Third-line drugs

Amitriptyline and imipramine, and the MAOI phenelzine, can be considered second- or third-line drugs for PTSD after SSRIs have failed. Mirtaza-pine and venlafaxine may also be effective. 

Felbamate has been approved and marketed in the USA and in some European countries. Although it is effective in some patients with partial seizures, the drug causes aplastic anemia and severe hepatitis at unexpectedly high rates and has been relegated to the status of a third-line drug for refractory cases. 

Usually a third-line drug to its potential severe adverse effects... 

Clonazepam (Klonopin) was approved in 1975 for monotherapy or adjunctive treatment of akinetic (atonic), myoclonic, and absence variant seizures (64). Clonazepam also was found to be effective in controlling absence seizures, but because of the high incidence of side effects. It Is rated second to ethosuximide. It may be useful, however. In absence seizures when succinimide therapy has failed. It Is considered to be a third-line drug after 1) ethosuximide or valproate and 2) lamotrigine or valproate for the treatment of absence seizures. It is ineffective for treatment of generalized clonic-tonic seizures. 

I. Pharmacology. Pentobarbital is a short-acting barbiturate with anticonvulsant as well as sedative-hypnotic properties. It is used as a third-line drug in the treatment of status epilepticus. It may also reduce intracranial pressure in patients with cerebral edema by inducing vasoconstriction. After intravenous administration of a single dose, the onset of effect occurs within about 1 minute and lasts about 15 minutes. Pentobarbital demonstrates a biphasic elimination pattern the half-life of the initial phase is 4 hours, and the terminal phase half-life is 35-50 hours. Effects are prolonged after termination of a continuous infusion. 

Third-line drugs Linezolid Rifabutin Macrolides Vitamin D Thioacetazone Thioridazine Arginine... 

Use in moderate pain Weak analgesic most effective when used with NSAIDs, aspirin, or acetaminophen This drug is not recommended in the elderly Will cause carbamazepine levels to increase 100 mg of napsylate salt = 65 mg of HCI salt Third-line agent for moderate-to-severe pain... 

The optimal timing of laser or surgical trabeculectomy is controversial, ranging from initial therapy to after failure of third- or fourth-line drug therapy. Antiproliferative agents such as fluorouradl and mitomycin C are used to modify the healing process and maintain patency. 

Fourth, total refusal of reimbursement of new technologies is rare, restrictions in use are much more common. In several countries the authorities seek to restrict the use of new drugs to certain subgroups of patients in whom their use would be particularly cost effective. Alternatively, they seek to ensure that new drugs are used second or third line, after cheaper treatments have failed. 

The TCAs and MAOIs are now relegated to second- or third-line treatments for MDD. Both the TCAs and MAOIs are potentially lethal in overdose, require titration to achieve a therapeutic dose, have serious drug interactions, and have many troublesome adverse effects. As a consequence, their use in the treatment of MDD or anxiety is now reserved for patients who have been unresponsive to other agents. Clearly, there are patients whose depression responds only to MAOIs or TCAs. Thus, TCAs and MAOIs are probably underused in treatment-resistant depressed patients. 

FIGURE 7—35. Combination treatments for bipolar disorder (bipolar combos). Combination drug treatment is the rule rather than the exception for patients with bipolar disorder. It is best to attempt monotherapy, however, with first-line lithium or valproic acid, with second-line atypical antipsychotics, or with third-line anticonvulsant mood stabilizers. A very common situation in acute treatment of the manic phase of bipolar disorder is to treat with both a mood stabilizer and an atypical antipsychotic (atypical combo). Agitated patients may require intermittent doses of sedating benzodiazepines (benzo assault weapon), whereas patients out of control may require intermittent doses of tranquil-izing neuroleptics (neuroleptic nuclear weapon). For maintenance treatment, patients often require combinations of two mood stabilizers (mood stabilizer combo) or a mood stabilizer with an atypical antipsychotic (atypical combo). For patients who have depressive episodes despite mood stabilizer or atypical combos, antidepressants may be required (antidepressant combo). However, antidepressants may also decompensate patients into overt mania, rapid cycling states, or mixed states of mania and depression. Thus, antidepressant combos are used cautiously. 

As social phobia is only recently becoming better recognized and researched, better documentation for the various treatments mentioned above is now evolving. This applies especially to the five SSRIs and to some of the newer antidepressants such as venlafaxine XR. Guidelines are emerging for the use of high-potency benzodiazepines, MAO inhibitors, RIMAs, beta blockers, and various drugs in combination as second- or third-line treatments for social phobia. 

The calcium channel blockers generally are considered seconder third-line options for preventive treatment when other drugs with established clinical benefit are ineffective or contraindicated. Verapamil is the most widely used calcium chaimel blocker for preventive treatment, but it provided only modest benefit in decreasing the frequency of attacks in two placebo-controlled studies." The therapeutic effect of verapamil may not be noted for up to 8 weeks after initiation of therapy. Side effects of verapamil may include constipation, hypotension, bradycardia, atrioventricular block, and exacerbation of congestive heart failure. Evaluations of nifedipine, nimodipine, diltiazem, and nicardipine have yielded equivocal results. ... 

At this time, the preferred first-line drug therapy for ADHD is either methylphenidate, dexmethylphenidate, mixed amphetamine salts, or dextroamphetamine. Atomoxetine, bupropion, or TCAs are good options for those umesponsive to or unable to tolerate stimulants. Clonidine and guanfacine are third-line options or adjuncts that require careful cardiovascular monitoring. Mood stabilizers (e.g., lithium, divalproex, and carbamazepine) and atypical antipsychotics are adjuncts for control of aggression or comorbid bipolar disorder. Other agents require further investigation before their status in the treatment of ADHD can be fuUy determined. 

MAO inhibitors are another group of antidepressant medications that have historically been used to treat major depressive disorders. Currently, this classification of medications is considered a second-line or third-line treatment of depression (Brophy, 1991 Tierney et al., 1997). There are times however, that this group of drugs can be utilized as the first line of treatment for depression of an atypical nature (Tierney et al., 1997). Generally, these medications with their dangerous treatment-effect profiles should only be considered after the tricyclic or the newer classifications of antidepressants have been tried (Tierney et al., 1997). 

Any of these four drug classes can be used as additive second- or third-line therapy. The P receptor antagonist timolol has been combined with the carbonic anhydrase inhibitor dorzolamide in a single medication (cosopt) that may improve compliance. 

Dartois, V., Barry, C.E., 2010. Clinical pharmacology and lesion penetrating properties of second-and third line antituberculous agents used in the management of multidnig-resistant (MDR) and extensively drug resistant (XDR) tuberculosis. Curr. Clin. Pharmacol. 5, 96—114. 

Antitumor drug used in combination therapy as third line against germ cell testicular tumor. 

---