TCAs (Anti-Depressants)

Question 1

What are the 2 prototypes of the TCA’s?

Answer 1

Imipramine and Amitriptyline, tertiary and secondary amines.

Question 2

What is the fate of tertiary amines in the TCA group in terms of PK?

Answer 2

Extensive hepatic metabolism, 3ary are demethylated to 2nd ary amines + aromatic hydroxylation. Oral admin.

Question 3

How are the TCA’s metabolized? Excreted?

Answer 3

Mainly 2D6, but also 2C19, 3A4 and 1A2. Also glucuronidation. Mainly renal excretion.

Question 4

Half life of TCA’s?

Answer 4

x1 daily dosing due to long half life (8-80 hours).

Question 5

Why do we especially care about genetic polymorphisms (of which enzymes?) with regards to TCA?

Answer 5

Genetic polymorphisms of 2C19 and 2D6, TCA’s have a very narrow therapeutic window so those who are slow and fast metabolizers will have either toxicity or ineffectivity.

Question 6

What is the MOA of TCA’s?

Answer 6

Inhibit both SERT and NET, but in addition also inhibit H1 receptors, Alpha 1, adrenergic and muscarinic receptors as well, so somewhat non-specific.

Question 7

Is there any bias of channel selectivity of TCA’s?

Answer 7

3ary amines hit both SERT and NET, whereas 2nd ary amines prefer NET more than SERT.

Question 8

Among the TCA’s which seem to have relative non-selectivity, which 2 are known for less anticholinergic effects among TCA’s and why does this matter?

Answer 8

Desipramine and nortriptyline, the less anticholinergic effects make them more tolerable to patients.

Question 9

What is interesting about the drug “Amoxapine?”

Answer 9

Its active metabolite, 7-OH amoxapine, antagonizes dopamine D2 receptors.

Question 10

What is the response of inhibiting the H1 receptors?

Answer 10

Drowsiness/sedation, sleep.

Question 11

What is the response of blocking alpha 1 receptors?

Answer 11

Orthostatic hypotension (drop of bp when standing up).

Question 12

What is the response of blocking the muscarinic receptors?

Answer 12

Dry mouths, dry eyes, constipation, mydriasis (dilation of pupils). Reduced sweating and tachycardia, all of this is associated with sympathetic effects.

Question 13

Which of the TCA’s is initiated first in pt therapy and why?

Answer 13

Nortriptyline, mainly because of more tolarability due to reduced anticholinergic effects.

Question 14

When would we use TCA’s today?

Answer 14

When SSRIs and SNRI’s fail to illicit a response, they are second line.

Question 15

General Tx uses of TCA?

Answer 15

Anxiety disorders, obsessive compulsive disorders (particularly climipramine, but it is less tolerable than SSRIs). Psychotic depression (Amoxapine), insomnia (amitriptyline, doxepin), pain conditions, nocturnal enuresis (imipramine, this is for wetting the bed).

Question 16

Which TCA is useful for obsessive compulsive disorder?

Answer 16

Clomipramine.

Question 17

Which TCA is useful for psychotic depression?

Answer 17

Amoxipine (inhibition of NET > SERT plus dopamine D2 receptor antagonism by active metabolite).

Question 18

Which TCA is given at low dose for insomnia?

Answer 18

TertiaryTCAs like amitriptyline and doxepin.

Question 19

What “can” be given for nocurnal enuresis?

Answer 19

Imipramine (unknown MOA).

Question 20

What are the CV adverse effects associated with TCA’s? What causes these symptoms?

Answer 20

Orthostatic hypotension due to alpha one inhibition, sinus tach (increased NorEpi), conduction defects and arrythmias (NorEpi).

Question 21

What are the anti-muscirinic AE’s of TCA’s?

Answer 21

Dry mouth, dry eyes, constipation, urinary retention, blurred vision, confusion.

Question 22

Other AE’s of TCA’s besides CV and anti-muscirinic?

Answer 22

Sedation (H1 blockade), weight gain, sexual dysfunction, seizures (TCA’s lower seizure threshold), bipolar disorder, and withdrawal symptoms.

Question 23

What’s special about TCA withdrawal syndromes?

Answer 23

Its withdrawal across the board with anticholinergic withdrawal, H1, alpha 1, SERT and NET block.

Question 24

What psychologic AE are TCA’s more likely to induce than other antidepressants?

Answer 24

Aactivation of mania or hypomania more likely than other drugs in this class, so be careful if administering for bipolar disorders.

Question 25

Admin of TCA and preg? kids? elderly?

Answer 25

Caution in preg, kids get cardiotox and seizure inducing effects and are esp susceptable, elderly are reported to have falls, so generally “no” across the board or use with extreme caution.

Question 26

Patients with these conditions should not take TCA’s or be used cautiously.

Answer 26

CV diseases, epilepsy, BPH, and narrow angle glaucoma.

Question 27

TCA overdose?

Answer 27

Lethal and children are particularly susceptable.

Question 28

Signs/Symptoms of TCA overdose? Tx?

Answer 28

Antimuscirinic, hypotension, conduction defects. Resp and cardio support, decontamination.

Question 29

Why can we not administer physostigmine for TCA overdose if the side effects seem to be generally anti-muscirinic?

Answer 29

It causes Brady arrythmias and seizures for TCA OD.

Question 30

Suicide and TCA?

Answer 30

Avoid or monitor closely.

Question 31

DDI’s with TCA’s?

Answer 31

If used with MAOI’s we will get serotonin syndrome. Drugs that inhibit 2D6 and/or 2C19 will increase TCA conc and lead to tox, (such as SSRIs, ritonavir, antipsychotics, etc). Drugs that prolong QT intervals such as anti-arrythmics, macrolides, FQ ABX and antipsychotics. Drugs that lower seizure threshold.