Amitriptyline
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Amitriptyline and its various uses

DESCRIPTION

Amitriptyline HCl is a dibenzocycloheptadiene derivative, designated chemically as 3-(10,11-dihydro-5H-dibenzo [a,d] cycloheptene-5-ylidene)-N,N-dimethyl-1-propanamine hydrochloride. Its empirical formula is C20H23N•HCl
Amitriptyline structure

Amytriptyline (Tryptomer, Elavil, Tryptizol, Laroxyl, Saroten, Sarotex, Lentizol, Endep) is a tricyclic antidepressant which, as well as reducing depressive symptoms, also ease migraines, tension headaches, anxiety attacks and some schizophrenic symptoms. It is also known to reduce aggression and violent behaviour.

CLASSIFICATION

• Tricyclic antidepressant
• Non-selective monoamine reuptake inhibitors
• Membrane stabilizing effect on the myocardium by blocking the cardiac myocyte fast sodium channels

INDICATIONS

• Depressions of varied causes (particularly endogenous forms)
• Chronic pain (e.g. therapy of migraines, postherpetic neuralgias and peripheral neuropathies)
• Psychological disorders (e.g. eating disorders, bipolar disorders, post-traumatic stress disorders,...)
• Used in ankylosing spondylitis for pain relief
• Used as a preventive for patients with recurring biliary dyskinesia (sphincter of Oddi dysfunction)

PHARMACOKINETICS

Amitriptyline is well absorbed from the gastrointestinal tract with peak plasma concentrations occurring between 2 and 12 hours after administration. Bioavailability of the drug is between 30 and 60% due to extensive first pass metabolism of the drug in the liver. Amitriptyline is demethylated in the liver to its primary active metabolite, nortriptyline.

Amitriptyline is over 90% protein bound. Its elimination half-life varies from 10 to 50 hours, with an average of 15 hours. Within 24 hours, approximately 25 to 50% of a dose of amitriptyline is excreted in the urine as inactive metabolites; small amounts are excreted in the bile.

MOLECULAR MECHANISM

• Its effects as an antidepressant

Amitriptyline is is the most widely used TCA (Tricyclic antidepressant - substances that contain a fused three-ring moiety and are used in the treatment of depression. These drugs block, in a still unclear way, the reuptake of norepinephrine and serotonin into axon terminals and may block some subtypes of serotonin, adrenergic, and histamine receptors-).

Effects in the CNS include an inhibitory effect on the re-uptake of 5-HT and noradrenaline that may reduce pain by enhancing synaptic inhibition in the spinal cord or brain stem.

• Its effects on neuropatic pain

Amitriptyline may also alleviate neuropathic pain via its action in the peripheral nervous system (it inhibits voltage-dependent sodium and potassium channels and also acts as an antagonist at ligand-gated ion channels such as nicotinic acetylcholine receptors -nAChRs -).

Differential inhibition of catecholamine secretion by amitriptyline through blockage of nicotinic receptors, sodium channels, and calcium channels in bovine adrenal chromaffin cells, 1998

It has been noted that this effect requires only sub-micromolar concentrations in contrast to the micromolar concentrations necessary to inhibit voltage-dependent sodium channels.
nAChRs are also expressed functionally in both the axons and cell bodies of a sub-population of peripheral sensory neurons, some of which are nociceptors.

PHARMACOGENOMICS

Amitriptyline dosing guidelines

• Modified CYP2D6 metabolizers

The recommended starting dose of amitriptyline or nortriptyline does not need adjustment based on genotype for CYP2D6 extensive metabolizers. A 25% reduction of the recommended dose may be considered for CYP2D6 intermediate metabolizers, but because patients with a CYP2D6 activity score of 1.0 are inconsistently categorized as intermediate or extensive metabolizers in the literature, these are difficult to evaluate resulting in a moderate recommendation classification.

CYP2D6 ultrarapid metabolizers have a higher probability of failing amitriptyline or nortriptyline pharmacotherapy due to subtherapeutic plasma concentrations, and alternate agents are preferred. There are documented cases of CYP2D6 ultrarapid metabolizers receiving large doses of nortriptyline in order to achieve therapeutic concentrations. However, very high plasma concentrations of the nortriptyline hydroxy-metabolite were present, which may increase the risk for cardiotoxicity. If a tricyclic is warranted, there are insufficient data in the literature to calculate a starting dose for a patient with CYP2D6 ultrarapid metabolizer status, and therapeutic drug monitoring is strongly recommended.

Adverse effects are more likely in CYP2D6 poor metabolizers due to elevated tricyclic plasma concentrations, therefore alternate agents are preferred. If a tricyclic is warranted, consider a 50% reduction of the usual dose, and therapeutic drug monitoring is strongly recommended.

• Modified CYP2C19 metabolizers

CYP2C19 ultrarapid metabolizers (UM) taking amitriptyline may be at risk of having altered plasma concentrations or adverse events. Although the CYP2C19*17 allele did not alter the sum of amitriptyline plus nortriptyline plasma concentrations, it was associated with higher nortriptyline plasma concentrations, possibly increasing the risk of adverse events. Due to the need for further studies investigating the clinical importance of the CYP2C19*17 allele and the possibility of altered tricyclic concentrations, the recommendation is to consider an alternative tricyclic or other drug not affected by CYP2C19. Because the clinical importance of CYP2C19*17 is currently poorly understood, this recommendation is classified as optional. If amitriptyline is administered to a CYP2C19 UM, therapeutic drug monitoring is recommended.

The usual starting dose of amitriptyline may be used in CYP2C19 extensive (EM) and intermediate metabolizers (IM). Although CYP2C19 IM would be expected to have a modest increase in the ratio of amitriptyline to nortriptyline plasma concentrations, the evidence does not indicate that CYP2C19 IM should receive an alternate dose.

CYP2C19 poor metabolizers (PM) are expected to have a greater ratio of amitriptyline to nortriptyline plasma concentrations. The elevated amitriptyline plasma concentrations may increase the chance of a patient experiencing side effects. Consider a 50% reduction of the usual amitriptyline starting dose along with therapeutic drug monitoring.

• Both CYP modified metabolizers

Although specific combinations of CYP2D6 and CYP2C19 alleles are likely to result in additive effects on the pharmacokinetic properties of tricyclics, little information is available on how to adjust initial doses based on combined genotype information.
Patients carrying at least one CYP2D6 non-functional allele and two CYP2C19 functional alleles had an increased risk of experiencing side effects when administered amitriptyline, while patients with at least one CYP2C19 loss-of-function allele and two CYP2D6 functional alleles had a low risk of experiencing side effects

SIDE EFFECTS

The main two side effects that occur from taking amitriptyline are drowsiness and a dry mouth.

Other common side effects of using amitriptyline are mostly due to its anticholinergic activity, including: weight gain, changes in appetite, muscle stiffness, nausea, constipation, nervousness, dizziness, tremor, blurred vision, urinary retention, and changes in sexual function.

Some rare side effects include seizures, tinnitus, hypotension, mania, psychosis, sleep paralysis, hypnagogic or hypnopompic hallucinations related to sleep paralysis, heart block, arrhythmias, lip and mouth ulcers, extrapyramidal symptoms, depression, tingling pain or numbness in the feet or hands, yellowing of the eyes or skin, pain or difficulty passing urine, confusion, abnormal production of milk in females, breast enlargement in both males and females, fever with increased sweating, and suicidal thoughts.

A side effect of many commonly used drugs with such effects appears to be to increase the risks of both cognitive impairment and death in older people

*Clinical Worsening and Suicide Risk

Possible emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

TOXICITY and adverse reactions

Amitriptyline official FDA information

• Cardiovascular: Myocardial infarction; stroke; nonspecific ECG changes and changes in AV conduction; heart block; arrhythmias; hypotension, particularly orthostatic hypotension; syncope; hypertension; tachycardia; palpitation.

• CNS and Neuromuscular: Coma; seizures; hallucinations; delusions; confusional states; disorientation; incoordination; ataxia; tremors; peripheral neuropathy; numbness, tingling and paresthesias of the extremities; extrapyramidal symptoms including abnormal involuntary movements and tardive dyskinesia; dysarthria; disturbed concentration; excitement; anxiety; insomnia; restlessness; nightmares; drowsiness; dizziness; weakness; fatigue; headache; syndrome of inappropriate ADH (antidiuretic hormone) secretion; tinnitus; alteration in EEG patterns.

• Anticholinergic: Paralytic ileus, hyperpyrexia; urinary retention, dilatation of the urinary tract; constipation; blurred vision, disturbance of accommodation, increased ocular pressure, mydriasis; dry mouth.

• Allergic: Skin rash; urticaria; photosensitization; edema of face and tongue.

• Hematologic: Bone marrow depression including agranulocytosis, leukopenia, thrombocytopenia; purpura; eosinophilia.

• Gastrointestinal: Rarely hepatitis (including altered liver function and jaundice); nausea; epigastric distress; vomiting; anorexia; stomatitis; peculiar taste; diarrhea; parotid swelling; black tongue.

• Endocrine: Testicular swelling and gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido; impotence; elevation and lowering of blood sugar levels.

• Other: Alopecia; edema; weight gain or loss; urinary frequency; increased perspiration.

RESISTANCE

The body may build up a tolerance with the drug and the doctor may up the dosage, but after certain levels the counterindications may surpass the lenitive effects, which may cause toxic effects (as seen before).

DEPENDENCE AND WITHDRAW

Side effects from discontinuation of amitriptyline include nausea, headaches, malaise, irritability, restlessness, abnormal dreams and insomnia.

The side effects of stopping amitriptyline are not caused by physical dependence. Rather, the symptoms occur because when the patient suddenly discontinue use of amitriptyline, chemical levels in his brain drop dramatically.
Some patients develop mania or severe depression within two to seven days of stopping amitriptyline,but, like the other symptoms caused by discontinuation, this is only temporary.

In order to avoid the side effects associated with stopping amitriptyline, the doctor is likely to gradually taper off dosage of the drug once the patient no longer need it to manage his depression.

A study about effects of low amitriptyline concentrations

Low concentrations of amitriptyline inhibit nicotinic receptors in unmyelinated axons of human peripheral nerve, 2009

In this study, it has been examined the effect of amitriptyline on the responses to nicotine of unmyelinated axons in peripheral human nerve. In particular, a comparison was made between the concentrations necessary for inhibition of nAChRs and for changes in amplitude and latency of compound action potentials (CAPs).

Preparations

Segments of sural nerve were removed from patients already scheduled for sural nerve biopsy, and each patient gave their written consent to the removal of an additional portion of nerve for research purposes. Experiments were carried out on 18 isolated fascicles of human sural nerve from seven patients (all male) with a median age of 66 years and ranging from 44 to 84 years.

Individual nerve fascicles were carefully extracted from an isolated segment of sural nerve (ca. 15–25 mm long) by grasping them with jewellers forceps and gently pulling them free. Each end of the nerve fascicle was drawn into a glass suction electrode within the organ bath and embedded in Vaseline to establish both a mechanical and a high resistance electrical seal. The organ bath (volume 1 mL) was continuously superfused at a rate of 6–8 mL·min−1 with physiological solution of the following composition (in mM) NaCl 118, KCl 3.0, CaCl2 1.5, MgCl2 1.0, D-glucose 5.0, NaHCO3 25 and NaH2PO4 1.2, and was bubbled with 95% O2/5% CO2 to pH 7.4. The temperature of the solution perfusing the bath was held constant at 32°C.

Electrophysiological analysis

The nerve fascicle was stimulated extracellularly with a constant current stimulator.
A silver wire inside the suction electrode served as the anode and a second silver wire, wound around the suction pipette, served as the cathode. Extracellular signals were recorded over the sealing resistance of the second suction electrode using a differential amplifier.

The signal was typically amplified with a gain of 1000× and filtered, low pass 1.3 kHz and high pass 3 Hz. The distance between stimulating and recording electrodes varied for each fascicle and was in the range 3–6 mm. Axonal excitability was assessed using a flexible, stimulus-response data-acquisition programme.

The isolated fascicles were stimulated with constant current pulses of fixed duration (1 ms) and varying amplitude. Stimulus frequency was invariably 0.5 Hz. For threshold tracking experiments, the current amplitude was automatically adjusted to maintain the C-fibre CAP response at constant amplitude (40% of the maximum, defined as ‘threshold’).

Statistics

Quantitative analysis of the effects of amitriptyline (10 µM) and tetrodotoxin (TTX) (10 nM) on the C-fibre compound action potential response to electrical stimulation of human nerve fascicles. TTX (10 nM) reduced the amplitude and prolonged the latency to half-maximum amplitude of the C-fibre response to supra-maximal stimulation. These effects of TTX on the C-fibre response were significantly more pronounced than those of amitriptyline (10 µM). In contrast, amitriptyline (10 µM) produced a significantly stronger inhibition of the reduction in threshold produced by nicotine (10 µM).

Quantitative analysis of the effects of amitriptyline on nicotine-induced (10 µM) increases in excitability and the amplitude and latency to onset of the C-fibre compound action potential (CAP) response to supra-maximal stimulation. In concentrations from 1 to 10 µM, amitriptyline reduced, concentration-dependently, the nicotine-induced (10 µM) increase in excitability in unmyelinated human axons. In addition, in concentrations above 1 µM, amitriptyline concentration-dependently reduced the amplitude and increased the latency to half-maximum amplitude of the C-fibre CAP. However, these changes are much less prominent than the reduction of the nicotine-induced increase in axonal excitability observed in the presence of amitriptyline.

Results

The effect of amitriptyline on unmyelinated axons in isolated fascicles of human sural nerve was tested by monitoring the compound C-fibre action potential response to electrical stimulation. A representative example of the CAP response is illustrated in the figure:

An Aα/β peak corresponding to the activation of large-diameter myelinated axons occurred at short latency in response to low stimulus strengths (stimulus duration 0.1 ms). This peak is designated Aα/β because, while in the majority of people the sural nerve is exclusively sensory, in some individuals it may contain both cutaneous Aβ afferents as well as Aα axons comprising efferent motoneurons and Ia and Ib muscle afferents.
At slightly higher stimulus intensities, small-diameter thinly myelinated axons were activated producing an Aδ peak at slightly longer latency. Further increases in stimulus intensity and duration (1 ms) activated unmyelinated axons and produced the C peak. In some human nerve fascicles, two classes of unmyelinated axon are discernible in the compound response, a lower threshold, more rapidly conducting class giving rise to the C1 peak and a higher threshold, more slowly conducting C2 peak. Quantitatively, the amplitude of the C-fibre compound potential varied between 0.1 and 1.5 mV.

Amitriptyline reduces the effects of nicotine on axonal excitability

The effect of amitriptyline on several electrophysiological C-fibre parameters was also examined.

Amitriptyline affects the nicotine-induced increase in excitability as well as the amplitude and latency of the C-fibre CAP response to supra-maximal stimulation. (A) Amitriptyline (1–10 µM) inhibits concentration-dependently the increase in C-fibre excitability induced by nicotine (10 µM). In addition, amitriptyline (1–10 µM, B) produces a rather modest concentration-dependent decrease in the absolute amplitude (peak-to-peak) and an increase in the latency to half-maximum amplitude of the compound C-fibre action potential response to supra-maximal electrical stimulation.

Amitriptyline reduces the magnitude of the nicotine effect on C-fibre excitability. Nicotine (10 µM) produces a robust increase in the electrical excitability of C-fibres as illustrated in panel Aa for three consecutive applications at 20 min intervals. There is no indication of tachyphylaxis. The inset to the right (Ab) shows an example of the C-fibre CAP recorded in response to supra-maximal stimulation. Amitriptyline (3 µM) substantially reduces the increase in excitability produced by nicotine (10 µM) as shown in the recording from a second isolated human nerve segment in B. At a concentration of 3 µM amitriptyline's action is restricted to an inhibition of the excitability increase brought about by nicotine (Ba), with only a small effect on the amplitude and latency to onset of the C-fibre response to supra-maximal stimulation (Bb, inset right).

Results

The small changes in latency and amplitude of the compound C-fibre action potential produced by amitriptyline may indicate that a reduction in the availability of voltage-dependent Na+ channels contributes to the amitriptyline-induced inhibition of the effects of nicotine.
This indicates that amitriptyline has a direct action on nAChRs and explain, at least in part, amitriptyline's therapeutic action in the treatment of neuropathic pain.