Block 5 Drugs Flashcards
fomepizole
treatment for ethylene glycol toxicity, inhibits alcohol dehydrogenase
disulfiram
ethanol addiction relapse prevention
Alcohol makes person very sick
Headache, sweating, dizziness, nausea, vomiting, respiratory difficulties, orthostatic hypotension and (very rarely) death
Disulfiram interferes with aldehyde dehydrogenase - leads to excessive acetaldehyde levels
naltrexone
ethanol addiction relapse prevention
propromazine/ chlorpromazine (Thorazine)
called chlorpromazine in objectives, but propromazine in powerpoint, with thorazine in captions in both cases.
Typical/FGA
First Generation Antipsychotics
FGA
First generation anti-psychotic drugs (FGAs), such as haloperidol, act by blocking dopamine receptors in the brain
First generation anti-psychotic drugs are only effective on the positive symptoms of the disease
Block DA receptors everywhere in brain
Haloperidol
FGA
Clozapine (Clozaril)
Effective for both positive and negative symptoms
NO Parkinson-like symptoms (EPS)
Life threatening adverse effect (agranulocytosis)
Other SGA do not have life-threatening adverse effects but are not as effective as clozapine
SGAs block D2 receptors AND 5-HT receptors
often causes weight gain
No incidence of Tardive Diskinesia
Risperidone
SGA
Olanzapine
SGA, often causes weight gain
Quetiapine
SGA
Aripiprazole
SGA with least common occurrence of weight gain
sympathoinmetics
Increased release of NE and DA ↑ amount of transmitter that can act on postsynaptic receptors Blocks NE and DA reuptake Further ↑NE or DA levels Inhibits monoamine oxidase (MAO) ↑ neurotransmitter levels even higher
Stimulation of medullary respiratory center
Rate and depth
Most effective if respiration is depressed
Decreased food consumption
Feeding center
Tolerance
non-CNS:
Increased systolic and diastolic BP (reflex decrease in HR)
High doses - arrhythmias
THERAPEUTIC USES:
Attention deficit hyperactivity disorder (ADHD)
Narcolepsy
Fatigue
Weight loss
Analeptic - reverses drug induced depression
No longer used
High mortality relative to other measures
With severe depression - risk of cardiac arrhythmias, seizures and delirium
xanthines
caffeine and theophylline
Stimulates cerebral cortex Clearer flow of thought Decreased reaction time Detter association of ideas Less fatigue Improved manual dexterity in well learned tasks (e.g., Typing) Medullary centers affected next Stimulates respiration Stimulates vasomotor center Large doses will affect spinal cord (hyperreflexia)
Direct stimulation of the heart
Theophylline potency > caffeine
Increased rate and force of contraction and cardiac output (CO)
Congestive heart failure,
Rapid and transient increase in CO
Diuresis
Sensitive individuals
Arrhythmias
Premature ventricular contractions (PVCs)
Stimulates skeletal muscle (↑ work capacity)
Smooth muscle relaxant
Theophylline is useful for treatment and prophylaxis of bronchial asthma
↓ Peripheral vascular resistance
↑ Cerebral vascular resistance
MOA:
Translocation of intracellular Ca++ from the sarcoplasmic reticulum
Inhibition of phosphodiesterase
Elevated levels of the second messenger cAMP
Nonselective adenosine receptor antagonist
Inhibit sleepiness-inducing adenosine
Toxicity:
CNS
Insomnia, excitement, mild delirium, sensory disturbances (e.g., ringing in ears, flashes of light)
Followed by convulsions
> 10 gm - clonic convulsions and death
Cardiovascular Increased HR, extra systoles, increased respiratory rate Decreased clotting time Increased gastric secretions Also seen with decaffeinated beverages
Therapeutic Uses:
Cardiac stimulation in CHF – controversial
Dilates coronary arteries
Increased coronary blood flow
Increased inotropic and chronotropic forces
Increase O2 demand by the heart
Paroxysmal dyspnea associated with left heart failure
Analeptic
Bronchial asthma
Plus ergot alkaloids for migraine
Vasoconstriction of cerebral vasculature
Amphetimine
treats ADHD
Enhances NE release
Amphetamine psychosis: Vivid hallucinations, paranoid delusions and compulsions Marked weight loss Drug screen Symptoms resolve in 7-10 days
Cocaine
More rapid onset due to preferred routes of administration
Mech of Action:
Blocked reuptake of norepinephrine - motor
Blocked reuptake of dopamine - euphoria
Local anesthetic properties
Toxicity:
Cardiac arrhythmias, coronary and cerebral thrombosis
Impairs in utero brain development leading to significantly decreased brain size and neurological manifestations
MDMA (Ecstasy)
Very fast action sympathomimeti
Unlike amphetamines:
Directly stimulates 5HT21A autoreceptors
Stimulates the release of serotonin and inhibits its reuptake
Bath salts (Methylenedioxypyrovalerone, Mephedrone)
Often contain various amphetamine-like chemicals
Chemicals act in the brain like stimulant drugs
Toxicity associated with Ingesting or snorting "bath salts": Chest pains Increased blood pressure Increased heart rate Agitation Hallucinations Extreme paranoia Delusions
Caffeine
xanthine
Theophylline
xanthine
Modafinil
Approved by the U.S. Food and Drug Administration (FDA) (DEA Schedule IV Controlled Substance)
Treatment of narcolepsy
Shift work sleep disorder
Excessive daytime sleepiness associated with obstructive sleep apnea
Promoted as a “wakefulness promoting agent” rather than a classic amphetamine-like stimulant
Effective treatment for attention deficit hyperactivity disorder (ADHD)
Discouraged for use by children for any purpose due to cases of severe skin rash
MOA: Monoamines Dopamine ↑ Release in striatum* ↑ Release in nucleus accumbens* DA antagonists do not entirely negate the wakefulness-promoting actions of modafinil May block DA reuptake* Norepinephrine ↑ Release in hypothalamus* Serotonin ↑ Release in amygdala and frontal cortex Elevates hypothalamic histamine levels Activates glutamatergic circuits Inhibits GABAergic neurotransmission
Armodafinil
Approved by the U.S. Food and Drug Administration (FDA) (DEA Schedule IV Controlled Substance)
Treatment of narcolepsy
Shift work sleep disorder
Excessive daytime sleepiness associated with obstructive sleep apnea
Promoted as a “wakefulness promoting agent” rather than a classic amphetamine-like stimulant
Effective treatment for attention deficit hyperactivity disorder (ADHD)
Discouraged for use by children for any purpose due to cases of severe skin rash
MOA: Monoamines Dopamine ↑ Release in striatum* ↑ Release in nucleus accumbens* DA antagonists do not entirely negate the wakefulness-promoting actions of modafinil May block DA reuptake* Norepinephrine ↑ Release in hypothalamus* Serotonin ↑ Release in amygdala and frontal cortex Elevates hypothalamic histamine levels Activates glutamatergic circuits Inhibits GABAergic neurotransmission
Atomoxetine
Highly selective NE reuptake inhibitor
Atomoxetine also elevates DA levels in the prefrontal cortex
But not in the nucleus accumbens or the striatum
Nucleus accumbens mediates the euphoric properties (i.e., abuse liability) of the psychostimulants
Only first-line ADHD medication that has no abuse potential
Not a DEA Schedule II controlled substance
Only drug approved by the FDA to treat adult ADHD
Methylphenidate
treats ADHD
Enhances DA release and blocks reuptake
galanatamine
Treatment for Alzheimer
Inhibits AChE
Stimulates nicotinic cholinergic neurons to release more stored ACh
Should be taken cautiously in patients taking…
Antidepressants paroxetine, amitriptyline, fluoxetine and fluvoxamine
Drugs with anticholinergic side effects
These drugs may interfere with the elimination of galantamine from the body
Galantamine and other cholinesterase inhibitors can increase the risk of stomach ulcers
rivastigmine
Treatment for Alzheimer
Inhibits both AChE and BuChE
Causes more gastrointestinal problems and cause muscle weakness than other cholinesterase inhibitors
tacrine
Treatment for Alzheimer
Short half-life Needs to be given multiple times per day Poor compliance Many drug interactions Especially NSAIDs May cause liver damage Second-line therapy for AD
memantine
Treatment for Alzheimer
Useful in patients with moderate to severe AD
Mechanism of action
Antagonist at the NMDA subtype of glutamate (GLU) receptor
Found to help patients in the later stages of the disease maintain additional independence
Most common adverse effects of memantine are dizziness, headache, constipation and confusion
ginko biloba
May have a modest benefit for AD patients
Serious side effects (bleeding, seizures, coma) have been reported with commercial pharmaceutical-grade ginko biloba preparations
Nootropics
Derived from the Greek words nous, or “mind,” and trepein meaning “to bend/turn”
AKA: smart drugs, memory enhancers, cognitive enhancers, and intelligence enhancers
Eugeroics
"Wakefulness Enhancers” Examples Modafinil (Provigil) Armodafinil (Nuvigil) Mechanism of action ? Increased release of norepinephrine and dopamine Elevates hypothalamic histamine levels Lower abuse potential as compared to traditional stimulant drugs DEA Schedule IV
FDA approved for
Narcolepsy
Shift work sleep disorder
Excessive daytime sleepiness associated with obstructive sleep apnea
Halothane
Halogenated Hydrocarbon Inhalation Anesthetic
Advantages
Potent (MAC ranges from 0.7 - 0.9)
Rapid induction and recovery
Among the least expensive volatile anesthetic
Does not irritate larynx - no laryngospasm
Disadvantages
Inadequate analgesia and muscle relaxation
Depresses myocardium and baroreceptor reflexes
↓ Cardiac output
↓ Blood pressure
Sensitizes myocardium to catecholamines
↑ automaticity
Particularly in the presence of adrenergic agonists (e.g., epinephrine) which might be used to raise blood pressure
Increases cerebral blood flow and intracranial pressure
Respiratory depression
Potential for acute or chronic hepatic toxicity
1:35,000 patients develop “halothane hepatitis”
Symptoms include hepatic necrosis, fever, nausea and vomiting, biochemical abnormalities as seen in hepatitis
May progress to complete hepatic failure and death
May be due to significant liver metabolism (~20%)
Malignant hyperthermia
Isoflurane
Halogenated Hydrocarbon Inhalation Anesthetic
Advantages
Potent
Induction in less than 10 minutes
Doesn’t sensitize the myocardium to catecholamines
Less hepatotoxicity and renal toxicity than halothane (may be related to lower rate of metabolism)
Disadvantages
Rarely arrhythmias
Pungent odor
Potential for malignant hyperthermia
Desflurane
Halogenated Hydrocarbon Inhalation Anesthetic
Sevoflurane
Halogenated Hydrocarbon Inhalation Anesthetic
Newest approved inhalation agent for use in North America (1996) High potency (low % of inspired gas) Low blood solubility Rapid onset – 5-10 min Rapid recovery – same day surgery Almost perfect inhalation anesthetic
Nitrous oxide
Halogenated Hydrocarbon Inhalation Anesthetic
Advantages
Low blood solubility (rapid onset)
Little effect on overall cardiovascular function
Second gas effect
Hastens anesthesia produced by more potent but more soluble inhalation anesthetics
Lowers MAC of other inhalation anesthetics
Mild to moderate analgesic activity
Disadvantages
MAC = 104% - can’t use as sole anesthetic agent
No muscle relaxing effect
Diffusion hypoxia if rapidly discontinued
During recovery, rapid transfer from blood to alveoli, displaces air
Lack of oxygen uptake – hypoxia
Pentobarbital
Short-intermediate acting barb
Injectable Anesthetics
Unlike Phenobarbitol, increasing urinary pH with sodium bicarbonate is ineffective in treating toxicity, since this requires metabolism before renal excretion
Thiopental
Injectable Anesthetics
Barbiturate
Mechanism of action
Facilitates GABA induced Cl- entry into neurons, leading to CNS depression
Rapid onset (sec) after iv administration and short action (min) allows quick recovery
Toxicity
anesthetic dose is between 50 and 75% of the LD50
Propofol
Injectable Anesthetics
Rapid induction (50 seconds) and recovery (4-8 minutes) from anesthesia
May be given alone to maintain anesthesia or used for induction as part of balanced anesthesia technique
May result in injection site pain
Etomidate
Injectable Anesthetic - best suited for induction of anesthesia, useful for short operative procedures, unsuitable as a single drug anesthetic
Midazolam
Benzodiazepines
Mechanism of action
Facilitates GABA induced Cl- entry into neurons, leading to CNS depression
Characteristics
Less cardiovascular and respiratory depression than barbiturates
Most important characteristic is amnestic action
Insufficient for anesthesia when given alone
Used as induction agent prior to anesthesia
Ketamine
Injectable Anesthetics
Dissociative anesthetic
Patient appears to be awake - eyes open
Unaware of environment and doesn’t feel pain
Pharm. Effects:
Principal drawback is the occurrence of emergence reactions (delirium and hallucinations)
Relatively high therapeutic index
Abuse - currently abused in the US
Single dose of ketamine significantly improved symptoms of depression in treatment resistant depressed patients in less than 2 hours and lasts at least one week
Fentanyl
Opioid
High dose opioids
Analgesia
Anesthesia
Hemodynamic stability - good for patients with compromised myocardial function
Respiration must be maintained artificially and may be depressed into the postoperative period
Usually supplemented with inhalation anesthetic, benzodiazepine or propofol
Sufentanil
Opioid
High dose opioids
Analgesia
Anesthesia
Hemodynamic stability - good for patients with compromised myocardial function
Respiration must be maintained artificially and may be depressed into the postoperative period
Usually supplemented with inhalation anesthetic, benzodiazepine or propofol
Halogenated Hydrocarbon Inhalation Anesthetics
Examples - halothane, isoflurane, methoxyflurane (vet), sevoflurane
CNS effects
Decrease brain metabolic rate
Increase cerebral blood flow
Increase intracranial pressure
CV effects
Decreased myocardial contractility and stroke volume leading to lower arterial blood pressure
Sensitizes myocardium to catecholamines
↑ automaticity
Particularly in the presence of adrenergic agonists
Halothane > isoflurane, desflurane, sevoflurane > nitrous oxide
Intravenous Anesthetics
Injectable anesthetics
Act faster
Best suited for induction of anesthesia
Useful for short operative procedures
Inhalation anesthetics
Maintain anesthesia for longer procedures
Muscle relaxation after IV anesthetics is poor
Unsuitable as a single drug anesthetic for many surgical procedures
Desipramine
TCA
Block the reuptake of NE
by nerve terminals
Imipramine
TCA
Block the reuptake of NE and 5-HT by nerve terminals
Phenelzine
MAO INHIBITOR
Fluoxetine
SSRI
Sertraline
SSRI
Citalopram
SSRI
Escitalopram
SSRI
Venlafaxine
Selective serotonin and norepinephrine reuptake inhibitor (SNRI) Blocks serotonin reuptake like SSRIs Also blocks NE reuptake So, why isn’t this the same as TCAs? Venlafaxine does NOT affect Adrenergic receptors Histaminergic receptors Cholinergic receptors Action of the TCAs on these receptors trigger majority of adverse effects
Raising the dose of venlafaxine improves efficacy due to secondary mechanisms of action
Desvenlafaxine
Active metabolite of venlafaxine
Approved by the FDA in a once-daily formulation for the treatment of adults with major depressive disorder
No evidence that it is any more effective than venlafaxine
Patent for venlafaxine expired in 2010
Lithium carbonate
Effect in normal subjects - none Effect in manic subjects Clinical use for over 50 years (30 years in US) Therapeutic effect seen in 5-21 days Effective in 60-80 % of treated patients
Most likely involves effect on postsynaptic rather than presynaptic neuron
Interferes with the production and release of IP3 (phosphatdylinositol-4,5-bisphosphate) and DAG (diacyl glycerol)
May uncouple receptor recognition site from GTP-binding protein (G-protein) by competing with Mg++
May affect several cell or nuclear regulatory factors
Competes with sodium for reabsorption Sodium deficiency (low sodium diet, diuretics) increases lithium toxicity
TOXICITY
No tolerance to excessive urination and thirst (must regulate H2O intake to prevent washout)
Fatigue, muscular weakness, slurred speech, ataxia, fine tremor of the hands
Valproic Acid
Anticonvulsant
Good for non-rapid cycling bipolar disorder
Superior to lithium for rapid-cycling bipolar disorder
Anticonvulsants work better for acute manic episodes than for long-term management of bipolar disorder
Carbamazepine
Anticonvulsant approved by the FDA for prophylaxis of bipolar disorder
Quetiapine
Atypical Antipsychotic Mechanism of action Blocks 5-HT2A subtype DA antagonist action ???? Antimanic properties Stabilizes mood
Lurasidone
Atypical antipsychotic – 2010
Approved to treat bipolar depression – 2013
Mechanism of action
Central dopamine (D2) and serotonin (5-HT2A) receptor antagonism seem to be involved
Precise mechanism is unknown
Tricyclic Antidepressants
Effect in normal subjects:
No stimulating or mood elevating effect
Sleepiness and light headedness
Effect in depressed subjects:
Elevation in mood only after 2-3 weeks
Block the reuptake of NE and/or 5-HT by nerve terminals
Orthostatic hypotension
Weight gain
Tachycardia and increased tendency for arrhythmias with high doses
Therapeutic index (TI = LD50 ÷ ED50) between 5-10 Depressed patients should not be given more than one week supply of TCAs
Drug Interactions Potentiates central depressants Alcohol Anxiolytic-sedative-hypnotics Opioids Antimuscarinic effect may delay gastric emptying time ↑ Inactivation of levodopa Decreases effectiveness when used to treat Parkinsonism
Monoamine oxidase (MAO) inhibitors
Irreversibly blocks the oxidative deamination of monoamines (e.g., NE and 5-HT)
Changes in neurotransmitters
Occur within 24-48 hr
Clinical improvement usually takes 3+ weeks to begin
Low therapeutic index (less than 5)
Treat:
Symptomatically
Hospitalize 1 week (Why?) (IRREVERSIBLY blocks, needs time to make more)
Potentiates sympathomimetic amines
Particularly indirect acting amines such as tyramine
Dietary tyramine is completely metabolized by hepatic MAO
If patient has taken MAO inhibitor, tyramine enters systemic circulation
Combined effect of tyramine and MAO inhibitor:
Massive adrenergic stimulation
May result in a hypertensive crisis
Selective Serotonin Reuptake Inhibitors (SSRIs)
WARNING:
SSRIs should not be used alone in bipolar disorder
Need to include a mood stabilizer to prevent rapid mood switch
May cause rapid onset of mania
Patients should be receiving prophylactic mood stabilizer therapy to prevent this from occurring
Depression
Other anxiety disorders
Nausea, diarrhea and weight loss
Stimulation - anxiety, nervousness, insomnia, sufficient to discontinue treatment
SSRIs are not sedating like TCAs or atypical antidepressants
33-50% of those that experience symptoms cannot continue treatment
Sexual dysfunction
MAY CAUSE SUICIDE!
MOA:
Selective inhibition of serotonin reuptake by CNS neurons
Serotonin receptor actions are much more complex than that of other neurotransmitters
5-HT2A – may contribute to clinical improvement seen with SSRIs
5-HT is released and can act…
Postsynaptically to trigger actions in an effector cell
Presynaptically on 5-HT1D autoreceptors to inhibit additional 5-HT release
NE from neighboring neurons act on a2 receptors to inhibit release of 5-HT (heteroreceptors)
Phenobarbital
Long acting Barb
(slow and partial metabolism)
Phenobarbital is selectively anticonvulsant
The remainder of the barbiturates are relatively unselective in their depression of the CNS
Less lipid soluble (phenobarbital) - 20 min to sleep onset
An overdose of a phenobarbital can be treated by administering sodium bicarbonate intravenously to elevate urinary pH
Triazolam
benzo
Flurazepam
Benzo
plasma half-life = 2 -3 hr.; half-life of active metabolite is >50 hr
Alprazolam
Benzo
Diazepam
benzo
Preanesthetic medication
Lorazepam
Benzo
Flumazenil
Benzodiazepine receptor antagonist
Administered intravenously
Antagonizes sedation, impaired recall, impaired psychomotor function, and respiratory depression
Reverses effects of benzodiazepines, zolpidem, zapelon (see below) but not barbiturates or ethanol
Zolpidem
Non-Benzodiazepine Benzodiazepine-Receptor Agonists
Mechanism of action
New drugs interact with benzodiazepine binding site on GABAA receptor
Benzodiazepines bind to all GABAA receptor subtypes
Selectively bind to certain subtypes of the receptor
Advantages
Rapid onset
Short duration of action (no residual effects upon wakening)
Slow tolerance development
Ramelteon
Mechanism of action Suprachiasmatic nucleus (SCN) Body's "master clock" Regulates 24-hour, or circadian, rhythms Includes sleep-wake cycle
Ramelton is an agonist at the melatonin MT1 and MT2 receptors located in the brain’s SCN
Adverse effects
Overall adverse events occur at rates generally comparable to placebo
NO evidence of formation of physical dependence or abuse potential, and the drug is not a controlled substance
Approved for long term use in adults
Propranolol
Useful in treating chronic anxiety, panic attacks and debilitating anxiety
Blocks autonomic signs
Less effective than BZs for anxiety and antidepressants for panic attacks
Melatonin
Classified as a “dietary supplement” rather than as a drug
Not regulated by FDA
Significant variation in dosages (2-3 mg vs endogenous levels of 0.1 - 0.3 mg) depending on brand
Clinical effectiveness is unclear - doses above 1 mg may disturb sleep
Non-Benzodiazepine Benzodiazepine-Receptor Agonists
Mechanism of action
New drugs interact with benzodiazepine binding site on GABAA receptor
Benzodiazepines bind to all GABAA receptor subtypes
Selectively bind to certain subtypes of the receptor
Advantages
Rapid onset
Short duration of action (no residual effects upon wakening)
Slow tolerance development
