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- Indiana
- Purdue University
- Biomedical Science
- Biomedical Science 814
- Lelievre
- Pharm 3.1 (Anticonvulsants, Opioids, Cancer)
Pharm 3.1 (Anticonvulsants, Opioids, Cancer)
Biomedical Science 814 with Lelievre at Purdue University
About this deck
By: Kimberly Jen
Created: 2011-11-14
Size: 134 flashcards
Views: 45
Created: 2011-11-14
Size: 134 flashcards
Views: 45
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Anticonvulsants
- seizure (convolsion): physical expression of abnormal paroxystic electrical discharges in brain neurons that reach somatic and visceral motor areas and initiate movements:
- spontaneous
- paroxysmal
- involuntary
Define: status epilepticus
- refers to failure of patient to recover to a normal alert state b/w repeated tonic-clonic attacks that last more than three minutes or cluster episodes that last "10" minutes
- don't return to normal
- medical emergency
Define true epilepsy
- syndrome of inherited, recurrent seizures that continues thruout life w. no underlying morphologic d+ process
- not induced by something you can identify
- can only be controlled, not cured
What do anticonvulsants do? ex?
- Block seizure initiation and propagation by blocking abnormal events in a single neuron or synchronization of related neurons
- drugs acting at more than one point more effective
- ex. Phenobarbital
Principles of anticonvulsant therapy
- tx seizures at neuronal level
- cure requires additional therapy to remove cause of seizure
- not always required to tx seizures
Use of anticonvulsants
- Optimal use of anticonvulsants required to be aware of:
- lipid-solubility vs. serum pr binding of drug
- high lipid solubility necessary for rapid distribution into brain
Phenobarbital
- long term control of epilepsy and seizures (not used for status epilepticus)
- seizures in cats (broad spectrum)
- steady state: takes 15-20 d to reach
- half-life: 9 h to 3-4 d, monitor
What to monitor with phenobarbital
- therapeutic range: 15-35 um/mL
- both peak and trough at steady state (2 wk after onset of daily tx); every 3-6 mo if patient is controlled
- liver enzymes: transaminases, phosphatases
- blood parameters (anemia)
Phenobarb side effects?
- polyphagia (during entire tx)
- liver damage
- most potent liver enzymes stimulatory agent known
Consequences of phenobarb
- missing even one dose can be sufficient to trigger seizure
- addiction is possible w/ long term use: weaning protocols
Primidone
DO NOT USE IN CATS (heavy sedation)
Pentobarbital
- use: anesthetic, short term control of status epilepticus and cluster seizures in dogs and cats
- side effects: careful monitoring of cardiovasc and resp, resp support may be needed
- contraindications: same as phenobarb (liver fxn) , do not use to tx lidocaine intoxication
Benzodiazepines
- act both in brain and spinal cord; anticonvulsants, anxiolytic, relaxant
- enhance inhibitory effects of GABA (decr seizure spread; blocks seizure arousal)
Diazepam (valium): class IV drug
- benzodiazepines
- first line choice for control of status epilepticus in small/large animals
- not good for long term therapy b/c rapid tolerance (after 2 wk) in dogs
- absorption: intra-rectal, highly lipid soluble (fast action in brain after IV)
- side effects: liver failure (cats)
Chlorazepate
- benzodiazepines; tolerance does not devo as often as diazepam
Potassium bromide
- bromide ions (more electronegative than chloride ions)
- inhibit electrical activity in brain (hyperpolarization)
- becomes difficult to initiate seizure
Potassium bromide contraindications
- avoid using w/ IV fluids
- do not use in cats (pneumonitis)
- overdose: NaCl helps counteract bromide overdose
Phenytoin
- not very effective anticonvulsant (difficult to achieve and maintain therapeutic concentrations)
- do not use in cats or puppies
- crossed out on slide, don't use anymore
Levetiracetam
- side effect: liver d+ or after phenobarb induced liver damage
- only mild sedation reported, also anticonvulsant effect may not last
Zonisamide
- dogs and cats, add on for seizure control; long half-life (BID)
- MOA: inhibition of Ca and Na channels, does not stim liver
- side effects: only mild sedation also anticonvulsant may not last
Examples of seizures in large animals
- metabolic or toxic origin: cause must be removed-anticonvulsant therapy is not enough
- status epilepticus easily occurs w/ snail bait (metaldehyde)
- anticonvulsants: diazepam or pentobarbital
How to tx post-ictus
- be aware of danger! animal can show aggressiveness
- first line choice: diazepam for acute phase, phenobarb for control
Define: status epilepticus
- 10 minutes of seizure activity or two or more seizures w/out full recovery b/w seizures
- DO NOT WAIT MORE THAN FIVE MINUTES DURING AN ACUTE PHASE
Status epilepticus tx
- first line anticonvulsant: diazepam (even intrarectal)
- can be used in home setting
- lorazepam, followed by levetiracetam
- second line: life support (resp/cardiac fxn), pentobarb/phenobarb
Eclampsia
- due to hypocalcemia
- symptoms: tonic-clonic convulsions of increasing violence, consciousness retained
- only cure: Ca injection
Protocol for long term tx w/ anti-convulsants
- start w/ one drug then add 2nd if no control @ max dose; monitor for side effects
- add 2nd drug if necessary when seizures under control; very progressively decr doses for 1st drug
- watch for changes in metabolism and/or efficiency when used w/ other drugs (ex. metaclopramide decr seizure threshold)
define: opioids
- Drugs that are addictive, analgesic and generally produce hypnosis, some excitement
define analgesic:
substance that temporarily abolishes pain
Define Hypnosis:
State close to physiological sleep, from which patient can be easily awakened by wide variety of stimuli
Action of opioid analgesic
Opioid analgesics reduce or abolish pain w/out causing loss of consciousness
Opioids alleviate pain, relieve coughs, spasms, fever and diarrhea...what else?
induce narcosis (depression of the CNS leading to state of in sensibility/stupor)
There is more to pain than pain..what else is there?
- there are physiologic consequences to poor analgesic practice
- pain triggers activation of neuroendocrine response (catecholamine) lead to gen catabolic state
- ischemia
- cardiac arrhythmias
What is the wind-up response?
- amplification caused by persistent nociception
- pain will be worse if you let it sit more receptors being recruited, more info to brain
- even if factor that induces pain does not incr, amplification in CNS
- ONLY DRUGS TO PREVENT WIND UP = OPIOIDS
Define preemptive analgesia
small doses admin BEFORE noxious stim, prevents wind-up phenomenon
what is Balanced Analgesia
- uses more than one analgesic agent, requires lower doses and induces less side effects
- used for moderate to severe pain, opioids alter both the
- conscious experience of pain
- wind-up responses
- also act as anesthetics, NSAIDS and a2- agonists (analgesia)
Where do the family of opioid receptors work?
CNS
How do opioid receptors work?
- decrease synaptic transmission
- binding activates G pr- that activate K+ channels (neuronal membrane hyperpolarization), inhibit voltage-operated Ca conductance and NT release
Main mech of how opioid work
- agonists and antagonists of opioid receptors
- some can be agonists
How do opioid agonist work?
acts on R, elicits full response
How do opioid antagonists work?
blocks R, elicits no physiologic response and reverses effects of opioid
Morphine, what class and what does it cause?
- Class II drug
- causes profound resp depression
- dose dependent and may occur rapidly
opioid agonists action
- act on mu R
- potent hypnotic analgesic effects
- cardiovasc depression
- alteration of thermoregulation
- euphoria
- addiction
Oxymorphone, class and effect
- Class II
- similar to morphine, 10 times MORE potent; more sedation
- less depressant effect on resp center
- Freq combined w/ diazepam/acepromazine for anesthesia/analgesia in old/sick animals
Oxymorphone cautions?
- anticholinergic should be given to prevent severe bradycardia
How to give liposomal oxymorphone
- SQ admin (safer than transdermal patch for household and human caretakers)
- risk for human use too high w/ patch
- patch used w/ fentanyl
Meperidine class, duration, effect and cautions?
- Class II, less sedation than morphine
- short duration (1-2 hr)
- only opioid w/ direct myocardial depressant effect
- NOT recommended for alleviating postsurgical pain (unless it is known that pain will not last more than 1/2 hr)
Fentanyl class, duration, comparison w/ morphine, caution
- Class II, transdermal patch, very lipophilic
- 75-125 x more potent than morphine
- short duration (45-60 min)
- minimal cardiovasc effects except bradyarrhythmias
- resp center depression more severe than w/ morphine and apnea may occur
Which opioid is used more commonly as CRI?
Fentanyl
Which opioid is used more commonly as transdermal patch?
Fentanyl
Etorphrine (M99) known for what?
EXTREMELY POTENT morphine derivative; produces initial excitement followed by depression
Etorphine (M99) used where?
- zoo and wild animals and certain cold-blooded animals
Etorphine (M99) risks?
- Extremely dangerous to humans
- diprenorphine (M5050) must be available for immediate reversal if accidental human exposure occurs
Carfentanyl potency, how admin and reversal w/ what?
- zoo vets use b/c higher potency than M99
- admin by swabbing/spraying of buccal/nasal mucosa
- reversed w/ cyprenorphine (M285) or diprenorphine (M5050) and naltrexone
- FATAL in humans if accidental injection
Tramadol R agonist, action how?
- Mu, Kappa, delta agonist
- serotoninergic and noradrenergic (action on descending inhibitory pathways of pain stim)
Opioid agonist/antagonists research are looking for what?
- analgesic agents w/ fewer side effect than pure mu agonists
- devo of partial mu agonists, poor mu antagonists and kappa agonists
- this group of drugs may be used to reverse depressant effects of opioid while preserving analgesic qualities
Butorphanol class, R effect, use and side effects?
- Class IV, kappa partial agonists and poor mu antagonist
- 5 x more potent than morphine
- suitable for controlling moderate/severe pain in several spp including cats
- minimal cardiovasc effects; induces resp depression that ultimately reaches plateau (doesn't incr w/ higher doses)
Nalbuphine, class, R, use and risks?
- NOT a classified drug
- kappa partial agonists and mu antagonist
- less potent than morphine
- it is primarily used to reverse resp depression and sedation caused by mu agonists postoperatively while maintaining analgesia
Opioid antagonists examples
naloxone hydrochlorine
naltrexone: long acting derivative of naloxone
Naloxone hydrochloride does what?
- reverse effects of opioid (including analgesia)
- does not produce resp/cardiovasc depression
- can be used to reverse effects (notably resp depression) of any of the opioid agonists/antagonists group
Neuroleptanalgesia define
state of sedation and analgesia produced by combo of tranquilizer (neuroleptic) and opioid
Innovar-vet is what?
- droperidol/fentanyl combo neuroleptanalgesic
- wide safety margin: well tolerated by animals in poor physical conditions
Side effects of opioid?
- vomiting, defecation, panting in animals premedicated w/ opioid agonists
- in painful patients, side effects rarely seen
- resp depression = risky side effect
- experienced clinicians say rare
How to deal with opioid side effects?
rapidly and easily reversed if necessary
Administration of opioids?
- depends on drug
- initial cumulative dose (fixed dosing schedule)
how does lipophilicity factor into admin of opioid
determines rapidity of uptake into spinal cord (low for morphine, high for fentanyl for epidural used) and onset of analgesia
What are the benefits of spinal admin of opioid?
- longer duration of action w/ lower dose to avoid brain-mediated effects like resp depression
- importance of lipophilic degree
what is an important step of admin of opioid?
titration up to predetermined dose
which lasts longer w/ opioid? analgesia or sedation or bradycardia?
- analgesia may be shorter than sedation or bradycardia
- do not base length of analgesia based on side effects
Key precautions for opioid admin (2)
- Initial cumulative dose should be given on fixed dosing schedule not on as needed basis
- good preemptive analgesic technique req that predetermined schedule be installed before animal begins exhibiting sins of discomfort
Species characteristics w/ opioid use - feline
excitement at high doses, then give tranquilizer to calm animal
Species characteristics w/ opioid use - equine
cause excitement in pain-free horse, prevented w/ concurrent admin of tranquilizer
Species characteristics w/ opioid use - ruminants
do not puncture dura matter - overdosage
butorphanol
Pain relief w/ cancer
- cancer pain can be acute/chronic (long term manifestation of pain recognized by state of depression or anxiety)
How does pharmacology control pain?
Pharmacology mediated pain control involves use of analgesics as well as other medications that potentiate analgesics' effect or modify pet's mood/pain perception
how to tx Acute pain in cancer
once pain relieved, medication decreased to lowest or mildest analgesic that maintains pain-free
how to tx Chronic pain in cancer
- starts w/ non-narcotic and moves to narcotic (opioids)
- more effective pain control needed
- around the clock rather than as needed to control chronic pain
What is cancer?
- Altered cell pop that do not respond normally to physio control
- unrestrained prolif
- invasion of adjacent normal tissues
- metastasize to distance sites
- d+ of epigenome/genome
Goal for tx of cancer?
- chemotherapy usually given to prolong life w highest quality (QOL) possible
- not kill all cancer cells and decr QOL
T/F: in normal tissues, cells may have different prolif capacities
TRUE
major problem in cancer?
- cell subpop of individual tumor mass can be compartmentalized into:
- dividing cells
- temporarily nondividing cells
- permanently nondividing cells
Most anticancer drugs exert their strongest activity on what fraction of tumor?
Proliferating fraction
Which tumors respond well to chemotherapy?
lymphosarcoma
TVT (transmissible venereal)
Goal of cancer therapy and most used type of therapy?
- prolong life w/ highest possible quality
- vs. human - cure patient w/ minimal fxnal and structural impairment
- most used: chemo
Define: cure?
absence of d+ resurgence during normal life expectancy
Curability w/ chemotherapy how?
- tx metastatic or potentially metastatic d+
- in dogs, cure sometime possible w/ sticker sarcoma (TVT) and certain lymphosarcomas
-
Chemotherapy aims at destroying tumor cells or inhibiting their aggressive behavior using drugs that selectively act on their proliferation, signal transduction or any molecular pathway that drives their survival and aberrant behavior.
Define palliative treatment
chemo given to control symptoms or prolong life in patient whom cure is unlikely
Define: combo therapy?
use of two/ more drugs w/ different mechanisms of action and toxicities which as single agents are effective against tumor
Therapeutic window large or small for chem drugs?
- VERY narrow
- usually drug amin as mg/m2 (based on metabolism which is linked to body surface)
principles of chemotherapy
- aims to destroy tumor cells/ inhibit agressive behav w/ action on prolif, signal transduction or molecular pathway
- kills at G0
Log cell kill hypothesis
- most anti-prolif drugs = cytotoxic
- given dose kills constant proportion of cell pop rather than constant # of cells
- impossible to eradicated 100%
Class I of antiprolif drugs?
- Class I: all parts of cell cycle
- resting cells as sensitive as prolif cells, therefore both normal and tumor cells affected
Class II antiprolif drugs
- phase specific agents in one phase
- continuous infusion or req small doses used to incr # of cells exposed at sensitive phase, may increase toxicity for patient
- resting cells spared
Cycle specific agents act where and types?
most phases of cell cycle
- alkylating agents
- nitrogen mustards
Alkylating agents are what and how do they work?
- cycle-specific agents
- form covalent bonds w/ DNA (no transcription/replication)
- can act on cells at G0 but only at high doses
- highly toxic for BM and immune
Nitrogen mustards example?
- cycle specific agent
- Cyclophosphamide
- chlorambucil
- ifosfamide
Cyclophosphamide
- cycle specific agent - N mustards
- cannot be used in patients w/ liver def b/c not effective, activated by p450!!!!!!
- toxicity: hemorrhagic cystitis due to acrolein, drink lots to prevent
Chlorambucil
- cycle specific agent - N mustards
- indications: most commonly used as substitiue for animals that experience chronic cyclophosphamide induced cystitis
Ifosfamide
- cycle specific agent - N mustards
- combined w/ mesna
Nitroso-ureas
- cycle specific agent
- liposoluble thru BBB
- spontaneous breakdown to form alkylating and carbamoylating compounds
- carbamoylating compounds = organic isocyanates that can carbamoylate lysine residues in protein and inactivate DNA repair enzymes
Carmustine
- cycle specific agent - nitroso-ureas
- indications: brain tumors
- toxicity: severe cumulative BM depression
Cytotoxic Abx moa?
- prevent mRNA transcription and DNA replication, introduce breaks into DNA
- cumulative toxicity
- total toxic dose - important to consider during tx.
Risk w/ cytotoxic Abx?
- cumulative toxicity
- total toxic dose - important to consider during tx.
Doxorubicine moa, toxicity and risks?
- cycle specific agent - effect on topoisomerase II
- toxicity: extravasation at injection site can cause local necrosis; histamine-mediated hypersensitivity (vomiting, diarrhea, pruritis, restlessness)
- risks: cumulative cardiotoxicity; nephrotoxicity in cats
Platinum derivatives examples?
- cycle specific agent
- cisplatin
- carboplatin
Cisplatin moa
- cycle specific agent - platinum derivative
- causes intrastrand cross-linking,
- cross-linking results in breaking of H bonds b/w guanine and cytosine and thus local denaturation of DNA
Cisplatin toxicity
- cycle specific agent - platinum derivative
- seriously nephrotoxic, GIT distress
- NEVER GIVEN TO CATS - fatal pulmonary edema
antifolate agents ex
- methotrexate
Methotrexate moa
- antifolate agent
- forms stable complex w/ dihydrofolate reductase and hence inhibits normal enzymatic activity
- also prevents extracellular tetrahydrofolates from entering into the cell
- cell death seems to occur b/c inhibition of thymidylate synthesis
Pyrimidine analogs ex
5-FU
5-FU moa and toxicity
- pyrimidine analog
- MOA: converted into fraudulent nucleotide which interacts w/ thymidilate synthetase and folate cofactors but cannot be converted into thymidylate
- Tox: neurotox, do not use in cats- fatal neurotoxicity
Gemcitabine
- cytosine arabinoside, inorporated into DNA/RNA, inhibits DNA polymerase
- deoxycytidine analog acting as pyrimidine antimetabolite
Vinca alkaloids ex
vincristine
Vincristine moa
- Vinca alkaloids
- prevents microtubule growth by inhibiting tubulin polymerization; affects mainly mitosis but also interferes w/ axonal transport in neurons
Vincristine toxicity
- low, induces peripheral neuropathy and constipation
- mild myelosuppressive activity
- can be used in animals w/ cytopenia
- use catheter to avoid extravasation - severe tissue rxn
Taxans ex
Paclitaxel
Paclitaxel
- Taxane
- pretreat w/ drugs that prevent hypersensitivity rxn
Miscellaneous agents
- L-asparaginase - breaks down asparagine, lymphomas/mast cell tumor
- Piroxicam - incr COX2 in cancer cells, block tumor prolif and induce apoptosis
Targeted therapy uses what class of drugs?
- inhibitors of tyrosine kinases
- imatinib mesylate
Imatinib mesylate
- inhibits tyrosine kinase
- kit snd abl inhibitor in cats w/ visceral mast cell tumor, takes time to show effect, $$$
Why are cytotoxic drugs so toxic?
do not discrim b/w cancer and normal cells (rapid division)
What determines sensitivity of tissue to anti-cancer drugs?
proportion of cells committed to cell division that determines sensitivity of cancerous or normal tissue to anti-cancer therapy
Do animals experience the same level of side effects as humans? or is it greater or less? why?
Less severe and fewer side effects b/c lower doses and not as many drugs combined
What are the most common and distressing early toxic effects of anti-cancer drugs?
- nausea and vomiting
- (mediated by emesis center in medulla)
drugs such as nitrosoureas and certain alkylating agents (chlorambucil) cause what?
- hematological toxicity
- drugs that affect primitive pluripotential stem cells and cause suppression of all cell lines include cycle nonspecific drugs
Order of hematological toxicity
neutropenia→thrombocytopenia→anemia
How does BM toxicity devo w/ anti-cancer drugs?
- infection 2ndary to myelosuppression is a major life-threatening complication
- tx as medical emerg
- neutropenia usually determines tx intervals
-
Risk is proportional to the neutrophil count, the duration of neutropenia and the
presence of breaks in the skin or mucosa
How does cystitis occur w/ anti-cancer drugs? and how to prevent
- w/ cyclophosphamide as result of direct contact of metabolites of these alkylating agents w/ bladder mucosa
- prevention: hydration ++++
How to tx hypersensitivity rxn w/ anti-cancer drugs?
tx as allergic anaphylaxis
What is the concern w/ injections sites w/ anti-cancer drugs?
- accidental extravasation may lead to
- mild erythema
- discomfort to severe pain
- tissue necrosis, skin ulceration
- invasion of deep structures (tendons/joints)
- doxorubicine
What other toxic effects can occur w/ anti-cancer drugs? (2)
- carcinogenicity
- teratogenicity
- greatest risk of exposure for personnel during prep (use closed system) and admin
- owners when @ home admin, handling drugs and excretions
define: chemoresistances
- major reason for anticancer tx failure
- 1ary: present when drug 1st given
- acquired: devo during tx
3 reasons for non-specific mech of resistance
- incr drug efflux/multidrug resistance gene - cross resistance b/w chemically unrelated drugs
- drug metabolizing pathway - cross-resistance
- enhancement of DNA repair activity - cross resistance
define: Combination therapy
- combining tx modalities provides alternatives for more effective tx in many types of cancer
- not always used in vet med
- some animals receive for rest of life
Combination therapy should include agents that...
- have some individual anti-tumor activity
- act by diff mechanisms
- different dose limiting toxicity
About this deck
By: Kimberly Jen
Created: 2011-11-14
Size: 134 flashcards
Views: 45
Created: 2011-11-14
Size: 134 flashcards
Views: 45
About StudyBlue
STUDYBLUE makes things that make you better at school.
Things like online flashcards with photos and audio.
Things like personalized quizzes and friendly reminders about when (and what) to study next.
Think of it as a digital backpack™: access to all of your study materials online and on your phone.
STUDYBLUE exists to make studying efficient and effective for every student, for free. Join us.
“Simply amazing. The flash cards are smooth, there are many different types of studying tools, and there is a great search engine. I praise you on the awesomeness.”
Dennis
Dennis