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Opioid Agonists & Antagonists (■ BASIC PHARMACOLOGY OF THE OPIOIDS…
Opioid Agonists & Antagonists
■ CLINICAL PHARMACOLOGY OF THE OPIOID ANALGESICS
Clinical Use of Opioid Analgesics
A.
Analgesia: Severe, constant pain
u relieved w/ opioid analgesics having high intrinsic activity, whereas
sharp, intermittent pain not as effectively controlled
C. Cough: expectorant codeine, Dextromethorphan (shouldn't be used too much)
D.
Diarrhea: diphenoxylate (has some atropine (antispasm)) or loperamide
B.
Acute Pulmonary Edema: pulmonary edema a. w/ left ventricular heart failure
E. Shivering
F.
Applications in Anesthesia: frequently used as premedicant drugs before anesthesia and surgery because of their sedative, anxiolytic, and analgesic properties
G. Alternative Routes of Administration
Toxicity & Undesired Effects
B. Diagnosis and Treatment of Opioid Overdosage:
dx
triad
pinpoint miosis
severe resp depression
high grade coma
IV naloxone
dramatically reverses coma due to opioid overdose;
half life short--> repeatedly inject
A. Tolerance and Dependence: NMDA Rs seem to be involved
C. Contraindications and Cautions in Therapy
Drug Interactions
enhance CNS depressants' effects
■ SPECIFIC AGENTS
AGONISTS
STRONG: cause tolerance from first dose
Morphine: u IV
Methadone: as strong as morphine but much longer half-life; used in quitting
Phentanyl: 10x stonger than morphine, only IV
Heroine: much more addictive than the rest
Meperidine
MODERATE
Codeine
and hydrocodone
MILD
Propoxyphene
MIXED RECEPTOR ACTIONS
buprenorphine: partial μ agonist + antagonist at κ
Pentazocine: strong κ agonist + a partial μ antagonist; less dependency and tolerance
ANTAGONISTS
Naloxone: IV
Naltrexone: oral; long half-life; not used in overdose; used when quitting
MISCELLANEOUS
Tramadol: block serotonin and norepinephrine reuptake
■ BASIC PHARMACOLOGY OF THE OPIOIDS
Source: Opium obtained from
Papaver somniferum
: incision--> poppy seed pod exudes white substance that turns into a brown gum: crude opium:
contains many alkaloids: morphine
Classification & Chemistry
natural: morphine, codeine
synthetic: meperidine, methadone
semisynthetic: from opium but doesn't have effects
Endogenous Opioid Peptides: Three families: endorphins,
enkephalins, dynorphins
;
also sedative, but short half-life
Pharmacokinetics of Exogenous Opioids
A. Absorption:
Most well absorbed when oral
routes; but
bc of first-pass effect, oral dose
to elicit a therapeutic effect may need to be
much higher than parenteral
ex
morphine and heroine
codeine
,
methadone
and oxycodone
effective orally bc they have reduced first-pass metabolism
B. Distribution: can
pass BBB and placenta
C. Metabolism: converted in large part to polar metabolites (
mostly glucuronides), then readily excreted by kidneys.
D. Excretion
Pharmacodynamics
A. Mechanism of Action
bind to specific
G pr-coupled Rs (esp K+ channels)
--> hyperpolarize and thus inhibit
postsynaptic
neurons;
presynaptic
action—depressed transmitter release—[glutamate, acetylcholine, norepinephrine, serotonin,] and
substance P
three major classes of opioid Rs (μ, δ, and κ); μ1 more in brain, μ2 more in spinal cord
important sites: periaqueductal gray, some thalamic-hypothalamic nuclei, limbic, cortex
B. Organ System Effects
1. Central nervous system effects
f. Miosis—Constriction of pupils seen w/ virtually all (although meperidine less); reversed by naloxane, atropine
g. Truncal rigidity
e. Cough suppression— Codeine in particular
h. Nausea and vomiting— activate brainstem chemoreceptor trigger zone; esp in first use, tolerance u developed
d.
Respiratory depression: may be well tolerated in px w/o prior respiratory impairment
. However in
incr ICP, asthma, overdosage-->may be significant
i. Temperature
c.
Sedation
j. Sleep architecture
b.
Euphoria
a. Analgesia— can reduce both emotional and sensory aspects of pain experience
Peripheral effects
a. Cardiovascular system:
incr in ICP
e. Uterus— may prolong labor; inhibit uterine contractility
f. Endocrine
d. Renal
g. Pruritus
c. Biliary tract—contract biliary smooth muscle--> biliary colic
but used in biliary colics w/ higher doses
h. Immune
b. GI tract—Constipation; resting tone incr, contractions markedly decr