DrugBuyers.Com: Depression Meds (incl Amphetamines & Narcotics)

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ANTIDEPRESSANT AGENTS

A. Introduction

1. Depression refers to a significant reduction in mood, wherein the subject experiences a gamut of behavioral changes ("the blues") and may exhibit various signs and symptoms including: extreme unhappiness, pessimism and a highly negative outlook on life; loss of self-esteem, occasionally accompanied by inappropriate self-reproach, and even self-destructive thoughts or behavior; psychomotor disturbance (manifested as either retardation wherein the patient becomes highly withdrawn and loses all interests, or by agitation, marked by a high level of discomposure, apprehension and tension); lack of energy; insomnia and sleep disturbance; and decrease in appetite, libido and social interactions.
a) Exogenous (also called reactive or secondary) depression is the most frequently encountered type of depression and it occurs secondarily to some external stress or misfortune. Psychotherapy - not drug therapy - is the most beneficial approach to this type of patient. The only useful application of drugs might be the administration of sedative-hypnotic agents (e.g., diazepam) to decrease anxiety or produce sedation during the apex of confrontation with reality and realization of personal loss.
b) Endogenous (or primary) depression may occur in the absence of any apparent cause and is allegedly biochemical in origin. Antidepressant drugs are most useful in treating these types of patients.

2. Neurochemical Theories of Affective Disorder
a) Catecholamine hypothesis - asserts that affective disorders are related to imbalances of catecholamines (particularly norepinephrine [NE]) in the limbic system. In depression, the concentrations are postulated to be below normal, while in manic - or excessive mood elevation - there is excessive catecholamine (NE) activity.
b) Serotonin hypothesis - also proposed that 5-HT might play a permissive role in the manifestation of affective disorders.
c) The monamine hypothesis is a combination of a. and b.
d) Enhanced beta-adrenergic activity in brain - chronic antidepressant therapy (but not seen with ECT or fluoxetine-like drugs) results in subsensitivity and decreased density of these receptors (no change in alpha-adrenergic receptors)
e) Enhanced 5-HT1A receptor sensitivity - seen with all antidepressants and with ECT.
3. The categories of antidepressant agents discussed in this section include the tricyclic antidepressants (TCADs), second and third generation heterocyclic agents, selective serotonin reuptake inhibitors (SSRI) and the MAO inhibitors. The activity of these agents has been related to their ability to cause an increase in availability of catecholamines (especially NE) and/or serotonin at the receptor.

B. Tricyclic Antidepressants
1. Agents
a) Amitriptyline (Elavil)
b) Imipramine (Tofranil)
c) Desipramine (Norpramin)
d) Others
(1) Doxepin (Adapin, Sinequan)
(2) Nortriptyline (Aventyl)
(3) Protriptyline (Vivactil)
2. Pharmacokinetics
3. Mechanism of Action
· Block NE and 5-HT reuptake pumps (see table)

4. Pharmacological effects
a) Effect in normal subjects
(1) Anticholinergic actions
(2) Sleepiness, lightheadedness
(3) No stimulating or mood elevation effects
b) Effect in depressed subjects
(1) Elevation in mood only after 2-3 weeks
(2) Not used prn

5. Adverse effects
a) CNS
(1) Disorientation
(2) "Sedation"
(3) Neurological disturbances; tremor, insomnia
(4) Aggravation of psychosis
(5) Seizures
b) Cardiovascular - orthostatic hypotension, tachycardia, and arrhythmias.
c) Anticholinergic effects - dry mouth, constipation, blurred vision, urinary retention.
d) Weight gain
e) Sexual disturbances
f) Overdose toxicity - similar to phenothiazines and similar antipsychotics
g) Allergic reactions - cholestatic jaundice.
h) Drug reactions

6. Clinical Uses
a) Treatment of depression
b) Panic Disorder
c) Enuresis
d) Chronic pain
e) Other

C. Heterocyclics: "Second and Third Generation" Antidepressants
Since 1980, a number of "second generation and third generation or heterocyclic antidepressant drugs have been introduced into clinical practice. These agents differ from the tricyclics in their pharmacological effects but none appear to be more effective in treating depression. However, these agents may have, to varying degrees, less anticholinergic side effects, less cardiotoxicity, and a faster onset of action.

1. 2nd generation agents
a) Amoxapine (Asendin)
(1) Metabolite of loxapine and retains some of its DA receptor antagonism and antipsychotic effects (useful for depression in psychotic patients?)
(2) EPS and amenorrhea-galactorrhea

b) Maprotiline (Ludiomil)
(1) Most important action on block of NE re-uptake
(2) High doses associated with seizures

c) Trazodone (Desyrel)

2. 3rd generation agents

a) Venlafaxine (Effexor)
(1) Like SSRI in low doses
(2) NE reuptake block with high doses
(3) High doses also result in block of DA reuptake

b) Nefazodone (Serzone)
(1) Fewer adverse sexual effects than SSRI
(2) Inhibits CYP3A4; should not be used in combination with cisapride, terfenadine, or astemizole.

c) Mirtazapine (Remeron
(1) 5-HT2A and alpha-adrenoreceptor antagonism

d) Bupropion (Wellbutrin)

D. Selective Serotonin Reuptake Inhibitors (SSRI)

Disadvantages of the phenothiazine antipsychotics as well as TCAD and even 2nd and 3rd generation agents relates to the multitude of their pharmacological actions. It seems that the antimuscarinic, antihistaminic and alpha adrenergic blocking effects of these agents contributes only to their toxicity. Therefore, the finding that fluoxetine had minimal autonomic toxicity and was a highly selective SSRI created a great deal of interest. Fluoxetine (Prozac) became the most widely prescribed antidepressant in the U.S.A. shortly after its introduction and several new SSRI have been marketed.

1. Agents
a) Fluoxetine (Prozac)
(1) Causes inhibition of CYP3A4 similar to nefazodone (above)
(2) Half-life is about 2 weeks
b) Paroxetine (Paxil)
c) Sertraline (Zoloft)
d) Fluvoxamine (Luvox)
e) Citalopram (Celexa)

2. Mechanism of Action
3. Pharmacological effects
· No significant effects on NE or DA and does not block cholinergic, histaminergic or alpha adrenergic receptors.

4. Adverse effects
a) Restlessness, nervousness, insomnia, anxiety [10-15% have some manifestation of CNS stimulation]; seizures with OD
b) Headache [up to 20%]
c) Nausea is also very common
d) Anorexia and weight loss
e) Decreased libido, sexual dysfunction
f) Less commonly: dizziness and fatigue, diarrhea, sweating, skin rash.
g) In contrast to phenothiazine antipsychotics and TCADS, there is no significant cardiotoxicity, hypotension, sedation, or muscarinic blockade.

5. Use
a) Depression
b) Obsessive-compulsive disorders
c) Others

6. Drug interactions
a) Serotonin syndrome [hyperthermia, muscle rigidity, myoclonus, etc.] when given with a MAO inhibitor; also reported when used with St. Johns Wort
b) Can increase levels of warfarin and other drugs bound to plasma proteins.
c) Can increase levels of lithium and TCAD

E. Monoamine Oxidase Inhibitors (MAOI)

1. Agents
a) Hydrazine-type inhibitors (e.g., iproniazid (Marsilid), isocarboxazid (Marplan), phenelzine (Nardil)). Associated with hepatotoxicity and high incidence of adverse effects on the CNS and cardiovascular system. Because of these disadvantages they are being replaced by nonhydrazine MAO inhibitors and newer drugs.

b) Tranylcypromine (Parnate) - nonhydrazine MAO inhibitor with structural and pharmacological similarities to amphetamine.

c) St Johns Wort?

2. Mechanism
3. Adverse effects
a) Cardiovascular
(1) Orthostatic hypotension [why?]
(2) Hypertensive crisis [when?]
b) Liver
(1) Inhibition of hepatic enzyme systems that metabolize various drugs.
(a) Results in potentiation of effects of these drugs.
(b) Tricyclic antidepressants, phenothiazines, barbiturates, a number of anesthetic agents, and narcotic drugs are among those medications that are enhanced by MAO inhibitors.
(2) Hepatotoxicity - primarily a problem with hydrazine type agents.
c) CNS
(1) Amphetamine-like CNS stimulation - insomnia, anorexia, euphoria, respiratory stimulation, excitement; may aggravate psychosis or cause agitation reactions.
(2) Sexual disturbances (phenelzine)

4. Overdosage toxicity
a) Toxic psychosis
b) Hyperreflexia, tremors and other neurological signs

5. Cautions and Contraindications

6. Food and/or drug interactions

7. Newer class of reversible inhibitors of MAOA (RIMAs) including moclobemide, befloxatone, and brofaromine not yet available in US but used in other countries.
a) Weak potentiators of pressor effect of tyramine & low risk of hypertensive crisis
b) MAO activity reestablished quickly after discontinuation

Table 1 Antidepressant Drugs

Block reuptake of
DRUG TRADE NAME DOSE(mg) t½ AM 5 HT NE D Sed AC GI OH SZ CA WG
Tricyclics
Amitriptyline Elavil 75-100 31-46 Yes 3+ 2+ 0 3+ 3+ 0 3+ 3+ 2+ 2+
Clomipramine Anafranil 75-300 22-84 Yes 3+ 3+ 0 3+ 2+ 0 4+ 3+ 3+ +
Desipramine Norpramin, Pertofrane 75-200 14-62 - 0 3+ 0 + + 0 3+ 2+ 2+ 2+
Doxepin Sinequan, others 75-300 8-24 Yes 2+ + 0 3+ 3+ 1+ 2+ 2+ 2+ 2+
Imipramine Tofranil, others 75-200 9-24 Yes 3+ 2+ 0 2+ 2+ 0 4+ 3+ 4+ 2+
Nortriptyline Aventyl, Pamelor 75-150 16-93 Yes 2+ 2+ 0 2+ 2+ 0 + 2+ 3+ +
Protriptyline Vivactil 20-40 54-198 - ? 3+ 0 2+ 0 2+ 2+ 4+ +
Trimipramine Surmontil 75-200 9-24 Yes 3+ 2+ 0 2+ 2+ 0 4+ 3+ 4+ 2+
Heterocyclics
Amoxapine Asendin 150-300 6 Yes + 2+ + 2+ 2+ 0 + 3+ 2+ +
Bupropion Wellbutrin 200-400 11-14 Yes 0 + + 0 0 0 0 4+ 0 0
Maprotiline Ludiomil 75-300 21-52 Yes 0 2+ 0 2+ 2+ 0 2+ 4+ 3+
Mirtazepine Remeron 15-60 20-40 Yes 0 0 0 3+ 0 2+ HT ? ? 2+
Nefazodone Serzone 200-600 2-4 Yes 2+ 3+ 0 2+ + 0/+ 0 0/+
Trazodone Desyrel 50-600 4-9 Yes 2+ 0 0 3+ 0 1+ 3+ 2+ 0 +
Venlafaxine Effexor 75-225 4-10 Yes 3+ 2+ + 0 0 3+ HT ? ? 0
Monoamine Oxidase Inhibitors
Phenelzine Nardil 45-75 24-96 N/A N/A N/A + - + 3+ 0 0 +
Tranylcypromine Parnate 10-30 15 N/A N/A N/A + - + 2+ 0 0 +
Selective serotonin reuptake inhibitors
Fluoxetine Prozac 10-60 24-96 Yes 3+ 0+ 0+ 0 0 + 0 0 0 +/-
Fluvoxamine Luvox, labeled only for obsessive-compulsive disorder 100-300 7-63 No 3+ 0 0 0 0 2+ 0 0 0 +/-
Paroxetine Paxil 20-50 24 No 3+ 0 0 + 0 3+ 0 0 0 +/-
Citalopram Celexa 20-40 23-75 Yes 3+ 0 0 0 0 + 0 0 0 +/-
Sertraline Zoloft 50-200 22-35 Yes 3+ 0 0 + 0 3+ 0 0 0 +/-
t½ = Serum half time (hrs); AM = Active Metabolites; 5HT = Serotonin; NE= Norepinephrine; D = Dopamine; Sed = Sedative;
AC = Anticholinergic (dry mouth, constipation, difficult urination, blurred vision, confusion); GI = gastrointestinal upset
OH = Orthostatic Hypotension; SZ = increased seizure threshold/convulsant action; CA = Cardiac Abnormalities; WG = Weight Gain.

CNS STIMULANTS

A. Amphetamines

1. Agents
a) Racemic (d, 1) amphetamine (Benzedrine)
b) d-amphetamine (dextroamphetamine, Dexedrine; others)
c) Methamphetamine (Desoxyn)

2. Mechanism

3. Pharmacological Actions
a) Effects on CNS
(1) Increased arousal and wakefulness
(2) Mood alteration - increased confidence, ability to concentrate, exhilaration, euphoria.
(3) Increase in motor activity
(4) Insomnia
(5) Anorexia
b) Cardiovascular effects - related to sympathomimetic actions

4. Uses
a) Management of Attention Deficit Hyperactivity Disorder (ADHD)[aka: the hyperkinetic (hyperactivity, minimal brain dysfunction) syndrome; attention deficit disorder; others]
(1) "Paradoxical" decrease in hyperactivity
(2) Improvement in psychomotor performance and increased attention spun.
b) Treatment of Narcolepsy
· A sleep disorder that usually appears in young adulthood, consisting of recurring episodes of sleep during the day, and often disrupted nocturnal sleep; frequently accompanied by cataplexy, sleep paralysis, and hypnagogic hallucinations; a genetically determined disease. From Stedmans
c) As euphoriant and antidepressant not FDA approved.
d) Obesity - no longer indicated
e) Analgesia- adjunct with other agents
f) Alleviate fatigue
g) Treatment of CNS depressant OD??

5. Adverse Effects
a) Acute overdosage
(1) Signs and symptoms
(a) Moderate:
confusion hypertension
delirium cardiac irregularities
hallucinations panic states
profuse sweating
fever
(b) Severe:
convulsions
cardiovascular collapse
hyperpyrexia
coma
death

(2) Treatment

b) Chronic toxicity
(1) Tolerance and dependence
(2) Toxic psychosis

c) Cautions and contraindications
(1) Hypertension, angina, hyperthyroidism

(2) Individuals exhibiting agitation or other psychological disturbances that could be aggravated by amphetamines.

(3) Drug interactions - will greatly intensify actions of sympathomimetic drugs and MAO inhibitors.
· Other drug interactions

B. Amphetamine Congeners

1. Methylphenidate (Ritalin)

a) MOA

b) Use

2. Pemoline (Cylert)

a) MOA
b) Use

3. Miscellaneous Anorexiants
a) Fenfluramine (Pondimin) and Dexfenfluramine (Redux)
· Discontinued in the US
· Combination of fenfluramine and phentermine associated with fatal pulmonary hypertension

b) Phentermine (Ionamin)

c) Phenylpropanolamine (PPA; numerous OTC products)
· Association with hemorrhagic stroke
· Removed from OTC formulations

d) Ephedrine and ephedra alkaloids (ma huang)
· FDA studies Increased health risk (hypertension, palpitations and/or tachycardia, stroke, seizures)

e) Diethylpropion (Tenuate)
f) Sibutramine (Meridia)
· Inhibits both NE & % 5-HT reuptake
· Unlike fenfluramine & dexfenfluramine, it does not induce 5-HT release & not associated with valvular heart disease

C. Xanthine Alkaloids

1. Agents
a) Caffeine - coffee, tea
b) Theophylline - coffee, tea; aminophylline is a solubilized form of theophylline and is the most commonly used therapeutic drug form of the xanthines.
c) Theobromine - cocoa

2. Mechanism
· Inhibition of phosphodiesterase
· Adenosine antagonist

3. Pharmacological Actions
Caffeine Theophylline Theobromine

a) CNS and Respiratory 1 (most) 2 3
Stimulation (least)

b) Diuresis 3 1 2

c) Smooth Muscle 3 1 2
relaxation

d) Cardiac 3 1 2
stimulation

4. Use

D. Analeptics (Convulsant Stimulants)

A variety of drugs increase the excitability of the CNS, stimulate respiration, cause hyperreflexia, and induce convulsions in a dose-dependent fashion. These drugs are mostly of toxicological interest, although they may occasionally be used as respiratory stimulants (e.g., doxapram).

1. Pentylenetetrazol (Metrazol)
2. Picrotoxin
3. Nikethamide (Coramine)
4. Doxapram (Dopram)
5. Ethamivan (Emivan)
6. Strychnine
7. Bemegride (Megimide)

XIV. NARCOTIC ANALGESICS

A. Classification

Drugs with a predominant pain-relieving action are called analgesics and are commonly classified as narcotic and nonnarcotic. The non-narcotic agents (e.g., aspirin, acetaminophen, etc.) include certain drugs that may also have useful antipyretic and/or anti-inflammatory actions; their analgesic effects are relatively weak and probably involve both peripheral and central actions. In contrast, the narcotic analgesics are effective in alleviating even severe pain through an action on the central nervous system. Narcotics can also produce physical dependence; the Federal Controlled Substances Act regulates their use in most instances.

The narcotic analgesics include the alkaloids of opium, semisynthetic derivatives of these alkaloids and several synthetic drugs that are structurally and pharmacologically similar to the opium alkaloids. An opioid is any drug, natural or synthetic, with actions like morphine; narcotic has been used to refer to opioids, cocaine, marijuana and LSD
1.
a) Morphine and codeine are naturally occurring narcotic alkaloids derived from opium. Morphine is the prototype drug of the entire class and other drugs are often described by comparisons of their action with that produced by morphine or codeine.
b) Probably the most common semisynthetic opiate derivative is heroin (diacetylmorphine); acetylation of morphine to produce heroin results in an agent that is more lipid-soluble and more potent than morphine and has a more rapid onset and shorted duration. Hydromorphone (Dilaudid) and oxymorphone (Numorphan) are clinically useful semisynthetic derivatives of morphine and hydrocodone (Hycodan) and oxycodone (Percodan) are examples of semisynthetic codeine derivatives.
c) Examples of synthetic narcotics include methadone and its analog, d-propoxyphene (Darvon) and meperidine (Demerol) and its analog, diphenoxylate (Lomotil).

2. Narcotic antagonists are structurally related to the narcotic alkaloids but these agents competitively displace narcotic agonists from the narcotic (opiate) receptor and thereby prevent or antagonize their actions. Nalorphine (Nalline) and naloxone (Narcan) are semisynthetic opiate derivatives that have structural alterations (N-allyl substitution) that confer narcotic antagonist properties.

The recent discovery of various endogenous opiates in the nervous system has had a dramatic impact on our understanding of narcotic mechanisms. These endogenous peptides, classified as endorphins or enkephalins, have been shown to produce morphine-like effects. Enkephalins, endorphins and dynorphins are found in the CNS and peripheral tissues and these endogenous opioid peptides serve as neurotransmitters, neurohormones, and neuromodulators

3. Specific receptors have been demonstrated that bind these peptides and also bind exogenous narcotic drugs. The opiate receptors are found on neurons in several brain areas including those in pain pathways and in the limbic system, which presumably mediates emotional aspects of pain sensitivity. It is believed that endogenous opiates are involved in the processing of pain sensations and other sensory information. It seems likely that narcotic drugs act, at least in part, by binding to opiate receptors, which are ordinarily activated by endogenous enkephalins and endorphins.
Opioid ReceptorsMu (the most important), kappa and delta
1. Mu activation includes analgesia, respiratory depression, euphoria and sedation
2. Kappa activation produces analgesia and sedation
3 Delta not really interacted with opioids

B. Classification of Drugs That Act at Opioid Receptors
1. Pure opioid agonistsActivate mu and kappa and divided into strong
opioid agonists (morphine) and moderate-to-strong opioid agonists
(codeine)
2. Agonist-antagonists opioidsFive are available (pentazocine, nalbuphine, butorphanol, dezocine, and buprenorphine); when administered alone, produce analgesia; but given to a person taking opioids, produce an antagonistic effect
3. Pure opioid antagonistsAntagonize mu and kappa receptors and are used for reversal of respiratory and CNS depression

B. Pharmacological Actions of Morphine

1. CNS
a) Analgesia
(1) Relatively selective effect on pain; other sensory modalities are not affected.
(2) Pain threshold -- effects not always consistent.
(3) Reduces the affective response to pain stimulation and increases pain tolerance without altering the threshold for perception of the stimulus.
b) Changes in mood; euphoria
c) Drowsiness
d) Pupillary constriction miosis
e) Depression of respiratory centers
(1) Decreased responsiveness to increases in CO2 concentration; also depresses centers involved in regulating rhythmicity.
(2) Primary cause of death from narcotic poisoning.
f) Depression of cough reflex center in the medulla.
g) Nausea and vomiting; from direct stimulation of chemoreceptor trigger zone (CTZ) for emesis in medulla.
h) Release of ADH with decreased urine output

2. Gastrointestinal tract
a) Used for relief of diarrhea
b) Delays passage of GI contents due to increase in tone and sphincter spasm.
c) Increase in biliary tract pressure; constricts sphincter of Oddi which prevents emptying and causes intraductal pressure to rise.

3. Other Smooth Muscle
a) Constricts urinary bladder sphincter.
b) Uterus -- large doses prolong labor, but mechanism is not clear.

4. Cardiovascular System
a) Postural hypotension due primarily to peripheral vasodilation.
b) Peripheral vasodilation -- depression of the medullary vasomotor center coupled with histamine release.
c) Cerebral circulation -- respiratory depression and CO2 retention result in cerebral vasodilation and an increase in CSF pressure.

5. Skin
a) Frequently becomes flushed and warm; pruritus; sweating.
b) Caused by cutaneous vasodilation due, in part, to histamine release.

C. Absorption, Distribution, Metabolism and Excretion

1. Narcotics are absorbed from gastrointestinal tract, the nasal mucosa, and after subcutaneous or intramuscular injection. With most, the effect of a certain dose is less after oral than after parenteral administration.

2. Narcotics, like most basic amines, are rapidly taken up from the blood into the liver, spleen, kidney and lung; they don't accumulate in tissues and only relatively small amounts cross the blood-brain barrier (Heroin is more lipid soluble than morphine and enters the brain more readily).

3. Morphine is inactivated by conjugation with glucuronic acid and N-demethylation; 90% of a dose is excreted within 24 hours, mostly via the urine although as much as 10% may be excreted in the feces from the bile.

D. Other Narcotics

1. Morphine-like
a) Meperidine (Demerolâ)-- therapeutic doses provide analgesia, euphoria, respiratory depression and other CNS effects comparable to morphine; shorter acting than morphine; less effect on smooth muscle.
b) Methadone (Methadoseâ)-- pharmacological properties qualitatively similar to morphine; longer duration of action, more effective orally; withdrawal has a slower onset, more prolonged.
c) OthersÞ fentanyl (Sublimaze) is used for induction and maintenance of anesthesia as
well as occasional analgesia
Hydromorphone (Dilaudidâ)

2. Codeine-like
a) Codeine -- has lower analgesic potency and lower addiction liability than morphine; very high oral efficacy.
b) d-Propoxyphene (Darvon) -- analgesia and CNS effects similar to those seen with
codeine and other opioids. Often combined with aspirin or acetaminophen.
Very weak analgesic properties. Used for dental procedures.
c) Hydrocodone (Vicodinâ)Þ highly abused
d) Oxycodone (Percodanâ, Percocetâ)

3. Others
a) Diphenoxylate -- prominent effect is constipation; shows typical opioid activity after chronic administration.
b) Dextromethorphan -- "non-narcotic" -- NO analgesic or addictive properties; about
the same as codeine for relieving cough, no gastrointestinal effects or sedation.
c) Tramadol (Ultram®) Analog of Codeine. MOA is via inhibition of reuptake of NE
and serotoninÞ leads to interference of pain transmission. Approved for use in USA
in 1995; currently unscheduled; for moderate-moderately severe pain; reported to be
'no more and sometimes less effective than combinations of codeine with aspirin or
acetaminophen' (The Medical Letter, 37:952, July, 1995).
d) Clonidine (Duraclonâ), administered by epidural infusion, also treats hypertension;
therefore, greatest concern is hypotension due to massive vasodilation; must assess
for infection from catheter placement

E. Clinical Use

1. Analgesia

2. Dyspnea -- e.g. left ventricular failure and pulmonary edema; morphine relieves vasoconstriction and reduces the sensation of air hunger (may indirectly reduce the work of the heart by reducing restlessness and fear).

3. Cough
a) Most effective antitussive agents; effect at doses lower than those needed for analgesia.
b) Codeine; dextromethorphan (non-narcotic; fewer side effects than codeine).

4. Diarrhea
a) Cause mild constipation; at dose below that required for analgesia.
b) Paregoric (camphorated opium tincture), codeine, diphenoxylate (Lomotil = diphenoxylate + atropine).

5. Long-action maintenance for narcotic addicts -- Methadone

6. Emetic
a) Apomorphine; morphine-like drug with low analgesic properties.
b) Since apomorphine causes respiratory depression, should be used with cautions with CNS depression.

F. Precautions and Contraindications

1. Head injury or conditions of increased CSF pressure; morphine induced respiratory depression and associated elevation of CSF pressure may be markedly exaggerated.
2. Conditions of decreased respiratory reserve (emphysema); asthmatic attack.
3. Treatment of chronic pain. There is the potential to develop physical dependence but this should not be a deterrent to administering the medication.
4. Severe hepatic or renal insufficiency.
5. Used with caution in patients with reduced blood volume; hypotensive effects also intensified by phenothiazines.
6. Pregnancy, labor and delivery, infants and elderly, patients with inflammatory bowel disease, those with prostatic hypertrophy due to urinary retention

G. Drug interactions
1. CNS depressants
2. Anticholinergic drugs
3. Hypotensive drugs
4. Monoamine oxidase inhibitors (the combination produces a syndrome of excitation, delirium, hyperpyrexia, convulsions, and respiratory depression)
5. Agonist-antagonist opioids, opioid antagonists, antiemetics of phenothiazines reduce nausea

H. Narcotic Antagonists

1. Agonist-antagonist agents.
a) Show morphine-like activity in narcotic-free subject but are non-constipating and produce dysphoria.
b) Withdrawal syndrome precipitated by removal of drug after chronic administration of high doses.
c) At small doses, immediately reverse all depressant effects of narcotics.
d) Agents
(1) Nalorphine (Nalline) -- given alone, it produces less respiratory depression and analgesia than morphine.
(2) Pentazocine (Talwin) -- possesses modern analgesic properties and weak antagonistic properties (l/50 potency of nalorphine). For mild to moderate pain, agonist at kappa receptors (get analgesia, sedation and respiratory depression), antagonist at mu receptors (get no euphoria; can get hallucinations, anxiety). If given to a person who is physically dependent on an opioid agonist, can precipitate abstinence syndrome
(3) Butorphanol (Stadol) -- has strong analgesic properties and low addictive and abuse liability but only used parenterally. Popular postoperative pain medication

2. Pure Antagonist
a) Naloxone (Narcan)
b) Chronic use and abrupt withdrawal of naloxone doesn't produce a noticeable
withdrawal.
c) 10-30% as potent as nalorphine.
d) Preferred for mixed poisoning cases since it lacks agonistic activity.

3. Clinical use of narcotic antagonists
a) Treatment of acute narcotic poisoning.
b) Treatment of neonatal respiratory depression secondary to administration of narcotics to mother.
c) Analgesia; Pentazocine and butorphanol.
d) Detection of narcotic use.

I. Tolerance, Physical Dependence and Withdrawal Symptoms

1. Tolerance
a) With repeated doses, the dose must be increased to produce the same effect.
b) High degree of tolerance to respiratory depression, analgesia, sedation, emesis and euphoria.
c) Tolerance doesn't develop equally or at same rate to all effects; miosis and constipation occurs even in users that are highly tolerant to other effects.
d) Most of the tolerance results from adaptation of cells to the drug's action.
e) Cross-tolerance between the different narcotic analgesics.

2. Physical dependence; altered physiological state produced by the repeated administration of a drug, which necessitates the continued administration of the drug to prevent a characteristic withdrawal syndrome.

3. Withdrawal symptoms; severity depends upon the particular drug, total daily dose, interval between doses, duration of use, health of individual, etc.

CASE STUDY

Ms. L.W. is a 35-year-old who had an abdominal hysterectomy this AM. She is ordered morphine IV, via patient-controlled analgesia (PCA) pump for her postoperative pain. The pump is set to deliver 1 milligram of morphine per injection and up to a maximum of 5 milligrams per hour. She is awake and occasionally moans, complaining of pain.

1. Ms. L.W. asks you if the morphine will make all of her pain go away. As Ms. L.W.s nurse, you would respond how?

ANSWER:

2. How do you assess the adverse effects that may be experienced when using opioids?

ANSWER:

3. Ms. L.W. is resting very quietly now. You check to see how she is responding and find that her respiratory rate is 8/ minute. What would you do?

ANSWER:

4. Describe how to document the patients change in pain status?

ANSWER:

5. The PCA pump has been terminated. However, the patient complains of severe pain. The physician has order 4 milligrams of morphine IV. The tubex comes with 10 milligrams/ml in it. How many ml will you administer to Ms. L.W.? If any medication is left over, what will you do with it?

ANSWER:

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