B5-Pharmacology

Faller, Paul Jerome; Feliciano, Daniel Dennison; Flores, Ciara Joyce;

Flores, Kathleen Joy; Fortuno, Julius Henry; Fuentes, Malou;
Gabaton, Niña; Gallardo, Sheila; Ganal, Jonathan; Garcia, Ma. Irka;
Gaspar, Irish Vanessa; Gatchalian, Cheryll; Generillo, Arvin;
Glorioso, Anna Ma. Jolina; Go, Ferranti; Go Ricci Gayle

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Objectives
General Objective: To determine the drug
interaction that exists between morphine
and nalbuphine

Specific Objective: To compare the

duration of the mouse tail erection with
morphine alone and with morphine
followed by nalbuphine

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Materials
Animals:
8 mice of the same sex and approximate
weight (32 mice used for the whole 2nd
year batch)
Instruments:
Animal weighing scale
Tuberculin syringe
Animal cage
Asbestos gloves
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Materials
Drugs:
Morphine
Prep : 10 mg/mL (1%)
Inject: 0.5 mL/20 g mouse

Nalbuphine
Prep : 10 mg/mL (1%)
Inject: 0.1 mL/20 g mouse

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Methodology
1. Assign the mice randomly and equally into 2
groups: Morphine and Morphine +
Nalbuphine.
2. Inject Morphine intraperitoneally to each
mouse based on the dose computations.
3. Observe for erection of the tail (90˚ angle).
4. Upon erection of the tail, inject Nalbuphine
intraperitoneally to all the mice of the
Morphine + Nalbuphine group based on
dose computations.
5. Compare the duration of tail erection 8
Inject the
mice
intraperitonea
lly
Rationale for Procedures
Mice of the same sex with similar weights
were assigned into two (2) groups.

 Rationale:
 To ensure precision and accuracy of obtained
data
 For easier calculation and preparation of
appropriate drug dosage
 To eliminate the effects of body weight and
sex on the pharmacokinetic and
pharmacodynamic parameters of each drug.

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Rationale for Procedures
1) Morphine Group:
Tx: Morphine
Morphine-Nalbuphine Group:
Tx: Morphine +Nalbuphine

 Rationale:
 Two groups were used to facilitate
comparison of the effect of morphine alone &
morphine-nalbuphine drug interaction.

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Rationale for Procedures
1) 1% Morphine solution (0.5 mL / 20 g mouse)
was injected intraperitoneally to all of the
mice.

 Rationale:
 Intraperitoneal injection for wider diffusion of
the drug

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Rationale for Procedures
1) When the tail was observed as erect, the
mice in the Morphine-Nalbuphine group
were injected with 1 % Nalbuphine (0.1 mL /
20 g mouse).

 Rationale:
 Morphine-induced tail erection (MITE) or
Straub tail is a marker indicating that
morphine has taken its effect.
 Tail erection was recorded when the tail rose
to an angle of 90˚relative to the plane of the
mouse body.
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
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 Morphine   Morphine with Nalbuphine
Mouse duration of tail Mouse duration of tail
weight (g) weight (g)
erection (s) erection (s)
A1 ≈ 20.00 1849.00 A5 ≈ 20.00 1690.00
A2 ≈ 20.00 1598.00 A6 ≈ 20.00 382.00
A3 ≈ 20.00 2010.00 A7 ≈ 20.00 316.00
A4 ≈ 20.00 1717.00 A8 ≈ 20.00 289.00
B1 23.50 3475.00 B5 24.00 3371.00
B2 23.00 1873.00 B6 22.50 1630.00
B3 21.00 2268.00 B7 21.50 1931.00
B4 20.50 2074.00 B8 21.00 1683.00
C1 23.30 564.00 C5 23.30 343.00
C2 20.09 1499.00 C6 20.90 819.00
C3 20.00 1478.00 C7 20.03 786.00
C4 19.80 1653.00 C8 19.50 1398.00
D1 29.20 845.00 D5 29.20 353.00
D2 28.10 1535.00 D6 28.80 900.00
D3 28.10 450.00 D7 27.20 1176.00
D4 26.50 981.00 D8 24.20 1440.00
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 Duration of Tail Erection in Morphine and Morphine-Nalbuphine Groups

4000.00
Morphine
3500.00
Morphine and
Nalbuphine
3000.00
Duration (in seconds)

2500.00

2000.00

1500.00

1000.00

500.00

0.00
A1/A5 A2/A6 A3/A7 A4/A8 B1/B5 B2/B6 B3/B7 B4/B8 C1/C5 C2/C6 C3/C7 C4/C8 D1/D5 D2/D6 D3/D7 D4/D8

Mouse
Results
Morphine with 
Descriptive Statistics Morphine Overall
Nalbuphine
Mean 1616.81 1156.69 1386.75
Standard Deviation 724.86 821.06 796.92

T-test for Independent groups
t critical 2.042 two-tailed
1.697 one-tailed
t value 1.680
 
α level 0.050
p value 0.103

The t and p value were both not significant.

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Results
In general, there was a decrease in the duration
of tail erection in the Morphine-Nalbuphine
group.
Only D3-D7 and D4-D8 mice pairs exhibited a
different result.
There was no significant difference in the tail
erection duration between the two groups.
Results
Sources of error:
Technique of drug administration
Different indications for tail erection and drug
administration among experimenters
Accuracy of time measurement and dose
computation
Level of expertise
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Agonist
bind to and activate the receptor which
directly or indirectly brings about the effect

1. Full Agonist- is able to elicit a maximal

response following receptor occupation and
activation
2. Partial Agonist – produces a lower
response, at full receptor occupancy, than
do full agonists

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Antagonism
the process of inhibiting or preventing an
agonist-induced receptor response

Based on the kinetics of interaction of the

antagonist with the receptor, antagonism is
classified as competitive and non-competitive.

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Antagonism
1. Competitive Antagonist
- competes with agonists for receptors
- when the receptor is occupied by the
antagonists, agonist cannot bind to the receptor

5. Noncompetitive Antagonist
- binds to the site other than the agonist binding
domain
- induces a conformational change in the receptor
such that the agonist no longer recognizes the
agonist binding domain

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Opioid Analgesics
Act on the opioid receptors in
the nervous system
Used to relieve moderate to
severe pain
Has antitussive, constipating
actions
Can cause respiratory
depression 27
Opioid Receptors
 three opioid receptors: μ, κ, δ
Mu (µ)
o Analgesia, drowsy, euphoria and respiratory depression
o Subdivided into µ1 and µ2: µ1 responsible for analgesia
o Most clinically useful drugs act: Morphine
Kappa (k)
o analgesia, sedation, limited respiratory depression and
some dysphoria.
o high affinity as agonists of k receptors
o act as µ receptor antagonists
o Example: Nalbuphine
Delta (d)
o endogenous opioids particularly the enkephalins
o but no drugs exist that act exclusively through this
receptor.

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Classification of Opioid
Analgesics
1. Full Agonist – ex. Morphine
2. Weak Agonist – ex. Codeine
3. Mixed agonist-antagonist – ex. Nalbuphine,
Pentazocine, Butorphanol
4. Pure Antagonist - Naloxone

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Morphine
• highly potent opiate
analgesic
• derived from the opium
poppy
• Classification:
phenanthrene
• full agonist
• Highly addictive and
tolerance occur rapidly
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Mechanism of Action
 Produce analgesia: binding to specific G protein-coupled
receptors in the brain and spinal cord regions involved in
pain transmission and modulation
 Acts specifically on: μ receptors
 Two established G protein-coupled actions:
o close Ca2+ channels: reduce transmitter release
o open K+ channels: hyperpolarize and inhibit
postsynaptic neurons
 Opioid agonists
o inhibit the release of excitatory transmitters from the primary
afferents
o directly inhibit the dorsal horn in pain transmission

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Pharmacokinetics
 Absorption: SC, IM, and oral routes
 Distribution:
o High: brain, lungs, liver, kidneys and spleen
o Low: skeletal muscle
o may accumulate in fatty tissue
 Metabolism:
o primarily conjugated: morphine-3-glucuronide
o 10% is metabolized to morphine-6-glucuronide
o these metabolites do not readily pass the BBB
 Excretion
o primarily in the urine
o small portion in the enterohepatic circulation (bile)

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Clinical Use
 Analgesia
 Acute pulmonary edema
o mechanism: reduces anxiety (perception of shortness of
breath), reduced cardiac preload (reduced venous tone),
reduced afterload (decreased peripheral resistance)
 Cough
 Diarrhea
o controlling diarrhea but not in treating infection
 Shivering
 Anesthesia
o premedicant drugs prior to surgery
o also used as regional analgesics (epidural administration)

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Contraindications
Tolerance
Withdrawal syndrome
Use in patients
o with head injuries: increase ICP
o during pregnancy: fetus may become dependent in utero
o with impaired pulmonary function: acute respiratory
failure
o with impaired hepatic or renal function
o with endocrine diseases: prolonged and exaggerated
responses

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Nalbuphine
synthetic narcotic
agonist-antagonist
analgesic of the
phenanthrene
series.
strong kappa
agonist and a mu
receptor
antagonist
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Nalbuphine
CNS
Nervousness, depression, restlessness, crying,
euphoria, floating, hostility, unusual dreams,
confusion, faintness, hallucinations, dysphoria,
feeling of heaviness, numbness, tingling, unreality.
Psychotomimetic effects: unreality,
depersonalization, delusions, dysphoria and
hallucinations

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Nalbuphine
CARDIOVASCULAR
Hypertension, hypotension, bradycardia,
tachycardia, pulmonary edema.
• GASTROINTESTINAL
-- Cramps, dyspepsia, bitter taste
• RESPIRATION
-- Depression, dyspnea, asthma
• DERMATOLOGICAL
 Itching, burning, urticaria

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Morphine + Nalbuphine
MORPHINE
Full agonist

NALBUPHINE
primarily a kappa agonist / mu antagonist analgesic

when administered following or concurrent with mu

agonist opioid analgesics (e.g., morphine),
nalbuphine may partially reverse or block opioid-
induced respiratory depression from the mu agonist
analgesic

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Pharmacology B5