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Sedatives/Hypnotics: what are the three drug classes involved?
- Benzodiazepines (BZ)
- Barbiturates
- Alcohols
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Sedatives/Hypnotics: General Info
- Dose dependent CNS depression that extends from sedation to anesthesia, respiratory depression and death
- BZ reach a plateau in CNS depression, while barbiturates and alcohols do not (making BZ safer at higher doses)
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Sedatives/Hypnotics: Mechanism
- 2 complexes:
- 1. GABAa: Cl influx, most sedatives
- 2. GABAb: K influx
- Activation results in membrane hyperpolarization (inhibition)
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Sedatives/Hypnotics: Benzodiazepines - General Info
- BENzodiazepines: are short duration = male-like sexual response
- -lam, -pam drugs
- Potentiate GABA
- GABA must be present for BZ to function
- Increases the frequency of opening the Cl- channels, decrease REM sleep
- No GABA mimetic activity
- long half lives & active metabolites
- Act through BZ receptors that are a part of the GABAa complex
- BZ1 receptors mediate sedation
- BZ2 receptors mediate antianxiety, impairment of cognitive function
- Acute anxiety
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Sedatives/Hynpotics: Benzodiazepines
Clinical use:
Anxiety, spacticity, status (lorazepam/dizpema), detoxification (especailly ETOCH w/drawal), night terrors, sleepwalking, general anesthetic (amnesia, muscle relaxation), hypnotic (insomnia)
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Sedatives/Hypnotics: Benzodiazepines Toxicity
- Dependence, additive CNS depression w/ ETOH, less respiratory depression and coma than barbidurates
- OD tx: flumazenil
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Sedatives/Hypnotics: Benzodiazepines
Short acting ones:
- TOM Thumb
- T= Triazolam
- O = Oxazepam
- M = Midazolam highest addictive potential
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Sedatives/Hypnotics: Benzodiazepine: Alprazolam
- Indication: anxiety, panic, phobias
- commonly prescribed
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Sedatives/Hypnotics: Benzodiazepine: Diazepam
- Indication: anxiety, preop sedation, muscle relaxation, withdrawal states
- Longest lasting
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Sedatives/Hypnotics: Benzodiazepine: Lorazepam
- Indications: anxiety, preop sedation, status epilepticus (IV)
- No active metabolites
- Metabolism: extrahepatic congugation, thus safe in elderly and liver damage
- Best choice of drug
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Sedatives/Hynpotics: Benzodiazepine: Midazolam (Versed)
- Indications: preop sedation, anesthesia IV
- Shortest acting
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Sedatives/Hypnotics: Benzodiazepine: Temazepam
- Indications: sleep disorders
- no active metabolites
- Metabolism: extrahepatic congugation, thus sfae in elderly and liver damage
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Sedative/Hypnotics: Benzodiazepine: Oxazepam
- Indications: sleep disorders, anxiety
- no active metabolites
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Sedatives/Hypnotics: Benzodiazepine: Flunitrazepam
- Indications: date rape drug, colonoscopy
- causes anterograde amnesia (cant remember after administration)
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Sedatives/Hypnotics: Benzodiazepines that help with sleep
Take a Time Out for sleep
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Sedatives/Hypnotics: Benzodiazepines that are good for the elderly/liver dysfunction patients:
- Oxazepam
- Temazepam
- Lorazepam
- Outside The Liver extrahepatic conguation and no active metabolites
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Sedatives/Hypnotics: Withdrawal signs of BZ
- rebound insomnia
- anziety
- seizures (when BZ are used as an antiepileptic or @ high doses)
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Sedatives/Hypnotics: Antidote for BZ overdose:
- Drug: Flumazenil
- Mechanism: nonspecific BZ receptor antagonist
- used to reverse CNS depression caused by BZ in overdose or anesthesia settings
- Limitation: cannot reverse the CNS depression caused by barbiturates and alcohols ONLY BZ!
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Sedatives/Hypnotics: Barbiturates: General Info
- BARBiturates = longer duration = female-like sexual response
- -tal drugs
- Prolong GABA activity
- increase duration of the Cl channel opening
- Have GABA mimetic activity at high doses
- do not act through BZ receptors
- have their own binding sites on the GABAa complex
- Also inhibit complex I of the electron transport chain
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Sedatives/Hypnotics: Barbiturates
- Drugs: Phenobarbital (for seizures), Thiopental (induction of anesthesia)
- Pharmacokinetics: liver metabolized, sometimes to active metabolites
- Mechanism: general inducers of CYP-450 enzymes, increases Cl- channel opening in GABAa = less neuron firing
- contraindicated in porphyrias
- Drug interactions: induce metabolism of most lipid-soluble drugs (OCP, carbamazapine, phenytoin, warfarin, etc.)
- Toxicity: dependence, additive CNS depressive effects with ETOH, respiratory or CV depression, death,
- OD tx: symptom management (assist in respiration, and increase BP)
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Sedative/Hypnotics: Withdrawal signs of Barbiturates & ETOH
- Anxiety
- Agitation
- life-threatening seizures (delirium tremens w/ ETOH)
- Management: supportive and long acting BZ
- (funny how you would use a BZ for ETOH and barbiturate withdrawal)
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Sedatives/Hypnotics: Tolerance to & Dependence
- Chronic use = tolerance
- Cross-tolerance btw BZ, barbiturates, ethanol
- psycholog & physical dependence
- Abuse liability BZ < barbiturates or ETOH
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Sedatives/Hypnotics: Drug interactions
- GABAa drugs are:
- Additive with other CNS depressants (respiratory depression) - like anesthetics, antihistamines, opiates, B-blockers
- Barbiturates: induce metabolism of most lipid-sol drugs (OCP, carbamazepine, phenytoin, warfarin, etc.)
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Sedatives/Hypnotics: Non-BZ Drugs
- Drugs: Zolpidem, Zaleplon, Ramelteon
- Mechanism: BZ1 receptor agonist (Z drugs), melatonin receptor agonist (Rmaelteon)
- Antidote to OD: flumazenil
- Clinical Use: sleep disorders
- less tolerance and abuse liability
Z-drugs to catch some zzzzz's
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Sedatives/Hypnotics: Non-BZ Drugs
- Drug: Busprione
- No effect on GABA **
- Mechanism:
5-HT1a partial agonist ** - Clinical use: generalized anxiety disorders, chronic anxiety
- non sedative effects (no CNS GABA effect)
- Takes 1 - 2 weeks for effects
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Sedatives/Hypnotics: Drugs used for sleep disorders are:
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Sedatives/Hypnotics: Drugs used for anxiety are:
- BZ (acute)
- Busprione (chronic)
- SSRI (chronic)
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Sedatives/Hypnotics: Alcohols: General
all alcohols cause CNS depression, partially thru GABA mimetic activity, and metabolic acidosis
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Sedatives/Hypnotics: Alcohols: Ethylene Glycol
metabolized by alcohol DH into glycoaldehyde whcih causes:
- 1. CNS depression
- 2. severe metabolic acidosis
- 3. nephrotoxicity
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Sedatives/Hypnotics: Alcohols: Methanol
metabolized by alcohol DH into formaldehyde which causes:
- 1. respiratory failure
- 2. severe anionic gap metabolic acidosis
- 3. ocular damage (blurry/snowy vision)
OD tx: Fomepizole: long acting inhibitor of alcohol DH, but may require hemodyalsis at high alcohol levels
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Sedatives/Hypnotics: Alcohols: Ethanol
- Ethanol side effects:
- 1. CNS depression
- 2. metabolic acidosis (ketones)
- 3. acetaldehyde toxicity
- Acetaldehyde effects:
- think hangovern/v, headache, hypotension
- combines with: folate to inactivate it
- combines with: thiamine to decrease availability
- Acetaldehyde DH (in mito)
- Inhibited by disulfiram
- tx used for alcoholics
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Drugs that cause disulfiram-like effects:
- Metranidazole
- Cefoperazone
- Cefotetan
- Chloropropamide
- Grisefulvin
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Treatments: Mechanism of Action:
- 1. decrease axonal conduction by preventing Na influx thru fast Na channels: carbamazepine, phenytoin
- 2. increase inhibitory tone by facilitation of GABA-mediated hyperpolarization: barbiturates, benzodiazepines
- 3. decrease excitatory effects of glutamic acid: lamotrigine, topiramate (blocks AMPA receptors); felbamate (blocks NMDA receptors)
- 4. Decreases presynaptic Ca influsx thru type T channels in Thalamic neurons: ethosuximide & valproic acid
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Anticonvulsants and Seizure States:
- Partial (simple/complex): valproic acid, phenytoin, carbamazapine, lamotragine
- General (tonic-clonic): valproic acid, phenytoin, carbamazepine, lamotrigine
- General (absence): EthoSUXimide, valproic acid
- Status epilepticus: Lorazepam, diazepam, phenytoin, fosphenytoin
cleanest question: Ethosuximide used for abnsce seizures
valproic acid works for almost everything
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Anticonvulsants: Phenytoin
- Mechanism: blocks axonal Na channels in their inactivated state (state dependent blockage), prevents seizure propagation
- Clinical Use: seizure states
- PK: variable reabsorption, nonlinear kinetics, induction of CYP450, zero order elimination
- Side Effects: CNS depression, gingival hyperplasia, hirsuitism, osteomalacia (decreased vit D), megaloblastic anemia (decreased folate), aplastic anemia (check hematology lab results), ataxia, nystagmus, diplopia, fetal hydantoin syndrome, SLE-like rxn, P450 induction
- Teratogenicity: cleft lip and palate
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Drugs that are zero order kinetics:
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Anticonvulsant: Carbamazapine
- Mechanism: blocks axonal Na channels in their inactivated state (state dependent blockage), prevents seizure propagation
- Clinical Use: seizure states, DOC for trigeminal neuralgia, bipolar disorder
- PK: induces CYP450, including its own metabolism
- Side effects: CNS depression, osteomalacia, megaloblastic anemia, exfoliative dermatitis, increases ADH secretion (SIADH), diplopia, ataxia, liver toxicity, induciton of P450, Steven Johnsons
- Teratogenicity: cleft lip, palate, spina bifida
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Anticonvulsant: Valproic Acid
- Mechanism: blocks axonal Na channels in their inactivated state, prevents siezure propagation, but also inhibits GABA transaminase and blocks the T type Ca channels
- Uses: seizure states, mania of bipolar disorders, migraines
- PK: inhibits CYP450
- Side effects: hepatotoxicity (from toxic metabolite), thrombocytopenia, pancreatitis, alopecia
- Teratogenicity: spina bifida (neural tube defects) CONTRAINDICATED IN PREGNANCY
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Anticonvulsant drugs that have p450 effects
- Activator: phenytoin, carbamazapine
- Inhibitor: valproic acid
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Anticonvulsant: Ethosuximide **
- Mechanism: blocking the T type Ca channels in thalamic neurons
- Use:
absence seizures
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Anticonvulsant drug use: General consideration
- are additive to CNS depressants
- avoid abrupt withdrawal, may preciptate seizures
- decreased efficacy of OCP via induction of CYP450
- safest in pregnancy: Phenobarbital
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Anticonvulsant drug: Felbamate & Lamotrigine
- Mechanism: block Na channels and glutamate receptors
- Used in seizure sates (often adjunct thereapy)
- Side effects: hepatotoxicity and aplastic anemia (felamate)
- Steven-Johnson syndrome (lamotrigine)
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Anticonvulsant drug: Gabapentin
increases GABA efects, used in neuropathic pain (ie post herpetic neuralgia)
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General anticonvulsant words of wisdom
- if you don't know what to give them, give them valproic acid
- if there are multiple types of seizures should give valproic acid
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Anesthesia Drugs: Classes
- 1. Inhaled Anesthetics
- 2. IV Anesthetics
- 3. Local Anesthetics (most #of q from here)
- 4. Skeletal Muscle Relaxants
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Anesthesia Drug: Inhaled Anesthetics: General Info
- Anesthesia protocols include several agents in combo
- Inhaled agest have varying potency wrt lipid solubility (need to be lipid sol to enter CNS)
- Minimum Alveolar Concentration: MAC: the concentration of inhaled anesthetic as a % of inspired air, at which 50% of the pts do not respond to a surgical stimulus
- - measure of potency: ED50
- - more lipid sol = lower MAC value = more potent
- MAC values are additive
- MAC values are lower in elderly & in the presence of opiates or sedative-hypnotics
- Rates of onset/recovery depend on the blood:gas ratio:
- - more soluble the anesthetic in blood = slower anesthesia
- - less soluble the anesthetic in blood = rapid induction and recovery times
- - high blood:gas ratio = slower onset and recovery
- - low blood:gas ratio = faster onset and recovery
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Anesthesia Drugs & Organs
- Lungs: high rate + depth of ventilation = high gas tension
- Blood: high blood solubility = high blood/gas partition coefficient = high solubility = more gas needed to saturate blood = slower onset of action
- Tissue (ie brain): AV concentration gradient high = high solubility = more gas required to saturate tissue = slower onset of action
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Anesthesia Drug: Inhaled Anesthetic: NO
- MAC value = 104% (less potent)
- Blood:gas ratio = .5 (fast onset)
- Characteristics: rapid onset/recovery, no metabolism, diffusional hypoxia, spontanous abortions
- toxicity: not potent enough to use on own, minimal CV effects, expansion of trapped gas
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Anesthesia Drug: Inhaled Anesthetic: Halothane, Desflurane, Sevoflurane
- MAC = .8% (very potent)
- Blood:gas ratio = 2.3 (slow)
- Characteristics: malignant hyperthermia, heptatits, cardia dysrhythmias
- Toxicity: CV effects: sensitizes heart to catecholamines (pheo), halothane (hepatotoxicity), methyoxyflurane (neprhotoxicity), enflurane (proconvulsant), malignant hyperthermia
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Anesthesia Drugs: IV Anesthetics:
- Thiopental
- Midazolam
- Propofol
- Fentanyl
- Ketamine
B.B. King on OPIATES PROPOses FOOLishly
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Anesthesia Drug: IV Anesthetic: Thiopental
- A barbiturate
- use: induction of anesthesia & short surgical procedures
- characteristic: highly lipid soluble: rapid onset, short acting due to redistribution, but remains in the fat for up to 9 hours, decreases cerebral BF
remember Barbs don't have an antidote
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Anesthesia Drug: IV Anesthetic: Midazolam
- A benzodiazepine
- Use: preoperative sedation, anterograde amnesia, induction, outpatient surgery, endoscopy, often used with gaseous anesthetics & narcotics
- toxicity: depresses respiratory function post-op, decreases BP, amnesia
- OD tx: flumazenil
antidote = flumazenil
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Anesthesia Drug: IV Anesthetic: Propofol
- Use: induction and maintenance of anesthesia, rapid in and out
- antiemetic, CNS and cardiac depressant
- Potentiates GABAA
Ie: eye surgery is very nauseating, thus this would be a good choice
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Anesthesia Drug: IV Anesthetic: Fentanyl/Morphine
- An opiate
- use: induction and maintenace of general anesthesia, depresses respiratory function
antidote: naloxone
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Anesthesia Drug: IV Anesthetic: Ketamine** (an Arylcyclohexylamine)
- Dissociative anesthetic: catatoric, no sensory input
- Mechanism: NMDA receptor antagonist
- Use:
induction of anesthesia - emergent delirium, hallucinations, CV stimuation, increases intracranial pressure, good for asthmatics (little effect on respiration)
- Toxocity: CV stimulation, disorientation, bad dreams, increases cerebral BF
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Anesthesia Drug: Local Anesthetics **
very common Q!
- Use: regional anesthesia
- Drugs: Esters & Amides (each have their own card)
Mechanisms: nonionized form crosses axonal membrane (most of the body is acidic thus ionized drug more common), from w/in, ionized form blocks the inactivated Na channel by binding on the inner part of the channel, slows recovery and prevents propagation of action potentials - Most effective in rapidly firing neurons
- 3* amine local anesthetics penetrate membrane in uncharged form, then bind to ion channesl as a charged form
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Anestheia Drug: Local Anesthetics Drugs: PRINCIPLE
An infected (acidic) tissue, alkaline anesthetics are charged and cannot penetrate the membrane effectively. More anethetic is needed in these cases
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Anesthesia Drug: Local Anesthetics Drugs
Esters: procaine, cocaine, benzocaine ...all metabolized by plasma and tissue esterases
one eyed ester has allergies: any of the local anesthetics that have one letter "i" in their name is an ester and allergies are more common
Amides: lidocaine, bupivacaine, mepivacaine... all metabolized by liver amidases
more than one letter "i" in the drug it is an amide
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Anesthesia Drug: Local Anesthetics: Nerve Fibre Sensitivity
- Small-diameter fibres > lg-diameter
- Myelinated fibres > non-myelinated
- Overall size predominants over myelination --small myelinated > small unmyelinated > large myelinated > large unmyelinated
Order of loss: pain (lose first) > temperature > tough > pressure (loose last)
- type B/C (pain)> type Adelta (pain/temp)> type Abeta/gamma(touch/pressure)> typeAalpha (muscle)recovery is in reverse order
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Anesthesia Drug: Local Ansthetics: Absorption
Coadministered with alpha1 agonists: to decrease local anesthetic absorption into systemic circulation and prolong effects/decrease toxicity
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Anesthesia Drug: Local Anesthetics: Side effects:
- neurotoxicity-CNS excitation
- CV toxicity (bupivicaine), hyper/hypotension, arrythmias (cocaine)
- Allergies (esters via PABA formation) if allergic then give amides
- Note: Amides are not metabolized into PABA
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Anesthesia Drug: Skeletal Muscle Relaxants General
- Physiology: nicotinic ACh receptor has 2 alpha subunits that need to be bound in order to open up the Na channel to depolarize the muscle
- Use: ICU or anesthesia protocols that require muscle relaxation/immobility Mechanism: interact w/ nicotinic ACh receptors at the NMJ (more selective for NMJ vs. autonomic receptors)
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Anesthesia Drug: Skeletal Muscle Relaxant: Nondepolarizing (competitive)
- Mechanism: nicotinic antagonists
- D-Tubocurarine is the prototype
- reversible with AChE inhibitors (neo-, pyridostigmine) to increase ACh binding to alpha subunits
- causes: progressive paralysis (face, limbs, respiratory muscle), no effects n cardiac or smooth muscle, no CNS effects
- Drugs: Atracurium, Mivacurium, succinylcholine, BZ, baclofen
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Anethesia Drug: Skeletal Muscle Relaxant: Nondepolarizing (competitive)
- Atracurium
- Rapid recovery
- safe in hepatic or renal impairment
- spontaenous inactivation due to laudanosine
- Laudanosine can cause seizures
- Mivacurium very short acting
- metabolized by plasma cholinesterases
- Other drugs: tubocurarine, pancuronium, vecuroniu, rocuronium
- Reversal of blockade: neostigmine, edrophonium, other cholinesterase inhibitors
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Anesthesia Drug: Skeletal Muscle Relaxant: Depolarizing (non-competitive)
- drug: Succinylcholine (ACh-ACh)
- nicotinic agonist
- 2 phases:
- phase I: prolonged depolarization, fasciculation, prolong depolarization, flaccid paralysis (due to receptor sensitization). no antidote, block potentiated by cholinesterase inhibitors
- Phase II:
desensitization - AChE inhibitors increase phase I and no effect on phase II. repolarized, but blocked, antidote consists of cholinesterase inhibitors (ie neostigmine)
- Metabolized: by pseudocholinesterase: short duration
- Caution: atypical pseudocholinesterase (genetic polymprphism), hyperkalemia, hypercalcemia, malignant hyperthermia
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Anesthesia Drug: Centrally Acting Skeletal Muscle Relaxants
- Drugs: BZ thru GABAa receptors, Baclofen thru GABAb receptors
- Use: spasticity
there is less excessive muscle tone or spasm injury and CNS muscle dysfunction
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Malignant Hyperthermia
Defn: a life threatening syndrome characterized by muscle rigidity, hyperthermia, hypertension, acidosis, and hyperkalemia
Associated with use of: skeletal muscle relaxants, especially succinyl CoA
Genetic susceptibility: mutations in the ryanodine receptor and/or protein part of the L-type Ca channel in muscle
- Treatment: Dantrolene
Mechanism: blocks the Ca release from SR in skeletal muscle and decreases muscle rigidity (as seen in malignant hyperthermia or neuroleptic malignant syndrome)
3 drugs that cause malignant hyperthermia: succinylcholine, halothane, tubocurarine
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Opioid Analgesics General
- Endogenous opiate peptides: endorphins, enkephalins, dynorphins
- 3 receptor families: mu, kappa, delta
- Mu pharm is most NB
- Mechanism: Act as agonists at these opioid receptors
- Mu = morphine
- Kappa = dynorphin
- delta =enkephalin
- All act to modulate synaptic transmission = inhibit the release of ACh, NEp, 5HT, glutamate, substance P
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Contraindications/Caution for opioids:
- Head injuries: possible increased intracranial pressure
- Pulmonary dysfunction: except pulmonary edema
- Hepatic/renal dysfunction: possible accumulation
- Adrenal/thyroid deficiencies: exaggerated responses
- Pregnancy: possible neonatal depression/dependence, except meperidine
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Side effects from opioid analgesics:
- Acute toxicity: Classic Triad: 1. pinpoint pupils
- 2. respiratory depression
- 3. coma
Management of acute toxicity: supportive, IV naloxone
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Opiate-related drugs w/ specific indications:
- Loperamide: for diarrhea, OTC, no abuse potential bc does not cross BBB
- Dextromethorphan: for cough, works centrally to elevate the threshold for coughing
- Benzonatate: is a non-opioid used for cought that anesthetizes cough/stretch receptors in lung
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Abuse liability of opioid analgesics:
- Tolerance: pharmacodynamic; occurs to all effects (except miosis & constipation)
- Dependence: physical and psychologic
- Withdrawal: yawning, lacrimation, rhinorrhea, salivation, anxiety, sweating, goose bumps, muscle cramps, spasms, CNS-originating pain
- Management of withdrawal: supportive, mehadone, clonidine
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Butorphanol
- Mechanism: partial agonist at opioid mu receptors, agonist at kappa receptors
- Clinical use: pain; less respiratory depression than full agonists
- Toxicity; causes w/drawal if on full opioid agonist
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Tramadol
- Mechanism: very week opioid agonist, also inhibits serotonin, NEp reuptake (works on multiple NT = tram it all!
Clinical use: chronic pain - Toxicity: similar to opioids, decreases seizure threshold
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Opioid Analgesics: Morphine
- prototype mu agonist
- mechanism: presynaptically 0 decreased Ca influx & substance P release, post synaptically increase K efflux = hyperpolarization (similar to M2 effects on heart)
- Pharmacology: analgsia: increases pain tolerance and decreases perception/reaction to pain (less NT), sedation
- Side Effects: respiratory depression if OD: decreased response to hi pCO2
- OD tx: naloxone
- Side effects: CV: minimal on heart, vasodilation (avoid in head trauma)
- Side effects SM: longitudinal relaxes, circular constricts: GI = decreased peristalsis, constipation, cramping, GU = urinary retention, urgency to void, Biliary: increased pressue (stones/colic), pupils: miosis
- Other actions: cough suppression (antitussive agent), stimulates the CTZ = n/v, increases histamine release
- PK: glucuronidation, morphine-6-glucuronide is highly active, caution renal function
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Opioid: Full Agonist: Meperidine
- Characertistics: antimuscarinic, no miosis or spasm of GI/GU/gallbladder
- tachy
- CYP450 metabolism to form normeperidine
- serotonin reuptake inhibitor
- normeperidine can cause serotonine syndrome & seizures
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Opioid Full Agonist: Methadone
Characteristics: used in maintenance of opiate addict
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Opioid Full Agonist: codeine
Characteristics: cough suppressant, analgesia, used in combo with NSAIDS
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Other Opioid Full Agonists:
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Opioid: Partial Agonist: Buprenorphine
Characteristics: precipitation of withdrawal
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Opioid: Mixed Agonist/Antagonist: Nalbuphine, pentazocine
Kappa agonist: spinal analgesia, dysphoria
Mu antagonist: precipitation of withdrawal
can precipitate a withdrawal
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Should you give a mixed agonist/antagonist to a pt on a full agonist?
NO!!!!!!
it can lead to immediate state of withdrawal
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Opioid Antagonists: Naloxone, Naltrexone, Methylnatrexone
- Naloxone: shorter half-life, IV, reversal for respiratory depression
- Naltrexone: longer half-life, PO (bc TREX is like TRIX and you eat that cereal), decreases cravings for alcohol and sed in opiate addiction
- Methylnaltrexone: treatment of opioid-induced constipation (does not cross BBB and won't precipitate a withdrawal)
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What are the 4 DA neural pathways?
- Nigrostriatal: cell bodies in substantia nigra project to striatum and release DA, in Parkinson's these DA neurons are lost = excessive ACh
- Mesolimbic-mesocortical tract: cell bodies in the midbrain project to the cerebrocortical and limbic structures, involved in reinforcement
- Tuberoinfundibular: cell bodies in the hypothalamus project to ant. pit. and release DA (decrease PRL release)
- Chemoreceptor trigger zone: activation by DA = increases emesis
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What are the DA receptors?
- D1-like = Gs coupled
- D2-like = Gi coupled:
- D2A = nigrostriatal (Parkinson's dz)
- D2C = mesolimbic (Schizophrenia)
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What are the signs and symptomas of Parkinson Disease?
- Bradykinesia
- Muscle rigidity (cogwheel)
- Resting tremor (low freq)
- postural instability
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Pathology of Parkinson Disease:
degeneration of nigrostriatal DA tracts w/ imbalance between DA (lo) and ACh (hi)
schizophrenia is opposite
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Strategies in Parkinson Disease:
- Agonize DA receptors: Bromocriptine, pergolid, pramipexol, ropinrole
- Increase DA: Amantadine, L-dopa/carbidopa
- Prevent DA breakdown: selegiline, entacoapone, tolcapone
- curb excess cholinergic activity: Benztropine
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Parkinsons Drugs: Bromocriptine
- other drugs: pergolide (ergot alkaloid and partial DA agonist), pramipexole, ropinirole (non-ergot), *non-ergots are preferred
- Mechanism: DA-receptor agonist
- Use: hyhperprolactinemia, acromegaly
- Side effects: dyskinesia & psychosis
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Parkinsons Drugs: Amantadine
- Mechansim: may increase DA release, blocks muscarinic receptors and increases DA release
- Side effects: atropine-like, livedo reticularis (purple skin discolouration), ataxia, edema, hallucinations
- Use: Parkinsons, influenza A, rubella
- Toxicity: ataxia
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Parkinsons Drugs: L-Dopa/Carbidopa
- Mechanism: levodopa can cross the BBB and turns into DA, prodrug converted to DA by aromatic amino decarboxylase (AAAD), usually given as carbidopa (periphreal decarboxylase inhibitors that increases bioavailibility in the CNS and decreases it peripherally)
- Side Effects: dyskinesias, 'on-off' effects = off (akinesia) & on (better mobility), psychosis (increased DA), hypotension, vomitind (DA is emetic), arrhythmias due to peripheral conversion to DA, decreased effectiveness w/ high protein meals (need to take long before you eat), dosage needs to increase w/ time
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Parkinsons Drugs: Selegiline
other drugs: toclcapone/entacopone (COMT-inhibitor that prevent Ldopa degredation = increased DA availability) ...has to be used w/ Ldopa
Mechanism: selective-MAO B inhibitor (no tyramine interactions), preferentially metabolizes DA over NE and 5-HT, thus increasing bioavailibility of DA (essentially prevents L-dopa breakdown)
- Selegiline is the initial tx & adjunct to levodopa
- Side effects: dyskinesias, psychosis, insomnia (metabolized to amphetamine), enhances the side effects of L-dopa
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Parkinsons Drugs: Benztropine
- Other drugs: trihexylphenidyl, diphenhydramine (both antimuscarinic)
- Mechanism: antimuscarinie (decreases ACh activity), DA agonist
- Use: improves tremor and rigidity but little effect on bradykinesia
- Side effects: atropine-like effects (dry picture), less dyskinesia, makes dementia/psychosis/autonomic instability worse
Park your Mercedes-Benz
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Parkinsons Drugs: Beta-blockers
can be used for essential or familial tremors
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Parkinsons Drugs: Tolcapone/entacapone
- Mechanism: inhibits the COMT (prevents the breakdown of levodopa into 3-O-methyldopa, increases levodopa into the CNS
- Side effects: tolcapone = hepatoxic
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Schizophrenia Positive SXS
- Thought disorders
- Delusions
- Hallucinations
- Paranoia
often seen with older drugs
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Schizophrenia Negative SXS
- Amotivation
- Social withdrawal
- Flat affect
- Poverty of speech
often seen with newer drugs
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Dopamine Hypothesis for Schizophrenia
- Symptoms arise bc of excessive dopaminergic activity in mesolimbic system
- DA agonists cause psychosis
- DA antagonists have antipsychotic actions
typical mechanism of treatment: block DA and 5HT 2 receptors
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Serotonin Hypothesis for Schizophrenia
more atypical theory
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Typical Tx for Schizophrenia
- Mechanism: blocks DA and/or 5HT2receptors
- Same tx can be used in: schizoaffective states, bipolar disorder, Tourettes syndrome, Huntingtons, drug / radiation emesis
- Side effects of DA blockade:
- Dyskinesia: EPS:
- Acute-pseudoparkinsonism, dystonia, akathisia
- Acute management- antimuscarinic drugs (benztropine/diphenhydramine)
- Chronic- tardiv dykinesia
- Chronic management-discontinuation, switch to atypical
- Dysphoria:
- Endocrine dysfunction: temp regulation problems (neuroleptic malignant syndrome, treated with dantrolene and bromocriptine), increased PRL, increased eating behaviours (weight gain)
- Side effects from muscarinic blockade: tachy, decreased seizure threshold
- Side effects from alpha blockade: hypotension
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TYPICAL ANTIPSYCHOTICS
- Drugs: haloperidol, trifluoperazine, fluphenazine, thioridazine, chlopromazine
- Mechanism: all block D2 receptors = increases cAMP1
- Clinical use: schizoprenia (positive symptoms), pscyhosis, acute mania, Tourette's
- Toxicity:
- 1. highly lipd soluble and stored in body fat, slowly removed from body
- 2. EPS
- 3. endocrine side effects
- 4. receptor blocking side effects: muscarinic (dry), alpha (hypotension), histamine (sedation)
- Neuroleptic Malignant syndrome-rigidity, myoglobinuria, autonomic instability, hyperpyrexia, tx: dandrolene, bromocriptine
- Tardive dyskinesia-stereotypic oral-facial movts due to LT antipsychotic use, often reversible
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Evolution of EPS side effects
- 4 hour: acute dystonia (muscle spasm, stiffness, oculogyric crisis)
- 4 days: akinesia (parkinsonian symptoms)
- 4 weeks: akathisia (restlessness)
- 4 months: tardive dyskinesia
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Antipsychotic Drugs (neuroleptics) TYPICALS: Chloropromazine
- Haloperidol + '-azines'
- Muscarinic block
- H1 (sedation) block
- Alpha block (mostly alpha1)
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Antipsychotic Drugs (neuroleptics): TYPICALS: Thioridazine
- Muscarinic block
- H1 (sedation) block
- alpha block (mostly alpha1)
- cardiotoxicity (Torsades, quinidine-like), retinal deposits
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Antipsychotic Drugs (neuroleptics): TYPICALS Fluphenazine
EPS (pseudoparkinsons)
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Antipsychotic Drugs (neuroleptics): TYPICALS Haloperidol
- EPS (pseudoparkinsons)
- Other: most likely the cause of neuroleptic malignant syndrome (NMS) and TD
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Neuroleptic Malignant Syndrome (NMS)
think FEVER:
Fever - Encephalopathy
- Vitals unstable
- Elevated enzymes
- Rigidity of muscle
Muscle rigidity, myoglobinuria, autonomic instability, hyperpyrexia
Treatment: Dantrolene: prevents the release of Ca ions from the SR in skeletal muscle
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ATYPICAL ANTIPSYCHOTIC DRUGS
Drugs: olanzapine, clozapine, quetiapine, risperidone, aripiprazole, ziprasidone
it's atypical for old closets to quietly risper from A to Z
Clinical use: schizophrenia (+ and - symptoms), Olanzapine can be used in OCD, anxiety, depression, mania, Tourettes - Toxicity: fewer EPS & anticholinergic side effects than typicals, all atypicals cause hyperglycemia = weight gain & insulin resistance
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Antipsychotic Drugs (neuroleptics): ATYPICALS Clozapine
- EPS (may or may not)
- muscarinic block
- alpha block
- D2C receptors block
- 5HT2 receptors block
- H1 receptor block
- no TD
- Agranulocytosis: weekly WBC count needed
- weight gain
- increased salivation (wet pillow syndrome)
- seizures
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Antipsychotic Drugs (neuroleptics) ATYPICALS Olanzapine
- EPS (may or may not)
- Receptors blocked: alpha1, 5HT2
- Improves negative symptoms
- no TD
- Clinical use: OCD, anxiety disorder, depression, mania, Tourette's
- always pick this one bc it is a better drug
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Antipsychotic Drugs (neuroleptics) ATYPICALS Risperidone
- EPS
- receptors blocked: H1, alpha 1 5HT2, maybe Muscarinic
- improves negative symptoms
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Antipsychotic Drugs (neuroleptics) ATYPICALS Aripiprazole
- EPS, maybe muscarinic, H1, alpha block, parital agonist of D2 receptors, blocks 5HT2 receptors
- improves negative symptoms
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Lithium
- Mechanism: not established, possibly inhibition of posphoinostitol cascade
- Clinical use: mood stabilizer for bipolar, blocks relapse and acute manic events, SAIDH
- Toxicity: tremor, sedation, edema, heart block, hypothyroidism, polyuria (ADH antagonist causing nephrogenic DI), teratogenesis, narrow therapeutic window thus requires close monitoring
- LMNOP
- Lithium side effects: Movement, Nephrogenic diabetes insipidis, hypOthyroidism, Pregnancy problems
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Methylphenidate (Ritalin)
Mechanism: increases NEp vesicular release (like amphetamies), but the actual mechanism of alleviating ADHD is unknown
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Buspirone
- Mechanism: Stimulates 5HT1a receptors
- Clinical use: generalized anxiety disorder, does not cause sedation, addiction, tolerance, does not interact with alcohol (vs. barbs and benzos)
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Antidpressant Drugs:
- MAO Inhibitors
- TCAs
- SSRI
- Others: Trazodone, Venlafaxine, Buproprion, Mitrazapine
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Antidepressant Drugs: MAO Inhibitors
- Drugs: Penelzine, tranylcypromine, isocarboxazid, selegiline (selective MAO-B inhibitor)
- Mechanism: nonselecitve MAO inhibition = increases amine NT
- Clinical use: atypical depression, anxiety, hyochondriasis
- Toxicity: hypertensive crisis w/ tyramine ingestion (ie wine and cheese) and B-agonists; CNS stimulation
- Drug interactions:
- hi NEp = Hypertensive Crissi: hi BP, arrhythmias, excitation, hyperthermia. caused by - releasers (ie tyramine), TCA, alpha1 agonists
- hi 5HT = Serotonin Syndrome: sweating, rigidity, myoclonus, hyperthermia, ANS instability, seizures. caused by - SSRI, TCA, meperidine
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Antidepressant Drugs: Tricyclic Antidepressants
- Drugs: imipramine, amitriptyline, desipramine, nortriptyline, clomipramine, doxepin, amoxapine
- Mechanism: block reuptake of NEp & serotinin
- Clinical use: major depression, enuresis (mipramine), OCD (clomipramine), fibromyalgia, neuropathic pain
- Side effects: sedation, alpha-blocking effect, atropine like effects (tachy, urinary retention), specific TCA drug effects
- Toxicity: Tri-C's: Convulsions, Coma, Cardiotoxicity (arrhythmias), respiratory depression, hyperyrexia, confusion/hallucinations in elderly due to anticholinergic effecs (should use nortriptyline), tx: NaHCO3 for CV toxicity
- Drug interactions: MAOI (hypertensive crisis), SSRI, MAOI, meperidine (Serotonin syndrome), alpha2 agonists, guanethidine (antihypertensive action)
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Antidepressant Drug: TCA: Amytriptyline
- 3* TCA
- more anitcholinergic effects than 2* TCA (nortriptyline)
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Antidepressant Drug: TCA: Nortriptyline
use in elderly to avoid confusion and hallucinations
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Antidepressant Drug: TCA: Desipramine
Least sedating TCA, has lower seizure threshold
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Antidepressant: SSRI
- Drugs: fluxetine, paroxetine, sertraline, citalopram
- Mechanism: serotonin-specific reuptake inhibitors
- Clinical use: depression, OCD< bulimia, social phobias, slow onset anxiety, premenstrual dysphoric disorder
- Toxicity: fewer than TCA, GI distress, sexual dysfunction (anorgasmia), Serotonin syndrome (with any drug that increases 5HT like MAOI = hyperthermia, muscle rigidity, CV collapse, flushing, diarrhea, seizures. Tx: cyprohetadine (5HT2 receptors antagonist)
- Duration of onset: 2 - 3 weeks to have an effect
- Benefits over other Rx: less sedative and cause initial weight loss
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Antidepressants: Other: SNRI:
- Drugs: venlfaxine, duloxetine
- Mechanism: inhibit serotonin and NEp reuptake
- Clinical use: depression. Venlfaxine - generalized anxiety disorder. Duloxetine more NEp effect
- Toxicity: increased BP is most common; also stimulant effects, sedation, nausea
- Benefit: nonselective reuptake blocker; avoids ANS side effects
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Antidepressants: Atypical: Buproprion
- aka Wellbutrin
- Clinical use: depression, smoking cessation
- Mechanism:
DA reuptake inhibitor - Toxicity: stimulant effects (tachy, insomnia), headache, seizure in bulimia, no sexual side effects
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Antidepressants: Atypical: Mirtazapine
- Mechanism: alpha2 antagonist (increases NEp release and serotonin, potent 5-HT2 & 5-HT3 receptor antagonist
- Toxicity: sedation, increased appetite, weight gain, dry mouth
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Antidepressants: Atypical: Maprotiline
- Mechanism: blocks NEp reuptake
- Toxicity: sedation, orthostatic htn
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Antidepressants: Atypical: Trazadone
- Mechanism: mostly serotonin reuptake
- Use: insomnia, high doses are needed for antidepressant effects
- Toxicity: sedation, nausea, pripaism, postural hypotension
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Drugs of Abuse: CNS Stimulant: COCAINE
- NT: NE, DA, 5HT
- Mechanism of action: blocks the NT reuptake in CNS; local anesthetic action from Na channel blockade
- Effects: NE: sympathomimetic, DA: psychotic episodes, paranoia, hallucinations, dykinesia, endocrine disturbances. 5HT: behavioural changes, aggressiveness, dyskinesias, decreased appetite
- Toxicity: NE: cardiac arrhythmias, generalized ischemia w/ possible MI & stroke; acute renal & hepatic failure. DA: major psychoseis, cocaine delirium. 5HT; possible serotonin syndrome. convulsion, hyperpyrexia, death
- Withdrawal: craving, severe depression, anhedonia, anxiety; manage with antidepressants
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Drugs of Abuse: CNS Stimulant: AMPHETAMINES
- NT: NE, DA, 5HT
- Mechanism: blockage of reuptake of NE and DA, release amines form mobile pool, weak MAO inhibitor
- Effects: NE: sympathomimetic, DA: psychotic episodes, paranoia, hallucinations, dykinesia, endocrine disturbances. 5HT: behavioural changes, aggressiveness, dyskinesias, decreased appetiteToxicity: NE: cardiac arrhythmias, generalized ischemia w/ possible MI & stroke; acute renal & hepatic failure. DA: major psychoseis, cocaine delirium. 5HT; possible serotonin syndrome. convulsion, hyperpyrexia, deathWithdrawal: craving, severe depression, anhedonia, anxiety; manage with antidepressants
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Drugs of Abuse: CNS Depressant: BENZODIAZEPINES
- NT: GABA
- Mechanism: potentiation of GABA interaction with GABAa receptors involves the BZ1 and BZ2 binding sites
- Effects: light to moderate CNS depression
- Toxicity: sedation, anterograde amnesia; in severe OD (or IV use), reverse with flumazenil
Withdrawal: rebound insomnia, reboud anxiety
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Drugs of Abuse: CNS Depressants: BARBITURATES & ETHANOL
- NT: GABA
- Mechanism of action: prolongation of GABA, GABAmimetic at high doses on GABAa receptors
- Effects: any plane of CNS depression
- Toxicity: severe CNS depression, respiratory depression, death
- Withdrawal: agitation, anxiety, hyperreflexia, life-threatening seizure + ethanol withdrawal delusions/hallucinations - delerium tremens (DTs)
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Drugs of Abuse: Opiods: Morphine, Heron, Methadone, Fentanyls, other opoids:
- NT: NE, DA, 5HT, GABA, many others
- Mechanism: activate opioid mu, kappa, delta receptors, potent mu receptor activation = most intense abuse / dependence liability,possibley effects via an increase in DA tranmission in mesolimbic tracts
- Effects: euphoria, analgesia, sedation, cough suppression, constipation; strng miosis (except meperidine)
- Toxicity: severe respiratory depression (reverse with naloxone), nausea, vomiting
- Withdrawal: lacrimation, yawning, sweating, restlessness, rapidly followed with centrally originating pain, muscle cramping, diarrhea; not life-threatening
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Drugs of Abuse: Hallucinogens: MARIJUANA
- NT: many
- Mechanism of action: interaction of THC with CB1 & CB2 cannabinoid receptors in CNS and periphery
- Effects: sedation, eurphoria, increased HR, delusions, hallucinations
- Toxicity: associated with smoking, possible flashbacks
- Withdrawal: irritability, anxiety
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Drugs of Abuse: Hallucinogens: HALLUCINOGENS
- NT: 5HT
- Mechanism of action: interaction with several subtypes of 5HT receptors
- Effects: hallucinogen, sympathomimetic, causes dysethesias
- Toxicity: poorly described, flashbacks likely
- Withdrawal: poorly characterized
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Drugs of Abuse: Miscellaneous: PCP
PCP: NMDA-receptor antagonist; extremely toxic; horizontal and vertical nystagmus, paranoid, rhabdomyolysis; OD is common with convulsions & death
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Drugs of Abuse: Miscellaneous: Ketamine
similar to, but milder than PCP; hallucinations, glutamate receptor antagonist
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Drugs of Abuse: MIscellaneous: Anticholinergics
scopolaime, atropine-like
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Drugs of Abuse: Miscellaneous: MDMA "Ecstasy", MDA, MDEA
amphetamine-like strong 5HT pharmacology, hallucinogenic, neurotoxic
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Drugs of Abuse: Miscellaneous: Inhalants
solvent use, multiple organ damage
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Alzheimer's Drugs: Memantine
- Mechanism: NMDA receptor antagonist, helps prevent excitotoxicity (mediated by Ca)
- Toxocity: Dizziness, confusion, hallucinations
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Alzheimer's Drugs: Donepezil, galantamine, rivastigmine
- Mechanism: AChE inhibitor
- Toxicity: nausea, dizziness, insomnia
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Huntington's Drugs
- Huntington's Dz: increased DA, decreased GABA + ACh
- Reserpine + tetrabenzaine: amine depletion
- Haloperidol: DA receptor antagonist
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Migraine Drug: Sumatriptan
- Mechanism: 5-HT1B/1D agonist, VC, inhibition of trigeminal activation and VIP, half life is < 2 hours
- Clinical use: acute migraine, cluster headaches
- Toxicity: coronary vasospasm, contracindicated in pts with CAD/Prinzmetal's angina), mild tingling
A SUMo wrestler TRIPs ANd falls on your HEAD
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Epilepsy Drug: Phenytoin
see chart on p. 428 in FA!!
- Mechanism: use-dependent blockade of Na channels, increases the refractory period; inhibition of glutamate release from excitatory presynaptic neuron
- Clinical use: tonic clonic sizures, status prophylaxis, class 1B antiarrhythmic
- Toxicity: nystagmus, ataxia, diplopia, sedation, SLE-like syndrome, induction of CYP450, chronic use = gingival hyperplasia in children, periphearly neuropathy, hirsuitism, megaloblastic anemia (decreased folate absorption), teratogenic Fetal Hydantoin Syndrome
Note: fosphenytoin is the IV parenteral form
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Epilepsy Drug: Benzodiazepene (diazepam, lorazepam)
- Type of seizure: acute use in status
- Mechanism: increase GABAA action
- Clinical use: seizures of preeclampsia (first line is MgSO4)
- Toxicity: sedation, tolerance dependence
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Epilepsy Drug: Carbamazepine
- Type of seizure: first line in tonic, clonic, simple and complex partial, makes absence seizures worse
- Mechanism: increases Na channel activation
- Use: 1st line for trigeminal neuralgia
- Toxicity: diplopia, ataxia, blood dyscrasia (agranulocytosis, aplastic anemia), liver toxicity, teratogenesis, induction of CYP450, SIADH, Stevens-Johnsons syndrome
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Epilepsy Drug: Ethosuximide
- Type of seizure: absence seizure
- Mechanism: blocks thalamic T-type Ca channels
- Toxicity: GI distress, fatigue, headache, urticaria, Steven-Johnsons syndrome
EFGH; Ethosuximide, Fatigue, Gi distress, Headache
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Steven Johnson's syndrome
prodrome of malaise and fever, followed by fapid onset of erythamtous/purpuric macules (oral, ocular, genital), skin lesions progress to epidermal necrosis and sloughing. more common in African Americans
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Epilepsy Drug: Phenobarbital
- Type of seizure: partial simple and complex, toninc clonic, 1st line in PREGNANCY
- Mechanism: increases GABAa action
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Epilepsy Drugs: Valproic Acid
- Type of seizure: first line in tonic-clonic, parital simple and complex, in absence (not if reproductive age), myoclonic seizures
- Mechanism: increases Na channel inactivation, increases GABA concentration)
- Toxicity: GI distress, rare but fatal hepatotoxicity (measure LFTs), neural tube defects (spina bifida), tremor, weight gain, contraindicated in pregnancy
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Epilepsy Drugs: Lamotragine
- Type of seizure: partial simple and complex, tonic clonic
- Mechanism: blocks voltage-gated Na channels
- Toxicity: Steven Johnsons, decreased BCP levels
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Epilepsy Drugs: Gabapentin
- Type of seizure: partial simple and complex, tonic clonic
- Mechanism: GABA analogue, but mostly inhibits the HVA Ca channels
- Clinical use: peripheral neuropathy, bipolar disorder
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Epilepsy Drugs: Topirimate
- type of seizure: simple partial and complex and tonic clonic
- Mechanism: blocks Na channels, increases GABA action
- Toxicity: sedation, mental dulling, kidney stones, weight loss
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Seizures and their tx:
- Tonic Clonic: pheytoin, carbamazepine, valproic acid
- Status: phytoin for prophylaxis, benzo for acute use
- Absense: ethosuximide, then valproic acid
- Partial Simple: all, but mostly carbamazapine, lamotrigine
- Partial Complex: all of them
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