Pharmacology Opioidanalgesics

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pharmacologynotes

MauChuaPHARMACOLOGY S.Y. 2011-2012

PIOID ANALGESICS & ANTAGONISTS

OPIOID ANALGESICS &ANTAGONISTS

Dr. George Firmalino

I. BASIC PHARMACOLOGY

SOURCEo opium from plant PAPAVER SOMNIFERUM

o opium has 20 ALKALOIDS

o ANALGESIC morphine, codeine

o NON-ANALGESIC thebaine, papaverine

MORPHINE - principal alkaloid of opium ( 10 % )

from w/c codeine (0.5 %) is synthesized

HEROIN - derived from morphine during acetylation

of hydroxyl group, penetrates blood brain barrier

more than morphine

THEBAINE

o precursor of several semisynthetic agents

ETHORPHINE a veterinary agent 500

1000 x as potent as morphine

NALOXONE an opiate antagonist

PAPAVERINE - a vasodilator w/ no clinical

application but led to the development of

VERAPAMIL a calcium channel blocker

antihypertensive

CLASSIFICATION

o FULL AGONIST (morphine) - strong agonist

o PARTIAL AGONIST (codeine) - produce agonist

effect, may displace other full agonist in binding

sites & reduce their effect (antagonist effect)

o MIXED AGONIST / ANTAGONIST (nalbuphine) -

when one opioid has agonist effect on one

receptor & antagonist effect on another receptor

o ANTAGONIST - binds to receptor site w/o producing

effects associated w/ agonist (like naloxone)

CLASSIFICATION BASED ON CHEMICAL STRUCTURE & MAIN

EFFECT

STRUCTURESTRONG(FULL)

AGONIST

MILD / MOD(PARTIAL)AGONIST

MIXEDAGONIST -

ANTAGONISTANTAGONIST

PHENANTHRENES morphinehydromorphoneoxymorphone

codeineoxycodonehydrocodone

nalbuphine nalorphinenaloxonenaltrexone

PHENYLHEPTYLAMINES methadone propoxyphene buprenorphine

PHENYLPIPERIDINES meperidinefentanyl

diphenoxylate

MORPHINANS levorphanol butorphanol levallorphan

BENZOMORPHAN pentazocine

CLASSIFICATION BASED ON SOURCE

A. NATURAL OPIUM ALKALOIDS

morphine, codeine, papaverine

B. SEMISYNTHETIC

heroin, oxycodone, hydrocodone,

oxymorphone

C. SYNTHETIC methadone, meperidine, fentanyl,

propoxyphene

OPIOIDS USED AS ANTITUSSIVE

Codeine

Dextromethorpan

Hydrocodone

Hydromorphone

Levopropoxyphene

Noscapine

ENDOGENOUS OPIOID PEPTIDES --- present in CNS w/

opioid-like analgesic pharmacologic properties &

function like a neurotransmitter

o PENTAPEPTIDES

o methionine-enkephalin, leucine-enkephalin

o 3 PRECURSORS

o propio melano cortin (pomc), pro-enkephalin

(pro enkephalin-a), pro-dynorphin (pro-

enkephalin-b)

o POMC CONTAINSo met enkephalin, beta endorphin, non opioid

peptides (acth, lipo proteins, melanocytestimulating hormone)

o PRO ENKEPHALIN-A CONTAIN

o met enkephalin, leu enkephalin

o PRO DYNORPHIN CONTAIN

o dynorphin-a, dynorphin-b, & neo

endorphins

PHARMACOKINETICS

A. ABSORPTION

o subcutaneous, im, iv, intra-spinal, mucus,

transdermal (like fentanyl), git (subject to first

pass metabolism in the liver by glucorinidation

o high dose is required to produce the desired

therapeutic analgesic effect

B. DISTRIBUTION

a. rapidly leaves the blood

b. concentrate in lungs, liver, kidneys, spleen

c. in muscles has lower concentration but

has greater bulk & acts as the main

reservoir

d. in fat also a reservoir for lipophilic opioid

like fentanyl

e. brain low conc. due blood-brain barrier


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MORPHINE - cross the blood-brain barrier less

readily

HEROIN & CODEINE - cross the blood-brain

barrier more readily

neonates has no blood-brain barrier thus makes

them prone to respiratory depression when an

opioid is given during labor where drugs crossthe placenta & into the brain

C. METABOLISM

o compounds w/ free hydroxyl like morphine &

levorphanol are readily conjugated w/

glucoronic acid

o ester compounds like heroin & remifentanyl

are rapidly hydrolyzed by common tissue

esterases

O heroin (a diacetylmorphine) is hydrolyzed to

monoacetylmorphine & finally to morphine w/cis then conjugated w/ glucoronic acid in the

liver

this morphine 6 glucoronide was

thought to be inactive but actually

produces more profound analgesia if

accumulated in cases of renal failure

D. EXCRETION - mainly in the kidneys

PHARMACODYNAMICS

A. MECH OF ACTION - binds to specific receptor site inbrain & spinal cord regions involved in transmission &

modulation of pain

1. RECEPTOR TYPES - (mu), (delta), (kappa)

RECEPTOR SUBTYPE ACTIVITY OF OPIOIDS

RECEPTOR SUBTYPE

DRUG MU DELTA KAPPA

ENDOGENOUS

OPIOID

PEPTIDES

ENKEPHALINS Agonist agonist

ENDORPHINS Agonist agonistDYNORPHINS Weak agonist agonist

AGONISTS CODEINE Weak agonist weakagonist

ETORPHINE Agonist agonist agonist

FENTANYL Agonist

MEPERIDINE Agonist

METHADONE Agonist

MORPHINE Agonist weak

agonist

weak

agonist

AGONIST-

ANTAGONISTS

BUPRENORPHINE partial agonist

DEZOCINE partial agonist

NALBUPHINE Antagonist agonist

PENTAZOCINE antagonist or

partial agonist

agonist

ANTAGONISTS NALOXONE Antagonist antagonist antagonist

2. RELATION OF PHYSIOLOGIC EFFECTS TO

RECEPTOR TYPES

a. MU RECEPTOR - target of morphine in

brain, produces typical agonist effect

(analgesia, euphoria, respiratory

depression, physiologic dependence

b. DELTA & KAPPA RECEPTORS - also

contribute to analgesia at spinal cord level

3. CELLULAR ACTION

a. 2 direct actions to neurons

- Close a voltage-gated Ca channel on pre-

synaptic nerve terminals & thereby transmitter release (like acetylcholine,

norepinephrine, glutamate, serotonin,

substance-P)

- They hyperpolarize & thus inhibit post

synaptic pain transmission neurons by

opening K+

channels at mu receptors

4. RECEPTOR DISTRIBUTION & NEURAL

MECHANISMS OF ANALGESIA

- Receptors are present in dorsal horn of spinal

cord pain transmission neurons & on the

primary afferents that relay message to the

dorsal horn

- Opioid agonist inhibit the release of excitatory

transmitter from these primary afferents &directly inhibit the dorsal horn pain

transmission neuron

- Thus, opioids exert a powerful analgesic effect

directly upon the spinal cord by direct

application (as in spinal anesthesia + morphine)

w/c provides regional analgesic effect w/o

respiratory depression, nausea, vomiting &

sedation noted w/ supra-spinal actions w/

systemic drugs

- systemic drugs generally act on both spinal &

supraspinal sites, thus increasing overall

analgesic effect

- Exogenous opioids (like morphine) act

primarily & directly at mu receptors but this

action may evoke the release of endogenous

opioids that additionally act at delta & kappa

receptors

5. TOLERANCE & PHYSIOLOGIC DEPENDENCE

a. TOLERANCE - gradual loss of effectiveness

of an opioid w/ frequently repeatedadministration, to reproduce the original

effect, the dose must be b. PHYSIOLOGIC DEPENDENCE - occurrence of

a characteristic WITHDRAWAL or

ABSTINENCE SYNDROME when the drug is

stopped or an antagonist is given,

mechanism is unknown

B. ORGAN SYSTEM EFFECTS OF MORPHINE

A. CNS at mu receptors

1. ANALGESIA - both sensory & affectivecomponents of pain are affected

2. EUPHORIA -a pleasant floating sensation &

freedom from anxiety & distress noted by

patients in pain or by addicts, other patients or

normal subjects may experience Dysphoria

(restlessness & a feeling of malaise, nausea &

vomiting)


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3. SEDATION - drowsiness & clouding of

mentation, little or no nausea, deep sleep if

taken w/ sedative hypnotic drugs, marked

sedation w/ phenanthrene (like morphine &

hydromorphone), less sedation w/ synthetics

(like meperidine, fentanyl)

4. RESPIRATORY DEPRESSION - secondary to

inhibition of the brain stem respy mech. (pCO2

but w/ response), dangerous for patientsw/ ( intracranial pressure, asthma, COPD, corpulmonale

5. COUGH SUPPRESSION - esply codeine, only for

pathologic dry cough, dangerous (may lead to

accumulation of secretions & atelectasis),

tolerance may develop

6. MIOSIS - constriction of pupils, no tolerance

develops (valuable in diagnosis of opioid

overdose), blocked by antagonist, mediatedthru parasympathetic (may be blocked by

atropine)

7. TRUNCAL RIGIDITY - supraspinal effect

(interfere w/ respiration), noted in high doses

of lipid soluble opioids (fentanyl, sulfentanyl,

alfentanyl) if given rapid IV

8. NAUSEA / VOMITING - effect on brain stem

chemoreceptor & on vestibular area on

ambulation

B. PERIPHERAL EFFECTS1. CVS bradycardia, hypotension (arterial &

venous dilatation)

2. GIT - stomach ( motility, tone, HClsecretion), small & large intestine ( motility, tone, peristalsis, passage of stool, waterabsorption, constipation), benzomorphans like

pentazocine has less constipation than others

3. Biliary tract - constricts smooth muscle (colic),

Sphincter of Oddi constricts (reflux of bile &pancreatic secretions into circulation plasmaamylase & lipase )

4. GUT - renal fxn, ureter & bladder tone(colic & retention)

5. Uterus - tone (prolonged labor)

6. Neuroendocrine (hypothalamus) - release of:

(ADH, prolactin, somatotropin), inhibit release

of: (luteinizing hormone)

7. Miscellaneous - histamine release (flushing &

warming of skin, sweating, itching), modulate

immune system (lymphocyte proliferation,

antibody production, chemotaxis)

C. EFFECTS OF MIXED AGONIST ANTAGONIST- ex pentazocine

- produce sedation & analgesia

- high dose sweating, dizziness nausea, vomiting,

respy depression (less severe as w/ pure agonist)

- respy depression is reversed by naloxone but not by

another agonist-antagonist like nalorphine

- may cause psychoto-mimetic effect: hallucination,

nightmares, anxiety

II. CLINICAL PHARMACOLOGY

CLINICAL USE OF OPIOID ANALGESIC

ANALGESIA

Severe constant pain is relieved BUT

sharp, intermittent & colicky pain is

not

Pain of terminal cancer should be

relieved & fear of tolerance &

dependence should be set aside

Regular dose at regular time is more

effective than whwen given on

demand

Stimulant drugs like amphetamine may

enhance analgesia & is thus useful as

adjunct for chronic pain

For obstetric labor pain,

phenylpiperidines (like Meperidine) is

the choice since it causes less respy

depression for the infant. Should ithappen, the antagonist Naloxone is

given

Renal & biliary colic may cause a

paradoxical in pain in dose may provide

adequate analgesia

ACUTE PULMONARY EDEMA

relieves pain of dyspnea assd w/ left

ventricular failure

preload ( w/ in venoustone )

afterload ( w/ peripheralresistance)

perception of dyspnea & anxiety (affective

component)

COUGH

Use of opioids as antitussive agent has

been replaced by non-opioid & non-

addicting agents like: carbetapentane,

caramiphen, chlophedianol,

diphenhydramine, glaucine

DIARRHEA

Opioids such as crude opium or

paregoric stops peristasis but they

must not be used infectious diarrhea

since retention of the bacteria will

worsen the infection


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Presently, synthetic ones replaced it

w/ less CNS effects like

phenylpiperidine (diphenoxylate)

ANESTHESIA

As pre-op meds sedative, anxiolytic,

analgesic For post-op analgesia epidural or

subarachnoid morphine 3-5 mg

gives long lasting effect

TOXICITY & UNDESIRED EFFECTS

A. TOLERANCE & DEPENDENCE

a. Tolerance

- Develops usually 2-3 wks after usual

frequent therapeutic dose- Readily develops w/ large dose at short

interval

- Usually in analgesia, euphoria, respy

depression, antidiuresis, emetic &

hypotensive effects

- Not noted in: miosis, convulsion,

constipation

- Tolerance to methadone develops slowly

than w/ morphine

- Cross tolerance is possible due to similar

mu receptor site effect between:

morphine, meperidine, methadone

- Tolerance to euphoria & respy depression

dissipates w/in a few days after stopping

the drug

- But tolerance to emetic effect persist for

months

- Tolerance does not develop to the

antagonistic action of agonist-antagonists

group nor to those of pure antagonists

b. Physiologic dependence

- Accompanies tolerance due to repeated

use

- Stopping the drug causes withdrawal orabstinence syndrome (rebound from the

effects of the drug)

- S/S rhinorrhea, lacrimation, yawning,

chills, gooseflesh (piloerection),

hyperventilation, hyperthermia, mydriasis,

muscle aches, vomiting, diarrhea, anxiety,

hostility

c. Toxic effects

- Common S/S dysphoria (behavioral

restlessness, tremulousness, hyperactivity),

respy depression, nausea & vomiting,increased intracranial pressure, postural

hypotension, constipation, urinary

retention, itchiness, urticaria

- TIME

MORPHINE & HEROIN - toxic effects start

6-10 hrs after the last dose, peaks in 36

48 hrs, disappears in 5 days, some s/s may

persist for months

MEPERIDINE - withdrawal syndrome

subside w/in 24 hrs.

METHADONE - peaks in several days, last

for 2 wks, its slow subsidence makes it a

choice in detoxification of heroin addicts

ANTAGONIST PRECIPITATEDWITHDRAWAL - transient, explosive

abstinence syndrome is noted when an

antagonist like naloxone is given to an

opioid dependent w/in 3 min. of injection,

peaks in 10 n- 20 min, subsides in 1 hr.

d. Psychologic dependence

- Euphoria, indifference to stimuli &

sedation tends to promote compulsive

use

- Especially the abdominal effects

likened to an intense sexual orgasm- This makes the abuse liability of

opioids very high & the individual

rationalize that if he stops using the

drug, withdrawal symptoms will follow

B. DIAGNOSIS & TREATMENT OF OVERDOSE

TOXICITY

a. Diagnosis - needle marks, miosis, S/S - already

mentioned, coma

b. Treatment - naloxone 0.2 0.4 mg IV will

reverse the coma secondary to opioid overdose

but not if caused by other CNS depressants

C. CONTRAINDICATIONS & CAUTIONS IN THERAPY

o Use of pure agonist w/ mixed agonist-

antagonist

o Giving Pentazocine ( a mixed agonist-

antagonist ) to a patient already using morphine

( a pure agonist ) may analgesic effect ofmorphine or induce withdrawal syndrome

o W/ head injuries - CO2 retention cause morerespy depression w/ cerebral vasodilatation &

further in ICP

o In pregnancy -if mother is an addict, consider

withdrawal syndrome in baby upon delivery

o W/ impaired pulmonary function - respy

depression may lead to respy failure

o W/ impaired hepatic & renal function - opioid

metabolites may accumulate in patients w/ liver

& kidney failure

o W/ endocrine disease - patients w/

hypothyroidism & adrenal insufficiency

(Addisons disease) may have prolonged &

exaggeratedn response to opioids


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DRUG INTERACTION W/:1. SEDATIVE HYPNOTICS - CNS depression,

particularly respy depression

2. ANTIPSYCHOTIC TRANQUILIZERS - sedation & respy depression, accentuation

of cardiovascular effects (antimuscarinic

actions, alpha blocking actions)

3. MAO INHIBITORS (ANTIDEPRESSANTS) -

relative contraindication to all opioids

because of the high incidence of

hyperpyrexic coma & hypertension

SPECIFIC AGENTS

A. STRONG AGONIST

A. PHENANTHRENES

o

Strong analgesics morphine,hydromorphone, oxymorphones,

heroin

B. PHENYLHEPTYLAMINES

o Methadone - similar to morphine,

longer acting, reliable even orally,

tolerance & dependence develops

slowly, withdrawal symptoms are

mild but more prolonged, useful

for detoxification of heroin addicts

(dose 5-10 mg oral, 2-3x / day

for 2-3 days)

o Levomethadyl acetate (L-

acetylmethadol) - longer half-life

than methadone, for detoxication

(given once every 2-3 days)

C. PHENYLPIPERIDINES

1. Meperidine - has antimuscarinic effect,

w/ negative inotropic effect, seizures

develops if retained & increased due to

renal failure

2. Fentanyl

a. Sufentanil 5 to7x more

potent than fentanyl

b. Alfentanil - less potent than

fentanil, rapid onset, short

duration

c. Remifentanil - rapidly

metabolized by tissue

cholinesterase, extremely

short half life

D. MORPHINANS

o Levorphanol - synthetic analgesic,

may have less nausea & vomiting,

less effective orally

B. MILD TO MODERATE AGONISTA. PHENANTHRENES

o Samples codeine, oxycodone,

dihydrocodeine, hydrocodone

o Characteristics - less efficacious

than morphine, adverse effect

may develop if dose is toachieve analgesia

o Present use - combined w/ aspirin

or acetamenophen at a low safe

dose

B. PHENYLHEPTYLAMINES1. Propoxyphene - related to methadone

but has low analgesic properties, w/

low abuse potential, not suitable as

analgesic even if combined w/ aspirin

C. PHENYLPIPERIDINES

1. Diphenoxylate (Schedule V), Difenoxin

(Schedule IV)

a. Not used for analgesia

b. Used to treat diarrhea in

combination w/ atropine

2. Loperamide - low abuse potential,antidiarrheal w/ limited access to brain

C. MIXED AGONIST-ANTAGONISTA. PHENANTHRENES - caution w/ patients

taking a pure agonist (may analgesia, maycause explosive withdrawal syndrome)

1. Nalbuphine (Nubain) - strong kappa

receptor agonist but a mu receptor

antagonist, may cause respy

depressionthat is resistant to Naloxone

reversal

2. Buprenorphine - long acting, partial

mu receptor agonist, resistant to

naloxone reversal, may be used for

detoxification of heroin addicts

B. MORPHINANS

1. Butorphanol - produce analgesia

similar to nalbuphine but has more

sedation, kappa agonist

C. BENZOMORPHANS

1. Pentazocine - kappa agonist, weak mu

antagonist, oldest mixed agonist-

antagonist, oral/parenteral, not

recommended for subcutaneous

injection (its an irritant)

2. Dezocine - high sffinity for mu

receptor, less affinity for kappa

receptor, analgesia similar to morphine

D. MISCELLANEOUSA. Tramadol synthetic, weak mu agonist,

inhibitory to norepinephrine, serotonin

reuptake in CNS, weak analgesic similar to

propoxyphene, partially antagonized by

naloxone


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E. ANTITUSSIVEA. Opioids have good antitussive effect even

at low doses below analgesia

B. OPIOID DERIVATIVE

o Dextromethorphan - free of analgesic

properties & of addictive effect, less

constipation

o Codeine - useful antitussive at low dose

below analgesia

o Levopropoxyphene - devoid of opioid

analgesic effects, still has sedative

effects

o Noscapine - naturally occurring, no CNS

analgesic effect, potent releaser of

histamine (causes bronchoconstriction

& transient hypotension)

C. Use w/ caution on patients taking MAO

inhibitors (antidepressants)

F. OPIOID ANTAGONISTA. Site of action - Binds w/ mu receptors &

also reverses agonist effects at kappa &

delta receptor sites

B. Morphine derivatives Naloxone,

Naltrexone, Nalmefene

C. Pharmacokinetics

o Naloxone - poor effect if given oral

due to first pass metabolism in liver,

short duration after injection, half life

10 hrs, single oral dose of 100 mg

will block effects of heroin injection

for 48 hrs

D. Pharmacodynamics

o When given in the absence of an

agonist drug, it has no effect

o When given IV to a morphine treated

patient, the antagonist effect willcompletely reverse the opioid effect

of morphine w/in 1-3 minutes

o In patients w/ opioid overdose, it will

normalize (respiration, level of

cosciousness, pupil size, bowel

activity)

o In patients taking an opioid but

appear normal, will trigger an

explosive withdrawal symptoms

o There is no tolerance to antagonist

effect nor withdrawal symptoms

develop if treatment is stopped

E. Clinical use

o Naloxone - pure antagonist,

treatment of acute opioid overdose,

short acting, 0.1-0.4 mg IV may

reverse the toxicity, but 1-2 hrs after,

relapse may occur, repeat dose may

be necessary

o Nalorphine - weak agonist-

antagonist, used as an antagonist

o Naltrexone - long acting, used as

maintenance for treatment programs

for addicts, given every other day,

may be used also to treat alcohol

withdrawal syndrome.

Pharmacology Opioidanalgesics

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