Transcript Opioid Analgesics - PharmaXChange.info

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BY:
AROOJ KHALID ALVI
Mphill.Pharmacology
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 Pain and the Pain management
 Endogenous Opioid Peptides
 Opioid receptors and effects
 Chemical Structure and Binding Features of Opioid
Analgesics
 Types of Opioid Analgesics
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 Pain is a crucial aspect of the body’s defense mechanisms
 Pain “is a part of a rapid warning relay instruction of the
motor neurons of the central nervous system to minimize
detected physical harm.”
 Pain can be defined as a somatic sensation of acute
discomfort, a symptom of some physical hurt or disorder,
or even emotional distress.
 Pain can be classified into two types:
 Acute pain
 Chronic pain
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 Acute pain is short-term pain
 Chronic pain is pain that last
or pain with an easily
identifiable cause
 Acute pain “is the body's
warning of present damage
to tissue or disease. It is
often fast and sharp followed
by aching pain. Acute pain is
centralized in one area before
becoming somewhat spread
out. This type of pain
responds well to
medications.”
much longer than pain normally
would with a particular injury.
 Chronic pain can be constant or
intermittent and is generally
harder to treat than acute pain.
 Pain can also be grouped by its
source and related pain
detecting neurons such as
cutaneous pain, somatic pain,
visceral pain, and neuropathic
pain
 Opioid Analgesics can be used
to treat many types of pain
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Pain Signaling
 There are certain nociceptive receptors present on on the
skin and various organs of the body.
 When any traume or stimuli for pain approaches, certain
substances are released at the site, causing the signalling
from sensory neurons.
 These neurons release excitatory neurotransmitters
which relay signals from one neuron to another.
 “The signals are sent to the thalamus, in which pain
perception occurs. From the thalamus, the signal travels
to the somatosensory cortex in the cerebrum, at which
point the individual becomes fully aware of the pain.”
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 Analgesia simply means the absence of pain without
loosing consciousness.
 “The analgesia system is mediated by 3 major
components : the periaquaductal grey matter (in the
midbrain), the nucleus raphe magnus (in the
medulla), and the pain inhibitory neurons within the
dorsal horns of the spinal cord, which act to inhibit
pain-transmitting neurons also located in the spinal
dorsal horn.”
 These areas are the areas in which the chemical
mechanisms of opioid analgesics will take place
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 Opioids are drugs derived from or related to the Opium
 Opium is derived from the juice of the opium poppy,
Papaver somniferum
 Opium contains over twenty distinct alkaloids
(morphine was the first alkaloid of opium to be isolated
in 1806)
 By the late 19th century use of these “pure” opium
derivatives spread throughout the medical world,
however, the method by which these drugs works was
unknown.
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 In 1973 researchers determined the existence of opiate binding sites in




the brain through the use of radioligand-binding assays
In 1975, an endogenous opiate-like factor called enkephalin was found
and shortly after this two more classes of endogenous opiate peptides
were isolated, the dynophorins and the endorphins.
“Endogenous opioid peptides are the naturally occurring ligands for
opioid receptors.”
These peptides are produced by the pituitary gland and by the
hypothalamus
Opioid peptides are found in the central nervous system mainly in
limbic and brainstem areas associated with pain reception, and the
certain areas of the spinal cord. Their distribution corresponds to
“areas of the human brain where electrical stimulation can relieve pain
.”
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 These natural peptides work as ligands that interact with their specific
receptors causing structural changes that result in other changes in the
effected neuron such as the opening or closing of ion gated channels or
the activation or deactivation of certain enzymes.
 Opioid peptides work by modulating the release and uptake of specific
neurotrasmitters in the neurons they are found. This alteration of
neurochemical balance creates a vast amount of possible physiological
effects, one of which is analgesia.
 All of the endogenous opioid peptides are derived from a
corresponding precursor proteins and all share a common aminoterminal sequence which is called the “opioid motif.”
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 Shortly after the discovery and observance of
endogenous opioid peptides, multiple classes of
unique opioid receptors were found
 Types:
 the mu receptor,
 the delta receptor,
 the kappa receptor, and
 the ORL-1 receptor.
 The receptors are found on cell membranes of cells in
the nervous system (neurons) and are found in unique
distributions and have different effects.
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 Morphine and its analogues bind most strongly to this
receptor and in fact most used opioid analgesic drugs
are selective for this specific receptor type.
 Location:
They are seen in significant amounts in all areas of
the central nervous system associated with pain
control
 Types:
There are two subtypes of the mu-receptor.
1. μ1-receptors: analgesic activities and the
2. μ2-receptors: effects of respiratory
depression and constipation. 13
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Mechanism:
When an opioid binds to the mu-receptor it induces a change in
shape which in turn induces a change in the ion channels of the
associated cell membrane
 The mu-receptor opens up the ion channel allowing potassium ions
to flow out of the cell causing hyperpolarization of the membrane
potential. This hyperpolarization causes it to become extremely
difficult for an action potential to be reached and therefore the firing
of the neuron become far less frequent and the neurons excitability
decreases.
 The release of potassium ions also causes less calcium ions to enter
the terminal end of the neuron. This is where neurotransmitters are
stored and as a result this significantly reduces neurotransmitter
release.
 These effects of a ligand binding to a mu-receptor essentially turn off
the neuron and in doing so block the relaying of pain signals from
pain receptors.
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 Effects produced by the stimulation of mu-rec.:
When and opioid binds to the mu-receptor it produces
the effects of analgesia. The mu-receptor is also associated
with other effects such as “sedation, reduced blood pressure,
itching, nausea, euphoria, decreased respiration, miosis
(constricted pupils) and decreased bowel motility often
leading to constipation.
 Respiratory depression is considered the deadly side effect of
opioid analgesic drugs. It is the cause of death in all overdose
cases.
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Synapses between afferent nociceptive neurons and secondary
ascending neurons relay pain signals to the brain. The entry of
Ca2+ into the pre-synaptic primary neuron and the release of K+
from the post-synaptic secondary neuron are processes involved
in signal transmission across the synapse.
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Opioids binding to ion channel associated m receptors inhibit the influx of
calcium ions into the pre-synaptic terminal and increase the outflow of
potassium ions from the post-synaptic membrane. This has the effect of
reducing the release of the neurotransmitter glutamate and hyperpolarising
the post-synaptic membrane. Synaptic transmission is inhibited.
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 The kappa receptor is very different from the mu-receptor in
the fact that there are not many significant agonist of the kappa
receptor known
 Types:
There are three subtypes of the kappa receptor however the
difference between these subtypes is not clearly known.
 Effects :
The kappa receptor is associated directly with analgesia and
sedation but with none of the undesired side effects associated
with the mu receptor.
 Because of this, it is an area of focus in current research and
shows promise in the development of a safer analgesic.
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 Mechanisn:
When and agonist or ligand binds to the kappa
receptor it induces a conformational change that results
directly in the closing of the calcium ion channels in the
terminal of the neuron and the neuron can not relay pain
messages.
 Diff. from mu-rec:
Another difference between the kappa and mu receptors is
that the kappa receptors only effect nerves that relay “pain
produced by non-thermal stimuli,” and mu receptors
inhibit all pain signals.
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 The delta receptor is the strongest binding site of the
body’s natural pain killer, the class of opioid peptides
called the enkephalins.
 Morphine and other commonly used opioid analgesics
also bind to this receptor strongly and act as an agonist
much like they do with the mu receptor.
 Location:
The delta receptor is found in larger cells than the
other receptors and seems to be important in spinal
analgesia. Present in spinal and limbic areas,so
responsible for reinforcement and dependence
actions.
.
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Mechanism:
 The delta receptor is a G-protein linked receptor. When an
agonist binds to the delta receptor is induces a conformational
change that causes the activation of a specific G-protein.
 This G-protein “inhibits the membrane bound enzyme adenylate
cyclase and prevents the synthesis of cAMP. The transmission of
the pain signal requires cAMP to act as a secondary messenger,
and so inhibition of this enzyme blocks the signal.”
 Also causes hyperpolarization by increase k+-efflux.
Effects:
 Most effects are similar to mu-rec, however kappa appears to
have some opposite effects in certain areas.
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 The ORL-1 receptor or the “orphan” receptor was very recently
discovered.
 The natural opioid peptide that is a ligand for this receptor is nociceptin
which is also called orphaninFQ.
 Whole system is called N/OFQ system.
Effects:
 The ORL-1 receptor is associated with many different biological effects
such as memory processes, cardiovascular function, and renal function.
 Capable of opposing mu-rec mediated analgesia as well as modulating
memory and learning processes.
 It is thought to have effects on dopamine levels and is associated with
neurotransmitter release during anxiety.
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Receptor
Subtypes
Location

delta (δ)
OP1 (I)
δ1, δ2

kappa (κ)
OP2 (I)
κ1, κ2, κ3

Function
brain

pontine nuclei(learning 
motor-skills)


Amygdala(emotional

rxns)

olfactory bulbs(smell) 

deep cortex(sens.,motor,
perception)
analgesia
antidepressant effects
physical dependence
Increase hormone
release(growth hormone)
brain

Hypothalamus(endo
+regulatory functions)

periaqueductal
gray(analgesia)

Claustrum(functional
timing)
spinal cord

substantia
gelatinosa(conduct pain
sens.)
Spinal and supra-spinal
analgesia
sedation
miosis
inhibition
of ADH release(diuresis)
dysphoria





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
mu (μ)
OP3 (I)
μ1, μ2, μ3



Nociceptin
receptor
OP4
ORL1

brain

cortex (laminae III and IV)

thalamus

Striosomes(moods)

periaqueductal gray
spinal cord

substantia gelatinosa
intestinal tract(myentric &
submucosal plexus)
brain

cortex

amygdala

Hippocampus(memory)

septal nuclei(reward &
reenforcement=euphoria)

Habenula(pain,nutrition,slee
p,stress,reward)

hypothalamus
spinal cord
μ1:
supraspinal analgesia
physical dependence
μ2:
respiratory depression
miosis
euphoria
reduced GI motility
physical dependence
μ3:
?




anxiety
depression
appetite
development of
tolerance to μ agonists
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 In order to examine
important structural
features of Opioid
analgesics, which are all
derived from the opiate
structure, we will refer to
the structure of morphine,
the first identified
alkaloid.
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 The structure of morphine consists
of five rings forming a T-shaped
molecule
 The important binding groups on
morphine are the phenol, the
aromatic ring, and the ionized
amine. These groups are found in all
Opioid analgesics.
 . “A free phenol group is crucial for analgesic activity.” The
aromatic ring of the opiate also seems to be integral to its
function as compounds that lack the aromatic ring show
no analgesic activity. The ionized amine also plays an
important role in its activity and is common in opioid
structure. In experiments where the Nitrogen was
replaced by a Carbon no analgesic activity was found. It
interacts with certain analgesic receptors in its ionized
form.
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Opoid-agonists.
1.Natural opium alkaloids:
i.Phenanthrene group:
morphine
codeine
thebaine
ii.Benzyl-isoquinoline group:
noscapine
papaverine
A.
2.Semisynthetic opium derivatives:
i.Morphine derivatives
heroin
hydromorphine
oxymorphine
ii.Codeine derivatives.
hydrocodone
oxycodone
iii.Thebaine derivatives.
buprenorphine
3.Synthetic opium substitutes:
i.Piperidine derivatives.
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pethidine
fentanyl
sulfentanil,alfentanil
ii.Phenyl-heptylamine derivatives.
methadone
propoxyphene.
iii.Morphinans
levorphanol
dextromethorphans
B. Opoids with mixed receptor actions:
1.Phenanthrenes.
nalbuphine
buprenorphine
2.Morphinans.
butorphanols
3.Benzomorphans
pentazocine.
C.Pure antagonists.
naloxone
naltraxone
nalmefene
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:Morphine:
 Morphine is the golden standard among
opioid analgesics to which the structure and
strengths of all other drugs are compared
 It is the primary ingredient in opium and
was isolated in 1806
 Morphine has strong binding affinity for the
mu and delta opioid receptors and some
weak affinity for the kappa receptor
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 Pharmacokinetics:
 i/v, S/C, I/M
 Oral bioavailability is low.
 T1/2 2-2.5 hrs, duration of analgesia is 4-5 hrs.
 Absorption: from GIT is usually slow and erratic


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

so not given orally .
Significant first-pass metabolism in liver
Distributed in highly perfused aread as liver,
kidney ,brain, lungs and to lower conc in skeletal
muscles (serving as a reservior)
Only small amount cross BBB.
Enters in the foetus,so shouldn’t be used in
pregnancy.
Metabolized in liver to 6 glucuronic acid(M6G),an
active metabolite with more potent analgesic
activity, and M3G,neuroexcitatory.
Excreted via glucuronide conjugate into the urine.
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1.Miosis:
 Due to excitation of autonomic segment of eye.
2.Respiration:
 Depressant effect. Due to direct effect on the brain-stem resp centres.Death is
always due to resp.depression.
3.Cough:
 Depress the cough,in part dur to direct effect on the cough centre in
medulla.
4.CVS:
 orthostatic hypotension and fainting.
(due to the release of histamine and depression of vaso-motor centre)
5.Nausea and vomitting:
 By triggering CTZ(may involve vestibular component)
 Gastric stasis
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6.GIT:
 Decrease HCl secretion.(indirectly due to the increased secretion of




somatostatins from pancreas and reduces release of Ach).
Diminish biliary, pancreatic and intestinal secretions. resting tone
increased and spasms observed.
Propulsive peristaltic movements in colon are abolished resulting in
morphine-induced constipation.
Along with this,inattention of the stimuli for defecation owing to
central effects.resulting in constipation.no tolerence to this dev.
Biliary colics. Due to increased pressure due to the constriction of
sphinctor of oddi
7.Ureter and urinary-bladder:
 inhibit the urinary voiding reflexes and tone of sphinctor and vol of
bladder increase.
8.Uterus:
 may prolong labour,restoring tone, freq. and amplitude to normal.(if
hyperactive by oxytocin)
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9.Skin:
Flushing of face,neck and upper thorax.(histamine release).
10.Immune-system:
May modulate the actions of immune sys, by effects on lymphocyte
proliferation ,a.body prod, and chemotaxis.natural killer cell cytolytic
activity and lymphocyte proliferative responses may be inhibited by
these.(med by sympathetic sys. And a/f prolong use by hypothalmicpituitaryadrenal sys.{corticosteroids})
11.Neuroendocrine effects:
Acts on hypothalamus to inhibit release of.
• GnRH ,Corticotropic releasing factor.—low conc of circulating
LH, FSH,ACTH
• .as a result of low conc. Of pituitary trophic hormones,the conc.
Of testosterone and cortisol decrease.
• It may increase the release of prolactin,probably by inhibiting
the dopaminergic inhibition of its secretion.
• Mu-agonists seems to have antidiuretic effects.(inc. release of
ADH).
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12..Analgesia.
• Opoid rec.on the terminal of pri afferent nerves mediate inhibition of
n/t release.(substance-P)
• post-synaptic inhibition of interneuons that conveys nociceptive info to
higher brain areas
13.Euphoria:(septal nuclei)
Patnts in pain experience a pleasant feeling
Ptnts not in pain feels dysphoria(malaise)
14.Sedation:(hebenula)
drowsiness,clouding of mentation,impairment of reasoning ability and
sleep.
15. Hypothermia:(hypothalamus)
Alter the equilibrium point of hypothalamic heat-reg mech.such that
body temp falls slightly.
16.Tolerence,physical dependence and potential for abuse:(locus
cerelus)
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characteristic feature of all opoids.
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1.
Analgesia





headache
Post-operative pain
Terminal illness
Cancers
Obstetrical procedure
2.Cough( low dose)
3.Diarrhoea.
4.Anaesthesia: preanesthetic medication.
5.Acute pulmonary edema(reduced awareness of
SOB,red.anxiety,red. Preload, red. afterload)
6.May have a.inflammatory effects(inh. Of subs. P)
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 Respiratory depression
 Nausea
 Vomitting
 Constipation
 Postural hypotension accenuated by hypovolemia
 Increased intracranial pressure(by retention of CO2)
 Urinary retention
 Itching and urticaria
 Apnoea
 Tolerence
 Physical and psychological dependence
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











Acute Action
Analgesia
Respiratory Depression
Euphoria
Relaxation and sleep
Tranquilization
Decreased blood pressure
Constipation
Pupillary constriction
Hypothermia
Drying of secretions
Reduced sex drive
Flushed and warm skin












Withdrawl Sign
Pain and irritability
Hyperventilation
Dysphoria and depression
Restlessness and insomnia
Fearfulness and hostility
Increased blood pressure
Diarrhea
Pupillary dilation
Hyperthermia
Lacrimation, runny nose
Spontaneous ejaculation
Chilliness and “gooseflesh”
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 May be due to clinical overdose,accidental overdose or suicidal
attempt.(40-60mg)
Symptoms:
 Respiratory depression
 Stupor or comma
 Cyanosis
 Miosis
 Fall in B.P.
 Pulmonary edema at terminal stages
 Death is due to resp depression
The triad of coma, pinpoint pupil and depressed resp. strongly
suggests opoid poisoning.
:Treatment:
Maintainance of ABC,lavage.
Opoid antagonist as naloxone produce dramatic reversal of
poisoning.(small i/v doses)
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 With mixed antagonist-agonist opioids
 Patients with head injury
 Patients with impaired pulmonary functions,asthma
 Pregnancy
 Liver disease
 Patients with endocrine disease.
Hydromorphones and Oxymorphones are strong
opioid agonists with morphine-like effects.
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 Oxycodone and methadone are
analogs of codeine
 Codeine itself has low binding
It differs structurally from
affinity to all of the opioid
morphine in that its phenol
receptors. Its analgesia producing group is methylated. It is
effects come from its conversion often referred to as methylmorphine.
to morphine.
 When codeine is administered
about ten percent is converted to
morphine by O-demethylation
that occurs in the liver by an
enzyme called cytochrome p450.
 Because of this Codeine is far less
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potent than morphine
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 Codeine is usually
administered orally and it is
much more effective orally
than morphine (about 60%)
 Slight sedation,NO euphoria
and NO noticeable
respiratory depression.
 Tolerence dev less rapidly and
dependence occurs rarely.
 Uses:
 Cough
 Diarrhoea
 Somatic pain
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 It is administered through intravenous injections but
can also be administered orally or vaporized.
 It binds most strongly to the mu receptor and is also
active in the form of morphine as its acetyl groups are
removed.
 It produces euphoric effects similar to morphine,
however, it is thought that these effects are greater and
more addicting because of its extremely rapid effect.
 Its fast action is a result of being extremely lipidsoluble because of its acetyl groups and therefore it
immediately crosses the blood brain barrier.
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 The use of Heroin causes the body
to produce far less of its natural
opioid peptides, the endorphins.
This creates a dependence on
heroin.
 When a heroin user stops using the
drug the withdrawal symptoms are
severe.
 Withdrawal symptoms include
anxiety, depression, cramps,
vomiting, diarrhea, restless leg
syndrome (hence kicking the
habit), and a severe sense of pain
caused by nothing.
 Many addicts in withdrawal
experience “itchy blood” which can
drive the addict to scratch cuts and
bruises into his body.
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1.Papaverine:
 No analgesic action
 Relaxes smooth muscles sp. Of blood
vessels.
 Used in various spastic conditions of
arteries of limbs
2.Noscapine:
 V effective cough suppressant. So used
instead of codeine.
 Less addictive
 Causes constipation.
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 Pethidine:
 Most frequently prescribed opoid
 Strong agonist
 Posses most of the effects of morhpine but less histamine
release.
 Also has anti-muscarinic effects of atropine
 No constipation and miosis
 Tachycardia(a.muscaranic action)
 Non-effective anti-tussive
 May cause bronchial dilation so may be given in asthma
 Less CNS depression
 For obstetrical analgesia as it doesn’t effect foetus.
 As an adjunct to anasthesia.(local)
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 Fentanyl: (100M)
 Strong agonist
 Chemically related to pethidine.
 Short duration and rapid onset
 Used in anesthesia
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 Strong agonist
 Pharmacologically v similar to
morphine
 Methadone is often used to treat
heroin addiction because it is a longer
lasting opioid.
 Mild withdrawal effects.
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 An agonist of kappa-rec and weak agonist of mu and





delta.
Weaker analgesic than codeine but equally addictive
Well absorbed orally
Used in combination with aspirin or paracetamol for
greater analgesia.
No constipation and lesser incidence of
N,V,drowsiness and dizziness.
For the treatment of
 Myalgia
 Nauralgia
 Migraina
 Arthritis pain.
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1.Phenanthrenes:
Nalbuphine:
 Agonist activity at delta and kappa, and weak antagonist of




mu-receptor.
Given parenterally
Analgesia equivalent to morphine with lower abuse
potential
At high dose,ceiling resp. depression.
No reversal with naloxone
Buprinorphine:
 Hign affinity for mu-rec act as partial agonist.
 Longer duration of action
 As effective in heroine-detoxification as methadone
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 A kappa-agonist with weak mu-antagonist activity.
 Used orally or parenterally(no s/c)
 Generally effects are similar to morphine but some




analgesic effects are due to kappa-rec.
High dose cause increase in heart-rate and B.P.
Vomitting is less common than with morphine.
Patients receiving opoids may experience abstinence
synd. when given pentazocine.
Used as an analgesic in those with drug-abuse prob.
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 Opioid Antagonists are used to treat opioid
overdose cases.
 Most are derived from Thebaine (an alkaloid of
Opium)
 The have strong binding affinity for the mu
receptors
 They work by competitive inhibition at the binding
site (It binds but does not change the receptor
while at the same time blocking the agonist).
 These involves naloxone,naltrexone, and
nalmefene.
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 Naloxone is an example of a




opioid antagonist.
It is administered
intravenously.
Short duration of action
Metabolized by
glucuronidation and excreted
in urine.
It is a competitive antagonist at
mu- delta and kappa rec. with
10 fold higher affinity for mu
than kappa.this explains
reversal of resp. depression
with minimal reversal of
analgesia due to kappa.
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Pharmacodynamics:
 Almost inert in the absence of agonist but with agonist
reverses the effects within 1-3 min .
 In opoid- addicts it’ll instantaneously precipitate
abstinance syndrome.
 There is no tolerence to antagonist activity.
Uses:
 To treat acute opoid-toxicity.
NALTREXONE:is also a pure antagonist and due to long
duration it is used as a maintainance drug for addicts in the
treatment prog.
It is also used for the treatment of chronic alcoholism to
decrease craving.
Nalmefene:newest agent, derivative of naltrexone,only i/v
available.t1/2=8-10 hrs,for opioid overdose.
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 Sedative-hypnotics
 Increased CNS depression
 Anti-psychotic
 Inc. sedation,accentuation of
tranquilizers
 MAO-inhibitors
particularly resp depression
CVS effects(a.muscarinic
&alpha-blocking effects)
 High incidence of hyperpyrexic
coma.(either retard its
metabolism or interaction at
central n/t.)
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Opioid analgesics
Route of
administration
Drug
Onset of
action (min)
Time to peak
effect (min)
Duration of
action (h)
Strong agonists
Fentanyl (Sublimaze)
Hydromorphone
(Dilaudid)
IM
7-15
20-30
1-2
IV
1-2
3-5
0.5-1
Oral
30
90-120
4
IM
15
IV
10-15
30-60
2-3
Sub-Q
Levorphanol (LevoDromoran)
Oral
30
15-30
10-60
90-120
4-5
—
60
4-5
10-60
within 20
IM
IV
Sub-Q
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Meperidine
(Demerol)
Oral
IM
15
60-90
2-4
30-50
2-4
30-60
90-120
4-6
10-20
60-120
4-5
—
60-120
4-5
30-60
4-5
10-15
IV
Sub-Q
Methadone
(Dolophine)
Oral
1
IM
IV
Morphine (many
trade names)
Oral
IM
10-30
IV
Sub-Q
Oxymorphone
(Numorphan)
—
Epidural
10-30
20
4-5
IM
10-15
30-90
3-6
5-10
15-30
3-4
IV
Sub-Q
Rectal
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Mild-to-moderate agonists
Oral
30-40
60-120
4
IM
10-30
30-60
4
Sub-Q
10-30
Hydrocodone (Hycodan)
Oral
10-30
30-60
4-6
(Percodan)
Oral
—
60
3-4
Propoxyphene (Darvon,
Dolene)
Oral
15-60
120
4-6
Butophanol (Stadol)
IM
10-30
30-60
3-4
IV
2-3
30
2-4
IM
within 15
60
3-6
IV
2-3
30
3-4
within 15
—
3-6
Oral
15-30
60-90
3
IM
15-20
30-60
2-3
IV
2-3
15-30
2-3
15-20
30-60
572-3
Codiene (many trade
names)
Nalbuphine (Nubian)
Sub-Q
Pentazocine (Talwin)
Sub-Q
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 Opioid antitussives: Dextromethorphan,
Levopropoxyphene, Noscapine, Codeine
 Anaesthetic: Pethidine, Fentanyl
 Detoxification of heroine: Buprenorphine, Methadone,
Naltrexone.
 Cardiac tachycardia and hypertension: Pentazocine,
Pethidine.
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