Biological Therapies

By:Santos, Edilberto DB.

Nefazodone

• Serzone• Antidepressant and anti-anxiety• Structurally related to trazodone (Desyrel)• Chemistry:phenylpiperazine analogue of

trazodone

NefazodonePharmacologic Actions

• Rapidly and completely absorbed but extensively metabolized

• Half-life: 2-4 hrs• Hydroxynefazone: active metabolite, steady

state 4 to 5 days• Low doses recommended for elderly women

NefazodoneEffects on Specific Organs and Systems1. CNS2. Extra-CNS = orthostatic hypotension, liver

failure3. Cardiovascular Effects

1. Significant drop in BP2. Postural hypotension3. Sinus bradycardia

4. Activation of Mania

NefazodoneTherapeutic Indications

1. Depression2. Moderate, severe, melancholic,

nonmelancholic, chronic and recurrent depression.

3. Depression accompanied by anxiety (panic d/o)

4. Reduce obsessive thoughts in OC d/o.

NefazodonePrecautions and Adverse Reactions

1. MC = nausea, dizziness, insomnia, weakness and agitation.

2. Cardiovascular Effects- Drop in BP postural hypotension

3. Activation of Mania- Bipolar d/o

4. Other precautions- Pregnancy- Lactating mothers- Hepatic disease

NefazodoneDrug Interactions

• Should NOT be given w/ MAOIs• Drug-drug interaction w/

triazolobenzodiazepines triazolam (Halcion) and alprazolam (Xanax) inhibition of cytochrome P450 isoenzyme 3A4 (CYP 3A4)

• Slow the metabolism of digoxin (Lanoxin) and haloperidol (Haldol)

NefazodoneLaboratory Interferences

• No known laboratory interferences

Dosage and Clinical Guidelines• 50-, 200-,& 250-mg unscored tabs• 100- & 150-mg scored tabs• Recommended starting dose: 100mg bid, but

50 mg bid better tolerated

Opioid ReceptorAgonists: Methadone, Levomethadyl

and Buprenorphine

Opioid Receptor Agonists

• Detoxification from heroin and other opioids• Maintenance opioid detoxification programs• Maintenance therapy is used in addicted

patients who are unable to remain abstinent from opioids.

• Drugs: methadone (Dolophine), buprenorphine (Buprenex), and levomethadyl acetate (ORLAAM), also called L-α-acetylmethadol or LAAM.

Opioid Receptor AgonistsPharmacological Actions

• Methadone, levomethadyl and buprenorphine are absorbed rapidly from the GI tract.

• Hepatic first-pass (bioavailability)– Methadone = reduce by half– Levomethadyl = normethyl-LAAM & dinormethyl-

LAAM– Buprenorphine = eliminates bioavailability

COMPLETELY!

Opioid Receptor AgonistsEffects on Organs and Systems

• Methadone maintenance improved health & dec. risk of HIV transmission

• Levomethadyl acetate prolongs the QT interval

• NO evidence of methadone toxicity.

Opioid Receptor AgonistsTherapeutic Indications

• Methadone1. Short-term detox (7-30 days)2. Long-term detox (up to 180 days)3. Maintenance Tx (>180 days)

- Methadone Maintenance Treatment Programs (MMTPs), hospitals and prison- opioid-dependent individuals.

4. Pregnancy – improves OB and neonatal outcomes for women addicted to heroin

Therapeutic Indications Cont….

5. Neonatal Methadone Withdrawal Symptoms1. tremor2. high-pitched cry3. inc. muscle tone and activity4. poor sleep and eating5. mottling6. yawning7. perspiration8. skin excoriation

Therapeutic Indications Cont….

• Levomethadyl– Used for maintenance tx of opioid dependent

patient.– 3x weekly: 100 mg Monday, 100 mg Wednesday,

140 mg Friday.

Therapeutic Indications Cont….

• Buprenorphine– Analgesic approved ONLY for tx of moderate to

severe pain.– Dose: 8 to 16 mg/day reduce heroin use– 3x weekly dosing

Opioid Receptor AgonistsPrecautions and Adverse Reactions• MC adverse effects:

1. Lightheadedness 9. Decreased libido2. Dizziness 10. Inhibition of orgasm3. Sedation 11. Insomnia4. Nausea 12. Sleep Irregularities5. Constipation6. Vomiting7. Perspiration8. Weight gain

Opioid Receptor AgonistsOverdosage

Acute effects: Severe Effects1. Sedation 1. coma2. Hypotension 2. cardiac effects3. Bradycardia 3. shock4. Hypothermia 4. death5. Respiratory suppression6. Miosis7. Decreased GI motility

Opioid Receptor AgonistsWithdrawal Symptoms

• Abrupt cessation of methadone use triggers w/drawal Sx w/in 3-4 days, peak on 6th day.

1.Weakness 7. sweating2.Anxiety 8. hot and cold flashes3.Anorexia4.Insomnia5.Gastric distress6.headache

Opioid Receptor AgonistsDrug-Drug Interactions

• Potentiate CNS-depressant effects of alcohol, barbiturates, benzodiazepines, other opioids, low-potency dopamine receptor antagonists, tricyclic and tetracyclic drugs and MAOIs.

Opioid Receptor AgonistsLaboratory Interferences

• Methadone, levomethadyl and buprenorphine can be tested sep. in urine toxicology to distingtuish them from other opioids.

• No known lab interferences!

Opioids Receptor AgonistsDosage and Clinical Guidelines

• Methadone = 5-, 10- and 40-mg dispersible scored tabs; 40-mg scored wafers; 5mg/5ml, 10mg/5ml, 10mg/ml sol.; 10-mg/ml parenteral form.

• Levomethadyl = 10mg/ml oral sol/ 3x weekly

• Buprenorphine = 0.3mg/ml sol in 1-ml ampules as analgesics.

Opioid Receptor Antagonists: Naltrexone and Nalmefene

Opioid Receptor Antagonists

• Naltrexone (ReVia) & Nalmefene (Revex) are effective Tx for opioid dependence when used in combination w/ structured cognitive-behavioral therapy.

• For alcohol dependence• Reduce or eliminate the subjective “high”

associated w/ consumption of opioids.• Naltrexone : FDA approved

Opioid Receptor AntagonistsPharmacological Actions

• Rapidly absorbed in the GI tract• First-pass hepatic metabolism = 60% of

naltrexone ; 40-50% nalmefene systemic circulation unchanged.

• 6-β-naltrexol (active metabolite); peak conc. reached in 1 hr

• Half life: Naltrexone = 1-3 hrs., 6-β-naltrexol = 13 hrs

• Nalmefene; peak = 1-2hrs; HF = 8-10 hrs.

Opioid Receptor AntagonistsTherapeutic Indications

• Opioid dependence– Rapid detox : avoid 7- to10-day period of opioid

abstinence generally is recommended;• Completed w/in 48 to 72 hrs

– Ultrarapid detox: variant technique, the body is cleared of opioid agonists activity over a period of only a few hrs by infusion of naloxone

Therapeutic Indications cont….

• Alcohol dependence– Reduce alcohol craving and alcohol consumption,

ameliorate the severity of relapses.– Nalmefene more advantageous for tx, no

associated hepatoxicity.

Opioid Receptor AntagonistsPrecautions and Adverse Effects

• Sx of Acute opioid withdrawal:– Drug craving– Feeling of temperature change– Musculoskeletal pain– GI distress

• Signs of opioid withdrawal– Confusion– Drowsiness– Diarrhea– Vomiting

Opioid Receptor AntagonistsDrug-Drug Interaction

• Because of its hepatic metabolism, naltrexone may affect or be affected by other drugs that influence hepatic enzyme levels. clinical importance of these potential interactions not known.

Opioid Receptor AntagonistsLaboratory Interferences

• No Laboratory interferences have been described for opioid receptor antagonists!

Dosage and Clinical Guidelines• Person should be opioid free• 5-days should elapse ff the last dose of short-acting

opioids & at least 10 days for long-acting opioids.• Confirm: urine toxicological screens

Other Anticonvulsants: Gabapentin, Lamotrigine, and Topiramate

Other anticonvulsants

• Gabapentin – chemically related to γ-aminobutyric acid (GABA) and is structurally similar to L-leucine.

• Lamotrigine & topiramate – novel 3-ringed compounds.

Other anticonvulsantsPharmacological Actions

• Gabapentin– Absorbed by the neural amino acid membrane

transporter system in the gut, crosses the BBB.– Bioavailability: 300-600 mg doses 60%, 1,600 mg

35%.– Higher doses not absorbed– Food no effect on gabapentin absorption.