Anti Depressants Flashcards
Antidepressants
capable of improving mood in patients with depression acts on lack of interest and energy, loss of appetite, sleep disturbances, concentration problems, feeling guilty or worthless, suicidal ideas, newer ones are used in anxiety, panic attack, phobia, pain. Goal is remission (symptom free 4-9 months) or recovery of patient (symptom free for more than 12 months)
Depression appears because of
serotonin (responsible of satisfaction, decreased anxiety), norepinephrine (energy, concentration) or dopamine deficiency. Inhibition of monoamine transport proteins.
Antidepressant effects
acute, sedative, and vegetative effects (healthy and depressive) and the antidepressant effect (weeks after treatment in patients with depression).
During the entire treatment association with
CNS depressants (alcohol, old histaminic, barbiturates, benzodiazepines, hypnotics, opioids, antipsychotics) should be avoided.
Tricyclic antidepressants - tertiary amine tricyclic antidepressants
Amitryptiline, imipramine, clomipramine, trimipramine, doxepin
TCA - secondary amine tricyclic antidepressants
nortriptyline, desipramine
Tetracyclic antidepressants
mapotiline, mianserin
SSRIs
citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline
serotonine norepinephrine reuptake inhibitors
venflaxine, desvenlafaxine, duloxetine, milnacipran
Atypical - NE and Dopa reuptake inhibitors
bupropion
Atypical -selective NE antagonist/reuptake inhibitors
Nefazodone, trazodone
Atypical - alpha 2
mirtazapine
MAO inhibitors
moclobemid, tranycypromine
TCAS
oldest class, contains 3 rings of atoms, most effective, but not first line due to side effects.
SSRIS
decreased serotonin level may play a role in depression. Serotonin is responsible for increased satisfaction and happiness, decreased anxiety, impulsivity, libido, and appetite and can cause nausea, diarrhea, decreased clotting function (decrease platelet and VC), fewer side effects, reduced danger of drug-drug interactions, less likely to excACERBATE other illness and less toxic in overdosage, agents of choice in treating depression.
Fluoxetine
widely prescribed, standard antidepressant, selective inhibitor of serotonin uptake in CNS, little effect on central norepinephrine or dopamine function, less adverse effects bc of minimal bleeding to cholinergic, histaminic, adrenergic receptors,
Venflaxine, desvenlafaxine, duloxetine, milnicarpan
inhibit reuptake of serotonin and norepinephrine,Indications
major depressive disorder;
social phobia (Venlafaxine);
generalized anxiety disorder (Venlafaxine, Duloxetine);
fibromyalgia (Duloxetine, Milnacipran);
attention deficit hyperactivity disorder (Venlafaxine);
premenstrual symptoms (Duloxetine);
stress urinary incontinence (Duloxetine).
Adverse effects
nausea, constipation or diarrhea;
xerostomia;
hypertension;
sleeping disturbances (Duloxetine).
Atypical antidepressants are
not structurally related to tricyclic antidepressants and do not have the same mechanism of action, no anticholinergic effects.
Bupropion
mild inhibitor of dopamine reuptake, inhibitor of norepinephrine reuptake; I: major depressive, smoking cessation, SAD, adjunct to SSRIs, substance abuse, ADHD, weight loss; AE : seizures in bulimic
Atomoxetine
blocks norepinephrine transporters, I: depression, ADHD
Mirtazapine
blocks presynaptic a2 adrenergic on noradrenergic and serotonergic neurons, blocks 5HT etc; I: major depressive (first line), panic attacks, nausea after chemotherapy/surgery, AE:Sedation, headache, dizziness, increased appetite, weight gain
Nefazodone, trazodone
block… I:major depressive, anxiety (trazodone), PTSD (nefazodone), depression with comorbid substance abuse (nefazodone), AE: liver toxicity, priapism (trazodone), increased QT (trazodone)
MAOI
effective antidepressants, third line drugs due to adverse effects
Opioid analgesics and antagonists - Strong agonists
morphine, fentanyl, meperidine, heroin, methadone
Opiod and antagonists - moderate agonists
codeine, prorpoxyphene
Mixed agonists and antagonists
buprenorphine, pentazocine
Opioid (antagonists)
naloxone, naltrexone; natural/synthetic, opiates reserved for drugs like morphine and codeine obbtained from juice of opium poppy
Opiod mechanism of action
bind specific opiod receptors found in areas of CNS for pain signal transmission, binding to receptors mediate pharmacological effects; see receptor table
Morphine
major analgesic. drug contained in opium and is prototype agonist, high affinity for mu receptors and varying for delta and kappa receptors.
Meperidine
entirely synthetic analgesic; I:severe, acute pain (1/8 potent Morphine), AE: respiratory depression, addiction liability (withdrawal effects less severe than morphine), duration of 2-4 hours (shorter than morphine
Methadone
controlled withdrawal of addicts from heroin and morphonine, oral, substitute for injected opioid, then slowly weaned; AE: similar to morphine, milder withdrawal syndrome, develops more slowly than morphine
fentanyl
80x analgesic potency and respiratory depressant properties of morphine, rapid onset and short duration of action (15-30 min)
codeine
obtained from opium or methylation of morphine, much less potent than morphine, higher oral efficacy, 30mg codeine = 6oomg aspirin, cough suppressant; AE: less sedation or respiratory depression, fewer GI effects, addiction liability lower than with morphine and withdrawal less sever
Pentazocine
Pentazocine acts as an agonist on kappa receptors and is a weak antagonist at mu and delta receptors; despite its antagonist action, Pentazocine does not antagonize the respiratory depression of Morphine, but it can precipitate a withdrawal syndrome in Morphine abusers; Pentazocine should not be used with agonists such as Morphine, since the antagonist action of Pentazocine may block the analgesic effects of Morphine; Indications moderate pain. Adverse effects less euphoria compared to Morphine; respiratory depression; increased blood pressure; hallucinations, nightmares; tachycardia; dizziness; tolerance and dependence.
Buprenorphine
partial agonist on mu receptors, long duration of action due to tight binding on receptor, administered parenterally/sublingual; AE: respiratory depression, nausea, dizziness, decrease in blood pressure
Naloxone
Mechanism of action
Naloxone, like other competitive receptor antagonists, blocks the opioid receptors; administration of antagonists produces no profound effects in normal individuals; however, in patients addicted to opioids, antagonists rapidly reverse the effect of antagonists, such as Heroin, and precipitate the symptoms of opiate withdrawal; the sedative effects, respiratory depression and adverse cardiovascular effects of opioid agonists are reversed within 1–2 minutes after parenteral administration of Naloxone.
Therapeutic notes
if Naloxone is administered to opioid-addicted patients, a withdrawal syndrome is easily precipitated;
mothers who have received opioids during labor receive Naloxone prior to delivery, to minimize neonatal respiratory depression.
Naltrexone
action similar to naloxone, opiate dependance maintenance programs, single dose blocks effect of heroin for up to 48 hours
TCA mechanism
block reuptake of noradrenaline and serotonin, block major route of neurotransmitter removal, increased concentrations of monamines in synaptic cleft, result in antidepressant effects, block H1 and muscarinic, work as sodium and calcium inhibitors
TCA pharmokinetics
well absorbed from the GI tract;
because of their lipophilic nature, this agents become widely distributed and readily penetrate into the CNS;
lipid solubility also causes TCAs to have a long t1/2 (e.g. 4-17 hours for Imipramine);
as a result of their variable first pass metabolism in the liver, TCAs have low and inconsistent bioavailability; therefore the patient’s response is used to adjust dosage; the initial treatment period is typically 4-8 weeks;
metabolized in the liver and excreted as inactive metabolites via the kidney.
TCA phrarmodynamic effects
CNS effects: TCAs elevate mood, improve mental alertness, increase physical activity and reduce morbid preoccupation; the onset of this effects is slow, requiring 2-3 weeks or more; they do not produce CNS stimulation or mood elevation in normal individuals;
cardiovascular effects: orthostatic hypotension, arrhythmias, tachycardia;
autonomic nervous system effects: anticholinergic effects;
increase effectivenes of analgetics, without having an analgetic effect themselves.
the TCAs have a narrow therapeutic index (TI = 7); for example 5-6 times the maximal daily dose of Imipramine can be lethal; remember that this drugs are being given to patients with high risk of suicide, the overdosage can be life-threatening and that is why depressed patients who are suiciidal should be given limited quantities and monitored closely.
TCA indication
severe major depression (second line, after SSRI); nocturnal enuresis (Imipramine).
TCA adverse effects
orthostatic hypotension, tachycardia; drowsiness, sedation, confusion; dry mouth, constipation, urinary retention, blurred vision; weight gain; sexual dysfunction.
TCA contraindication
acute intoxication with CNS inhibitors (opioids, sedativ-hypnotics, alcohol);
acute mania;
glaucoma, prostate adenoma, ileus;
severe cardiovascular diseases (grade III AV block);
combination with MAOI (2 weeks pause).
SSRI indication
major depressive disorder (Fluoxetine, Venlafaxine are first line drugs);
obsessive-compulsive disorder (except Citalopram, Escitalopram);
social phobia (Sertraline, Fluvoxamine, Paroxetine);
posttraumatic stress disorder (Sertraline, Paroxetine);
generalized anxiety disorder (Fluoxetine, Fluvoxamine, Paroxetine, Escitalopram are first line drugs);
premenstrual disphoric disorder (Fluoxetine, Paroxetine, Sertraline).
SSRI adverse effect
loss of apetite, nausea, vomiting, diarrhea;
decreased libido, delayed ejaculation;
headache, insomnia or somnolence, nightmares;
increase of QT interval (Citalopram, Escitalopram);
in case of abrupt stopping: agitation, flu-like symptoms, increased suicidal risk.
SSRI contraindication
acute mania;
combination with MAOI;
caution in patients with diabetes (glycemia oscillations), on anticoagulant therapy (increased bleeding risk) or epilepsy (increased seizure senzitivity).
Fluoxetine Pharmokinetics
well absorbed after oral ingestion;
it undergoes extensive hepatic biotransformation to the active metabolite norfluoxetine; the elimination t1/2 is 1–3 days for Fluoxetine and 7-15 days for Norfluoxetine; the inactive metabolites are excreted in the urine;
the onset of action is within 1-3 weeks after beginning treatment.
FLuoxetine indications
depression; bulimia nervosa; obsessive-compulsive disorders; anorexia nervosa; panic disorders; pain associated with diabetic neuropathy; premenstrual syndrome.
Fluoxetine adverse effects
nausea; headache; insomnia, fatigue; sexual dysfunction; hypoglycemia in patients with diabetes.
MAOI mechanism of action
MAO is a mitochondrial enzyme found in neural and other tissues; in the neuron MAO functions as a “safety valve” to degrade and inactivate any excess of neurotransmitter molecules (norepinephrine, serotonin and dopamine) that may leak out of synaptic vesicles when the neuron is at rest; the MAOIs may irreversibly (for 7-10 days; Tranylcypromine, nonselective) or reversibly (for 24 hours; Moclobemid, selectiv on MAO-A) inactivate the enzyme, permitting neurotransmitter molecules to escape degradation and therefore to both accumulate within the presynaptic neuron and to leak into the synaptic space; this causes activation of norepinephrine and serotonine receptors, and may be responsible for the antidepressant action of these drugs.
MAOI pharmacokinetics
rapidly absorbed from the GI tract, but, inexplicably, the observed therapeutic response does not occur for 2–3 weeks;
enzyme regeneration terminates the drug effect, but this frequently takes several weeks after use of the drug is stopped; thus, when switching antidepressant therapy, a minimum of 2 weeks delay is required after termination of MAOI therapy.
MAOI indications
atypical depression: hypersomnolence, hyperphagia and hyperanxiety;
depression in patients who are unresponsive or allergic to other antidepressant drugs or who experience strong anxiety.
MAOI adverse effects
drug-food interactions;
orthostatic hypotension;
weight gain.
MAOI interactions
MAO (from the gut) normally inactivates tyramine, contained in certain foods (cheese, chicken liver, beer and red wines); individuals receiving a MAOI are unable to degrade tyramine obtained from the diet; tyramine causes the release of large amounts of stored cathecolamines from nerve terminals, resulting in headache, tachycardia, nausea, HBP, cardiac arrhythmias and stroke; patients must therefore be educated to avoid tyramine-containing foods;
concurrent use of MAOIs with SSRIs can cause a “serotonin syndrome” which includes hyperpyrexia, agitation, neuromuscular irritability, hypotension, coma, and death; if the treatment has to be changed: allow 2 weeks washout period between administrations if we switch from MAOI to SSRI and 5 weeks between administrations if we switch from Fluoxetine (long t1/2) to MAOI.
Morphine pharmacodynamic effect
analgesia, primarily by interacting with mu receptors;
respiratory depression (dose-dependent), due to decreased sensitivity of the respiratory center chemoreceptors to CO2 and direct effects to decrease respiratory rhythmicity; respiratory depression is variable from patient to patient and the most common cause of death in acute opioid overdose;
sedation;
mood changes;
miosis (as a result of increased activity in the parasympathetic nerve innervating the pupil);
nausea and vomiting (as a result of direct stimulation of the chemoreceptor trigger zone for emesis);
cough suppression;
truncal rigidity (as a result of increased tone in large trunk muscles probably due to increased impulse activity from supraspinal sites);
orthostatic hypotension;
cutaneous flushing, hypothermia;
bronchoconstriction;
constipation;
constriction of biliary smooth muscle and the sphincter of Oddi;
increased tone in the ureter, detrusor muscle of the urinary bladder and vesicle sphincter can produce urinary retention.
Morphine pharmacokinetic
it is well absorbed from the GI tract;
Morphine rapidly enters all body tissues, including the fetuses of pregnant women, and should not be used for analgesia during labor;
significant first pass metabolism of Morphine occurs in the liver; therefore IM, SC or IV injection produce the most reliable responses; Morphine is metabolised in the liver to glucuronides; Morphine-6-glucuronide is a very potent analgesic;
the duration of action of Morphine is 4–6 hours.
Morphine indications
severe pain;
diarrhea;
cough;
dyspnea due to pulmonary edema.
Morphine adverse effects
respiratory depression (dose-dependent);
nausea;
increased biliary tract pressure;
tolerance (after 1-3 weeks) to all effects except miotic and constipating effects;
physical dependence;
the elevation of intracranial pressure, particularly in head injury;
acute urinary retention (important in prostatic hypertrophy);
toxicity (depressed respiration, pinpoint pupils, coma).
