35. Antidepressants Flashcards
Intro
what causes depression
how do AD work in general
whats the issue w/ D/C
What can they be used to Rx
Depression is thought to occur,
due to an imbalance in neurotransmitters such as serotonin, norepinephrine and dopamine.
Antidepressants work by altering the
balance of these central neurotransmitters.
The different classes of antidepressants differ in the neurotransmitters they affect.
This determines their side
effect profile and potential drug interactions.
All antidepressant drugs are prone to causing dependence syndromes, particularly drug withdrawal, and pre-operative discontinuation should be avoided
or be gradual in the case of monoamine oxidase inhibitors.
Antidepressants are used to treat many
other conditions such as anxiety disorders,
obsessive-compulsive
disorders, eating disorders,
post-traumatic stress disorder,
attention-deficit and hyperactivity disorders.
What are the different classes of
antidepressant agents?
Describe their mode of action,
side effects
and anaesthetic implications
.1
Monoamine oxidase inhibitors (MAOIs)
First class of antidepressant to be developed.
Used infrequently now due to
potentially lethal interactions
with drugs and tyramine-containing foods.
Mode of action:
> Prevents breakdown of
monoamine neurotransmitters by inhibiting
monoamine oxidase (MAO) enzyme.
> MAOs exist in two isoforms:
• MAO-A
(selectively breaks down serotonin,
epinephrine and
norepinephrine)
- MAO-B (selectively breaks down phenethylamine)
- Both break down dopamine.
> Older agents inhibit both MAO-A and MAO-B.
> Newer agents (e.g. moclobemide)
selectively inhibit MAO-A
and are classed as RIMAs
(reversible inhibitors of monoamine oxidase-A).
> MAO-B inhibitors (e.g. selegiline)
are used as anti-Parkinson’s
medications due to their
dopaminergic properties.
MOAI S/E
Side effects:
> Hypertension and hypertensive crises –
both types of MAOs breakdown tyramine
(a chemical present in aged cheese and wines).
MAOIs decrease tyramine breakdown,
leading to increased plasma concentrations,
which
can elevate blood pressure.
> Serotonin syndrome when
used with other serotonergic agents.
> Orthostatic hypotension.
> Psychosis, headaches, insomnia, sexual dysfunction, weight gain.
Implications for anaesthesia:
MAOI
> Treatment should be gradually
discontinued pre-operatively.
If treatment continued
(e.g. emergency case)
a benzodiazepine premedication
should be used.
> MAOIs reduce metabolism of
barbiturates,
so lower doses should be used.
Avoid ketamine.
Propofol, etomidate, benzodiazepines, inhalation
agents can all be used safely.
> Morphine, fentanyl, alfentanil and remifentanil
can all be used safely.
> Avoid tramadol,
pethidine and linezolid
as they can precipitate serotonin syndrome.
> Avoid pancuronium as it can
cause noradrenaline release.
> Local anaesthetics containing
adrenaline should be used with caution.
> Indirect-acting sympathomimetics (e.g. ephedrine) are absolutely contraindicated as they may precipitate potentially fatal hypertensive crises.
> Direct-acting sympathomimetics
(e.g. phenylephrine) should be
administered at lower doses.
Tricyclic antidepressants
Named for their chemical structure
containing three rings.
They have now
largely been replaced by
second-generation antidepressants
with a more favourable side effect profile.
They are also used to treat
chronic and neuropathic pain.
Examples include imipramine, amitriptyline, doxepin and dosulepin.
Mode of action:
TCAs
Mode of action:
> Act primarily as serotonin–norepinephrine re-uptake inhibitors by blocking the serotonin transporter (SERT ) and norepinephrine transporter (NET) on the presynaptic membrane, resulting in a higher concentration of neurotransmitters in the synaptic cleft, and increased neurotransmission.
> Also act as antagonists at multiple
other receptor sites including 5-HT,
α1-adrenergic, NMDA, H1 and H2,
and mACh receptors.
These additional actions contribute
to their efficacy as antidepressants
and to their side effect profile.
> Many are potent inhibitors of
sodium channels and L-type calcium channels
(they act like class 1 anti-arrhythmic agents).
This effect is potentially cardiotoxic
and is responsible for the high risk of mortality
when taken in overdose.
Side effects:
TCAs
> Anticholinergic effects –
dry mouth, dry nose, blurred vision, constipation,
urinary retention, sweating and increased body temperature.
> Changes in appetite and weight,
nausea and vomiting,
sexual dysfunction.
> CNS – drowsiness, confusion, muscle twitches. In overdose – seizures, hallucinations, hyper-reflexia, myoclonus and coma.
> CVS –
postural hypotension,
tachycardia,
arrhythmias.
In overdose – hypotension or transient hypertension, ventricular tachyarrhythmias (VT and VF)
and ECG changes (sinus tachycardia, prolonged QRS, QT and PR intervals).
Implications for anaesthesia:
TCAs
> Continue peri-operatively.
> Increased levels of central neurotransmitters
may increase anaesthetic requirement.
> Depleted levels of cardiac catecholamines
may potentiate cardiac depressant
effects of anaesthesia.
> Increased response to anticholinergics.
Atropine, which crosses the blood–brain barrier,
may lead to post-operative confusion.
> Exaggerated BP response to
indirect-acting sympathomimetics,
which should be avoided,
and direct-acting sympathomimetics,
which should be used in lower doses.
> Avoid ketamine,
pancuronium,
epinephrine-containing solutions and
sympathetic stimulation.
TCA OD
Overdose:
> TCAs have a narrow therapeutic index and are readily absorbed in the alkaline environment
of the small intestine;
therefore severe symptoms
may occur within 1 hour of overdose.
> Symptoms include
anticholinergic effects,
cardio- and neurotoxicity as
described above,
pulmonary hypoventilation due
to CNS depression
and reduced gut motility
with absent bowel sounds.
Metabolic and respiratory acidosis can occur.
> Treatment includes both
supportive and specific measures:
• ITU monitoring for symptomatic patients with continuous BP, ECG, and frequent CNS and arterial pH monitoring, with ventilatory support if required.
• Activated charcoal to adsorb
TCA in stomach
(if within 2 hours of ingestion),
although other methods of
gastric decontamination are not
recommended.
• Maintain normothermia
• IV sodium bicarbonate infusion and fluids in the presence of metabolic acidosis (TCAs are highly protein bound and become less bound in acidic environments. By reversing the acidosis, protein binding increases and bioavailability is reduced).
The sodium load may help to
reverse sodium channel blockade.
• Antiarrhythmics such as
phenytoin and magnesium may be
required if dysrhythmia is refractory to sodium bicarbonate.
Class 1 antiarrhythmic agents should not be used.
• Hypotension may require vasopressors/inotropes.
• Seizures may resolve untreated,
but if needed,
benzodiazepines and
other anticonvulsants can be used.
• Lipid therapy (intralipid) may have a role in
treating refractory TCA overdose.
Selective serotonin re-uptake inhibitors (SSRIs)
examples
MOA
Selective serotonin re-uptake inhibitors (SSRIs)
Second-generation antidepressants
(e.g. citalopram, fluoxetine (Prozac),
paroxetine, sertraline).
Mode of action:
> Increase levels of the neurotransmitter
serotonin after it is released into
the synaptic cleft,
by selectively inhibiting SERT
on the presynaptic membrane,
and preventing its re-uptake.
More serotonin is therefore
available for entry via the
postsynaptic membrane and neurotransmission.
SSRI
Side effects
Side effects:
> GI effects
(diarrhoea, nausea and vomiting),
CNS effects
(headaches, drowsiness, agitation),
sexual dysfunction,
increased risk of bone fractures.
> Suicidal behaviour,
particularly in children
and adolescents.
> Withdrawal symptoms/discontinuation syndrome
if stopped abruptly
(especially paroxetine).
> Serotonin syndrome when
used with other serotonergic agents.
> Bleeding (especially GI bleeding).
SSRI
Implications for anaesthesia:
Implications for anaesthesia:
> Continue peri-operatively.
> Drug interactions precipitating serotonin syndrome: linezolid, tramadol, pethidine, methylene blue dye, MOAIs, mirtazapine, TCAs, SNRIs, lithium.
> Inhibition of cytochrome
P450 enzymes increases
levels of drugs metabolised
in the liver
(warfarin, theophylline, phenytoin, benzodiazepines).
> Increased risk of GI and
post-operative bleeding
(inhibits cytochrome P450 potentiating effects of warfarin and impairs platelet function increasing bleeding in patients on antiplatelet agents, NSAIDs and those with liver disease).
Serotonin–norepinephrine re-uptake inhibitors (SNRIs)
Serotonin–norepinephrine re-uptake inhibitors (SNRIs)
Second-generation antidepressants.
Examples include venlafaxine and duloxetine.
Mode of action:
> Selectively block SERT and NET at presynaptic membrane, allowing increased levels of serotonin and norepinephrine to enter postsynaptic membrane and promote neurotransmission.
Side effects:
> Dose-dependent hypertension.
Common side effects on GI and CNS as per SSRIs.
Implications for anaesthesia:
> Continue peri-operatively.
May potentiate effects of warfarin.
Drug interactions may cause serotonin syndrome as above, and should be avoided.
Tetracyclic antidepressants (TeCAs)
Tetracyclic antidepressants (TeCAs)
Examples include mianserin and mirtazapine.
Mode of action:
> Promote noradrenergic and
serotonergic neurotransmission via α2 antagonism.
Side effects:
> Sedation and weight gain due to
blockade of various postsynaptic 5-HT2
receptors.
> Drug interactions –
cytochrome P450 enzyme inhibitors
and inducers can increase levels or
reduce efficacy respectively.
Implications for anaesthesia:
> Continue peri-operatively.
Lithium
Lithium
Mood stabiliser used in the
management of bipolar disorder.
Mode of action:
> Its specific mood-stabilising
mechanism remains unclear.
> It can promote the release of serotonin.
Side effects:
> GI
(nausea, vomiting, diarrhoea)
and CNS
(headache, sedation, tremors, hyper-reflexia).
> Hypothyroidism
> Narrow therapeutic index,
risk of lithium toxicity (plasma levels >1.5 mmol/L).
Signs include –
CNS: sedation, confusion, tremors, muscle
weakness and slurred speech;
CVS: sinus bradycardia, sinus node
dysfunction, AV block, T wave changes, hypotension and ventricular irritability.
