Pharm Review Yellow Slides Flashcards
How does the reactive reward pathway work?
VTA activation releases DA onto NA neurons so pleasure perceived and identifies stimulating activity as one to be repeated
Drugs of abuse share this final common pathway and also increase DA release in the nucleus accumbens
Mechanism of actions of hallucinogens
Partial agonist at 5HT2 receptors (DA releaser)
Acute toxicity opioids and treatment
Respiratory depression-pinpoint pupils-coma
Treatment: naloxone
Acute toxicity CNS depressants and treatment
Respiratory depression, coma (extremely rare with BDZs)
Treatment
Ethanol: supportive plus fluids-electrolytes-thiamine
Benzodiazepines: flumazenil
Barbiturates: supportive
CNS stimulants acute toxicity and treatment
SNS overactivity, increased HR-BP-temp, chest pain-MI, psychosis
Treatment: CVS support, vasodilators for BP, BDZs for agitation-seizures
Nicotine acute toxicity and treatment
rare – ingestion of insecticide or cigarettes by children
Nausea-vomiting, diarrhea, CVP collapse, convulsions
Treatment: CVS support, emetics-gastric lavage-charcoal
Cross tolerance
Tolerance develops to one drug – then will be seen to other drugs of the same class - same target
Tolerance and opioids
Develops rapidly (up to 100-fold); not to constipation
Tolerance and CNS Depressants
Rapid to barbiturates > ethanol, benzodiazepines
Significant to sedation-intoxication, less to lethal dose
Tolerance and CNS stimulants
develops to euphoria-anorexia-hyperthermia, but can see supersensitivity to paranoia
Tolerance and nicotine
Develops to subjective effects and nausea
Tolerance to hallucinogens
Not common, since repeated use minimal
Tolerance to cannabinoids
Rapid to most effects, also disappears rapidly
Cross dependence
Ability of one drug to suppress the withdrawal associated with physical dependence on another drug
Related to pharmacological effects at target – not chemical similarities
Ex: BDZ used for ethanol withdrawal
Do tolerance and dependence necessarily coexist? What about addiction and physical dependence?
NO! and No!
Withdrawal from opioids and treatment
Rarely life-threatening: insomnia, diarrhea, irritability, cramps, muscle aches, increased BP
Treatment: clonidine, methadone
Withdrawal from CNS depressants and treatment
Significant risk of mortality due to seizures (monitor)
Treatment: substitution with BDZs: loading dose - then taper to prevent seizures
Withdrawal from CNS stimulants and treatment
Sleepiness, fatigue, depression, hyperphagia, craving
Treatment: largely behavioral
Side effects of ethanol metabolism
increased NADH Hepatic Metabolic Disruption
increased levels of NADH leads to decreased Krebs activity -> decreased gluconeogenesis -> hypoglycemia
increased levels blood lactate leads to acidosis, behavioral disturbances
Increased Mg++ excretion can lead to convulsions
Increased Acetyl CoA leads to increased F.A. synthesis + decreased fat breakdown leading to a fatty liver
Decreased uric acid excretion may precipitate gout attacks
Ethanol and tolerance
Development of tolerance occurs - limited relative to opioids
Cross tolerance with other CNS depressants (BDZs-GAs)
Drugs used for reducing alcohol consumption
Disulfiram [Antabuse]
Opioid antagonists (Naltrexone)
NMDA receptor drugs (Acamprosate)
Positive symptoms of schizophrenia
Increased dopamine in the Nucleus Acumbens
Delusions
Hallucinations
Disordered thoughts
Negative symptoms of schizophrenia
Decreased DA in the prefrontal cortex
Blunted affect-anhedonia
Alogia - Asociality
Effects of Antipsychotic Receptor Block (D2) on Mesolimbic pathway
Decrease + symptoms of schizophrenia
Effects of Antipsychotic Receptor Block (D2) on Mesocortical pathway
Increase − symptoms of schizophrenia
Effects of Antipsychotic Receptor Block (D2) on Nigrostriatal pathway
Increase Extrapyramidal Side Effects
loss of inhibition of inhibitory indirect pathway leads to drug-induced movement disorder (pseudoparkinson’s)
Effects of Antipsychotic Receptor Block (D2) on Tuberoinfindibular pathway
Hyperprolactinemia
Effects of Antipsychotic Receptor Block (D2) on Hypothalamus
Poikilothermia, Weight Gain
Effects of Antipsychotic Receptor Block (D2) the Chemoreceptor Trigger Zone
Anti-Emetic Effect
D2 block side effects and treatments
Extrapyramidal Side Effects - increased with typical-high potency
Acute dystonia (onset 1-5 days): Torticollis, trismus, opisthotonos
Treatment: anticholinergic agents [diphenhydramine-benztropine]
Akathisia (onset 6-60 days): Motor restlessness – “can’t sit still”
Treatment: reduce dose – change drug – anticholinergic – β blocker, benzodiazepine
Pseudoparkinsonism (onset 5-90 days): Tremor, bradykinesia, rigidity, shuffling gait
Treatment: anticholinergic agents
Tardive dyskinesia (onset 3-6 months or longer, 20-40% incidence in elderly females): D2 receptor supersensitivity?
Involuntary movements of orofacial muscles, choreathetoid movements
Treatment: rarely effective, prevention best strategy
5HT2A Receptor Block effects
Mesocortical pathway: decreased negative schizophrenia symptoms
CNS: Weight gain
Muscarinic Cholinergic Block side effects
ANS: Blurred vision, dry mouth, constipation, difficulty urinating
CNS: Toxic-confusional state
Alpha-1 Receptor Block side effects
ANS: Orthostatic hypotension, impotence, failure to ejaculate
Histamine H1 Receptor Block side effects
CNS: Weight gain, sedation
What drug causes agranulocytosis?
clozapine - dose-related
Galactorrhea
excessive or inappropriate production of milk.
due to block of hypothalamic DA receptors
Lowered seizure threshold with antipsychotics
1-4% with clozapine
Neuroleptic malignant syndrome
Similar to malignant hyperthermia
Treat with dantrolene sodium
First line therapy for depression
Generic SSRIs
Bupropion
Equal efficacy as SSRIs
Less weight gain and sexual side effects
Not effective in anxious depression
SNRIs
May be more effective than SSRIs
Side effects > SSRIs
SSRIs side effects
Acute (diminishes over time): nausea, diarrhea, active-insomnia, somnolence
Delayed onset: weight gain, sexual dysfunction, cognitive blunting
Weight gain with antidepressants
More: TCADs – mirtazapine – paroxetine
Less: fluoxetine – sertraline – venlafaxine
Least: bupropion
Sexual dysfunction with antidepressants
Less with bupropion and mirtazapine
Anticholinergic side effects and antidepressants
Concern with TCADs (
Arrhythmias as side effect of antidepressants
Concern with TCADs (avoid if cardiac disease - ↑ QT)
Orthostatic hypotension as side effect of antidepressants
Trazodone - TCADs - MAOIs
Hypertension as a side effect of antidepressants
Venlafaxine
Withdrawal syndrome and antidepressants
Paroxetine and venlafaxine most likely
Fluoxetine least likely
Most common drug-drug interaction of antidepressants
Additive CNS depressant effects when used with other sedatives
Drug-drug interactions and MAOIs
Hypertensive crisis with drugs (meperidine, decongestants) or with foods high in tyramine (beer-wine-cheese) [results from acute increase in NE release]
serotonin syndrome
SSRIs + MAOIs
Hyperthermia, muscle rigidity, myoclonus
Rapid changes in mental status (confusion / agitation) and vital signs (hypertension and tachycardia)
Lithium mechanism of action
Slow onset
Effects greatest on cells with highest level of activity (use-dependence)
Enhance 5HT action and/or diminish NE and DA effect – most favored MOA:
Interference with PIP recycling (Gq protein: IP3 and DAG)
Also interference with Gs and Gi (adenylyl cyclase) can lead to side effects
In thyroid leads to anti-TSH release, leading to hypothyroidism
In kidney leads to anti-ADH release leading to polyuria-polydipsia
May affect gene regulation for growth factors and neuronal plasticity
Lithium uses
Prevention (maintenance use) of both manic and depressive episodes
Commonly used in combination with other agents
Lithium food interactions
Competes with sodium for reabsorption - Food-Drug
Interactions possible
Increase in dietary Na+: decreased Li+ Cp
Na+ restriction: increased Li+ Cp
Adverse effects of lithium
Related to plasma concentration - narrow therapeutic index
Decrease in thyroid function (weight gain possible)
Polyuria, polydipsia (anti-ADH action) (12%)
Moderate toxicity: Confusion, sedation, lethargy, twitching
Severe toxicity: Seizures, stupor, coma
Lithium drug interactions
Drug Interactions:
Diuretics can decrease renal clearance by 25%
Increase in lithium levels also seen with NSAIDs
Treatment of anxiety
- Antidepressants are first line (SSRIs, SNRIs, NOT NDRIs)
- BDZ (abuse potential): limits use to acute and situational anxiety
- Busprione: Weaker anxiolytic effect than benzodiazepines, but fewer side effects
- Barbiturates: Rarely used for anxiety because of low safety margin - drug interactions - high abuse potential
Buspirone
Alternative as an anxiolytic agent
5HT1A partial agonist - NOT a benzodiazepine
Moderate D2 receptor block so monitor for possible extrapyramidal system side effects
NO sedation or additive CNS depression or anticonvulsant or myorelaxant action
Requires 2 weeks for onset of anxiolytic effect and 4-6 weeks for maximal efficacy
More useful and effective in chronic anxiety
Less patient acceptance
Must be administered on routine schedule - not prn use
How does the GABA Receptor-Cl Ion Channel Complex work and how to BDZ, barbiturates, and ethanol interact with it?
GABA binds to receptor which opens Cl channel leading to ↓ Em and ↓ excitability
BDZs bind to site on α subunit [α1 and α2-5] intensifying the action of GABA. Presence of GABA required for BDZ effect.
BARBs bind to distinct site on channel
Low dose: action similar to BDZs
Higher doses: direct interaction with channel – NO GABA required - plus inhibition of excitatory NTs
Ethanol binds both specifically and non-specifically at distinct sites so action similar to barbiturates
Z drugs
(structurally distinct from BDZs) bind to same site as BDZs [only α1] - same action
What is the antagonist that binds to same site as BDZs and “Z”-drugs and is used in the treatment of benzodiazepine overdose toxicity?
Flumazanil
Alpha 1 GABA receptors (agonist, location in brain, and actions)
Agonists: BDZ and “z-drugs”
Location: cortex
Actions: Sleep, anticonvulsant, amnesia, additive CNS depression
Alpha 2-5 GABA receptors (agonist, location in brain, and actions)
Agonists: BDZ
Location: limbic system, brain stem
Actions: Anxiolytic, Myorelaxant, motor incoordination, tolerance, dependence, addiction, decreased REM
Effects of BDZ and Z-drugs on sleep stages
Sleep Latency: Both BDZ and z-drug decrease latency
Stage I: Both increase it
Stage 2: Both increase it
Stages 3-4: BDZ decrease it and z-drugs have no effect
REM: BDZ decrease it and z drugs have no effect
Tolerance to effects of BDZ and z drugs
BDZ: if used for more than one week
Z-drugs: very little tolerance
Triazolam
A BDZ
Rapid oral absorption
Short t1/2: 1.5-5 hrs - eliminated in 1 dosing cycle
Less daytime sedation (hangover)
Rebound insomnia next day due to rapid elimination
Use cautiously in elderly – dosage reduction
Temazepam
Slow absorption - minimal effect on sleep latency
Intermediate t1/2 (9-13 hrs)
Flurazepam
Long t1/2 + active metabolite (75-90 hrs) - low tolerance
Can accumulate in elderly - impaired hepatic clearance leads daytime sedation (“hangover”) / overdosage
Zolpidem and Zaleplon
Z drugs
Rapid oral absorption
Shortest durations of action (6-8 hours) and half-lives of available agents (zolpidem: 2-2.5 hrs - zaleplon: 1 hr)
Eszopiclone
Z-drug
Structurally different from zolpidem or zaleplon with longer t1/2 (approximately 6 hrs)
BDZ: adverse rxns
Daytime sedation and performance impairment
Anterograde amnesia (triazolam > temazepam)
Rebound insomnia
Psychologic and physiologic dependence – schedule IV
Z-drugs: adverse rxn
Safety similar to benzodiazepines
Common side effects: drowsiness, amnesia, headache, GI complaints – rarely bizarre behavioral disturbances
Rebound effects or next-day psychomotor performance alteration appear minimal with zolpidem and zaleplon
Increased with eszopiclone (longer t1/2) at higher doses
Tolerance-dependence-withdrawal are possible but less likely than with BDZs - BUT they are Schedule IV
Are fatal overdoses common with BDZ and Z drugs?
No, overall pretty safe
What’s the most widely prescribed agent for insomnia and what are its effects?
Zolpidem
Effective for:
Reducing sleep latency (immediate release formulation - Ambien®)
Reduce nocturnal awakenings (sustained release formulation - Ambien CR®)
Insomnia associated w/ middle-of-the-night awakening (low dose sublingual formulation - Intermezzo®)
Clinical use of zaleplon
Effective for:
Decreasing time to sleep onset – rapid oral onset
NOT for reducing nocturnal awakenings - short half-life
BUT is suitable to aid sleep onset for middle-of-the-night awakenings with elimination by morning
Clinical use of Eszopiclone
Effective for:
Sleep maintenance – longest half-life of “Z”-drugs
Safe for long-term use (6 months) – little evidence for tolerance-dependence-abuse – BUT Schedule IV
What is general anesthetic potency proportional and inversely proportional to?
Potency proportional to Lipid Solubility (O/W)
INVERSELY proportional to MAC
What factors affect the rate of onset of anesthetic action?
Concentration of anesthetic in the inspired air (higher conc increases rt of onset)
Solubility of the anesthetic in blood: Lower the blood solubility of the gas the faster the rate of induction
Drugs for treatment of grand mal (tonic clonic) seizures
Phenytoin
Carbamazepine
Valproate
Levetiracetam
Treatment for seizures: broad spectrum
Phenobarbital
Diazepam
Valproate
Divalproex
Treatment for absence seizures
Ethosuximide
Valproate
Treatment for partial seizure
Levetiracetam
Treatment for status epilepticus
Diazepam / Lorazepam / Midazolam
Antiseizures meds that increase inhibition of Sodium Channel Function
Block sustained high-frequency repetitive firing of APs that can initiate seizure formation
Blockade is use-dependent (blocks the ones firing too much, while leaving normal neurons alone)
Prolongs the inactivated state of the sodium channel and prolongs refractoriness
Phenytoin, carbamazepine, valproate
Mechanisms of antiseizure meds
Inhibition of Sodium Channel Function
Decrease in low-threshold Ca++ (T-type) current
Inhibition of high-voltage activated Ca++-channels
Inhibits function of synaptic vesicle protein SV2A
Enhancement of GABA Action
Antiseizure meds that cause a decrease in low-threshold Ca++ (T-type) current
Oscillatory currents in thalamic neurons are abnormal in absence seizures -
blocked by ethosuximide-valproate
Antiseizure meds that cause inhibition of high-voltage activated Ca++-channels
VSCC (aka N-type) involved in regulation of glutamate neurotransmitter release
Antiseizure meds that inhibit function of synaptic vesicle protein SV2A
Impairs Ca++-mediated neurotransmitter release -
levetiracetam
Antiseizure meds that enhance GABA Action
Benzodiazepines and phenobarbital enhance the inhibitory effect of GABA (increased opening of Cl- channels)
Valproate appears to act partly by this mechanism
Carbamazepine
A drug of choice for partial seizures
Often tried first in tonic-clonic seizures
Pharmacokinetics:
Strong inducer of CYP450 enzymes leads to self-induction + drug-drug interactions
Adverse Drug Reactions:
Diplopia-ataxia-sedation (dose-related), GI upset
Rare but serious adverse drug rxns:
Aplastic anemia-agranulocytosis: monitor CBC
Hepatotoxicity: monitor liver function tests
Phenytoin
Very effective against partial and tonic-clonic seizures
Pharmacokinetics:
Oral absorption is formulation dependent – concern with generic switching
IM absorption erratic (better with prodrug Fosphenytoin)
Zero-order (saturation) metabolism in therapeutic range
Strong inducer of CYP450 enzymes: DDIs
Adverse Drug Reactions:
Nystagmus-diplopia-ataxia-sedation (dose-related), Rash; gingival hyperplasia-hirsutism develop gradually
Long-term use: osteomalacia, peripheral neuropathy
Lamotrigine
Newer AED
Effects on VSSCs (suppress repetitive APs) and VSCCs (decrease Glu release) - broad spectrum
1st line for partial or generalized seizures - better tolerated than phenytoin or carbamazepine
ADRs: Similar to phenytoin (lower incidence): diplopia, ataxia, dizziness, skin rashes, sedation
Levetiracetam
Newer AED
Precise mechanism unknown - affects Ca++ channels
1st line in treatment of generalized tonic-clonic seizures
ADRs: Somnolence, asthenia, dizziness
Low incidence of cognitive effects
No CYP450 metabolism - minimal DDIs
Ethosuximide
Drug of choice in absence seizures
Adverse Drug Reactions – generally few side effects
Possible DDIs with CYP inhibitors or inducers
Dose-related gastric distress most common (nausea-vomiting, pain)
Less common: transient lethargy-fatigue, dizziness, headache
Valproate
Broad spectrum agent with efficacy against the most common seizure types
Pharmacokinetics: Administered as enteric-coated and delayed-release formulations
Inhibits metabolism of other AEDs: phenytoin, lamotrigine, carbamazepine, phenobarbital, ethosuximide
Adverse Drug Reactions – generally few side effects
Dose-related GI upset (nausea-vomiting, pain)
Weight gain common
Black Box Warnings: Hepatic failure (deaths [increased risk
Phenobarbital
Used for: Neonatal status epilepticus and as an adjunct for partial and tonic-clonic seizures
Pharmacokinetics: Metabolized slowly by P450 system - t1/2 of 4-5 days
Classic enzyme inducer
Adverse Drug Reactions: Irritability - overactivity in many children, sedative effects in others; Mild ataxia, nystagmus, skin rash, osteomalacia; May interfere with learning (cognitive deficits)
Status Epilepticus
State of recurrent major motor seizures between which patient does not regain consciousness
Mortality of 20-25% - death can occur from respiratory arrest or circulatory collapse
Treatment Options:
Initial therapy IV diazepam (lorazepam or midazolam) until seizures stop or 20 mg given
Then start phenytoin or fosphenytoin slow infusion
If seizures persist IV phenobarbital until seizures stop
If seizures still continue, pentobarbital or propofol infusion with pressor support
