
Q

Ciclopirox

A

Dermatophytic Infections - Topical for nail infections (ONCHOMYCOSIS)

(Loprox cream or Penlac lacquer for nail infections)
Use: nail lacquer for topical prescription - specifically for nail infections. Daily for 48 weeks!

MOA: possibly inhibits metal-dependent enzymes, chelated metal ions.

Side effects: few, local irriation

190
Q

Terbinafine

A

Oral Preperations for Severe Dermatophyte - refractory infections to topical therapy

Also used for hair/skin infections.
12 week therapy for nail infections; shorter for other dermatophyte infections. Likely superior to griseofulvin for nail infections.

MOA: inhibits fungal squalene epoxidase, non-competitively. Accumulation of squalene damages fungal cell membranes - FUNGICIDAL.
Admin: ORAL, well-absorbed, stays in skin for 12 weeks after therapy has been stopped. Metabolites are excreted in the urine.

Toxicity: diarrhea, dyspepsia, abdominal pain (

191
Q

Griseofulvin

A

Oral Preperations for Severe Dermatophyte - refractory infections to topical therapy

For realcitrant infections of skin, hair, nails, that are beyond the scope of topical therapy. Often requires long term tx (6-12 mon) especially for nail infections, clinical relapse will occur if longterm tx is not completed.
Tx for: TINEA CAPITIS – ringworm of scalp

Narrow spectrum, only for Epidermophyton, microsporum, and trichophyton (dermatophytic) infections of skin, hair, nails - not justified for skin infections which are responding to topical agents.

FUNGISTATIC or FUNGICIDAL -depends on the fungi metabolic rate.
MOA: slowly deposited into the skin, hair, nails, interferes with the microtubule function/mitotic spindle/ mitosis –arrests fungi in metaphase of mitosis
Admin: ORAL, only 50% absorbed - absorption aided by high fat foods. NOT EFFECTIVE TOPICALLY. Recommended concomitant use of topical agents- especially for tinea pedis.
Metabolism is in liver via demehtylation and glucuronidation; bulk excreted unchanged in feces, rest in urine, as metabolites

Toxicity: incidence of side effects is very low. Can lead to headache. Contraindicated in those with porphyria and advanced liver disease. Periodid monitoring of hepatic, renal, and hematopoietic systems recommended. Increased metabolism of other drugs (contraceptives and warfarin)
Caution: penicillin allergies
Increases porphyrin excretion, impaired judgement, fever, skin rashes, hypersensitivity, photosensitivity, headache, nausea, diarrhea, heartburn

192
Q

Itraconazole

A

2nd use: Oral Preperations for Severe Dermatophyte - refractory infections to topical therapy

3 month therapy for TOENAIL infections.

ORAL admin also available.

Toxicity: N/v, rash, diarrhea, headache, edema. DISCONTINUE if signs of liver dysfunction appear. Inhibits metabolism of many drugs including: digoxin, cyclosporine, warfarin, sulfonylurea oral hypoglycemic agents, and antihistamines (terfenadine, astemizole)

193
Q

Lamivudine

A

MECH: monophosphate prodrug; converted to triphosphate form inhibits the reverse transcriptase domain on Hepatitis B polymerase –> causes dna chain termination

-NRTI

USE: Hepatitis B; synergistic w/ AZT (zidovudine)

SE: generally well tolerated;nausea; diarrhea

194
Q

Tenofovir

A

MECH: monophosphate prodrug; converted to triphosphate form inhibits the reverse transcriptase domain on Hepatitis B polymerase –> causes dna chain termination

-NRTI

USE: Hepatitis B; combination tx for HIV infected pts

SE: GI upset

195
Q

Interferon alpha

A

USE: condyloma acuminata (venereal warts); Hepatitis B and C (combination w/other drugs)
*pegylation of the drug decreases the clearance (thus works longer, less doses needed)

SE: flu like sx; leudopenia; bone marrow suppression; neurotoxicity; myalgia

196
Q

Ribavirin

A

MECH: interferes w/ viral mRNA syn

  • mono phosphorylated form–> inhib inosine-5’-P dehydrogenase and thus GTP syn
  • tri phosphorylated form–> inhib GTP dependent capping of viral mRNA

USE: severe lower respiratory syncytial virus in infants and young kids (aerosol form); Hep C in combination w/other drugs (oral form)

SE: aerosol form–> drug may precipitate in/clog respiratory equipment; pulmonary function deterioration; rash
IV/oral use–> anemia, bone marrow suppression

197
Q

Simeprevir

A

MECH: reversibly inhib Hep C NS3/NS4A protease –> block cleavage of polyprotein and formation of inf virus

USE: Hep C genotype 1 (in combination w/other drugs)

SE: rash, nausea, itching
***avoid Use w/ mod to strong inducers or inhib of CYP3A (will cause significant changes in simeprevir levels)

198
Q

Sofosbuvir

A

-nucleoside analog prodrug
MECH: conversion to triphosphate form –> inhib HSV NS5B rna polymerase; causes chain termination

USE: all Hep C genotypes (give w/ other genotype specific drugs)

SE: avoid potent inducers or inhibs of P glycoprotein

199
Q

Ledipasvir

A

MECH: inhib HCV NS5A phosphoprotein

USE: HepC genotypes 1,4,5,6 (in combination w/ sofosbuvir)

SE: avoid potent inducers of P glycoproteins

200
Q

Zidovudine (AZT)

A

MECH: thymidine nucleoside analog; AZT-triphosphate inhibts reverse transcriptase –> dna chain terminator
-NRTI (nucleoside reverse transcriptase inhibitor)

USE: nucleoside RT inhib for tx of HIV in adults and children

SE: bone marrow suppression: neutropenia, anemia

  • drugs that inhib glucuronyl transferase increase hematologic toxicity of AZT and should be avoided
  • myopathy
201
Q

Emtricitabine

A

MECH: analog of lamivudine

  • same mech as lamivudine (converted to triphosphate form–> inhib reverse transcriptase domain of Hep B polymerase, causing dna chain termination)
  • NRTI

USE: combination tx for HIV inf pts

202
Q

Abacavir

A

MECH: nucleoside analog

  • triphosphate form inhib RT –> causes dna chain termination
  • NRTI

USE: combination tx for HIV inf pts

SE: hypersens rx assoc w/ HLA-B*5701 antigen (v severe, genetic testing done for this pretreatment)

203
Q

Efavirenz

A

MECH: non nucleoside inhib of reverse transcriptase

  • does not req phosphorylation for activity
  • NNRTI

USE: part of multi drug tx for HIV

SE: rash; cns/psychiatric sx; nightmares

204
Q

Lopinavir

A

MECH: prevents viral protease from cleaving Gag-pol polypeptide into separate functional proteins

  • competitive inhibitor
  • results in non infectious viral particles

USE: use in combination w/ inhibitors of RT
**significantly decreases viral blood load

SE: diabetes

  • alt in lipid metabolism
  • fat redistribution
  • alt metab of many other drugs (potent CYP3A inhibitor)
  • diarrhea
205
Q

Ritonavir

A

MECH: (same as lopinavir) prevents viral protease from cleaving Gag-pol polypeptide into separate functional proteins

  • competitive inhibitor
  • results in non infectious viral particles

USE: use in combination w/ inhibitors of RT

  • *significantly reduces viral blood load
  • boosts levels of other PIs

***used as BOOSTER not PI

SE: diabetes

  • alt in lipid metabolism
  • fat redistribution
  • alt metab of many other drugs (potent CYP3A inhib)
206
Q

Enfuvitide

A

MECH: inhibits fusion of viral (HIV 1) and cellular (CD4) membranes
-binds to gp41 subunit of HIV glycoprotein blocking changes required for membrane fusion

USE: effective against only HIV 1
-for treatment of “experienced” HIV pts w/ detectable viral replication despite ongoing therapy (last resort for them??)

SE: local injection site rxs

  • diarrhea
  • nausea
  • fatigue
207
Q

Maraviroc

A

MECH: chemokine co receptor (CCR5) antagonist
-blcoks entry of HIV into cells

USE: tx CCR5 tropic HIV 1
*works on strains resistant to other drugs

SE: hepatotoxicity
-cardiovascular events

208
Q

Raltegravir

A

MECH: inhib HIV 1 integrase ax –> prevents integration of HIV 1 dna into genome

USE: tx HIV 1
*works on virus resistant to other drugs

SE: potential for severe skin and hypersensitivity txs

209
Q

Immunization

A

Active: vaccination, generate protective immune response

Passive: injection of immune globulin often blocks viral penetration (must be soon after exposure)

210
Q

Amantadine

A
  • Prophylaxis against influenza A (NOT B); reduces fever in 50% of pt’s, and illness duration by 1-2 days if given in 1st 2 days
  • Blocks viral uncoating by interfering with influenza A M2 protein (an ion channel)
  • Oral
  • CNS effects
  • Resistance: for the last few years, influenza has been amantadine-resistant
211
Q

Oseltamivir

A
  • Tx of uncomplicated influenza A and B, best when given within 48 hrs of symp; prophylaxis [>1yo]
  • Prodrug, competitive inhibitor of influenza neuraminidases; interferes with viral release and viral penetration (mostly viral release)
  • Oral
  • Nausea/vomiting, diarrhea, bronchitis
  • Cost-effective, short-lasted resistance now gone away
212
Q

Trifluridine

A

-Ophthalmic for Herpes simplex types 1 and 2 -Interferes with DNA synth, thymidine analog -Ophthalmic - too toxic systemically

213
Q

Acyclovir

A
  • (IV): HSV, including HSV encephalitis, disseminated neonatal HSV, severe initial herpes; (oral): primary genital herpes, primary herpetic gingivostomatosis; (topical): some effect when applied early to mild genital herp -Phosphorylated form is produced 40-100x faster in infected cells by herpes thymidine kinase, inhibits DNA pol 10-30x more than host cell DNA pol, acts as competitive inhibitor of dGTP and DNA chain terminator
  • IV, oral, topical
  • Generally well-tolerated (high selectivity); rash, itching, nausea, vomiting, headache, fatigue
214
Q

Famciclovir

A

-Acute herpes zoster (shingles)

215
Q

Penciclovir

A
  • Recurrent herp of the lips and face
  • Very similar to acyclovir
  • Topical
216
Q

Ganciclovir

A
  • CMV retinitis in AIDS patients, CMV prophylaxis for transplant recipients
  • Similar to acyclovir, except monophosphorylation is catalyzed by CMV protein kinase
  • IV or oral
  • Bone marrow suppression, leukopenia, thrombocytopenia, anemia (40% of pt’s)
217
Q

Foscarnet

A
  • AIDS pts with CMV retinitis; approved for acyclovir-resistant herpes simplex (those with thymidine kinase mutations)
  • Selectively inhibits CMV DNA pol by binding to its pyrophosphate-binding site; does NOT require conversion to triphosphate to be active -IV
  • Renal damage (reversible), electrolyte imbalances (binds Ca and Mg), seizures (possibly from hypocalcemia)
  • Higher % of patients must be taken off due to side effects (compared to Ganciclovir)

Pharm (4 decks)

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