ANALGESIC

DRUGS

BY - DR KHUSHBOO
BAIRWA
OPIODS INTRODUCTION
Word opium juice greek
• 1803-morphine
• 1832-codeine
• 1848-papaverine
• Opioids are unique in producing analgesia without loss of
touch proprioception or consciousness
•
STRUCTURE ACTIVITY RELATIONSHIPS

• Alkaloids of opium 1-phenanthrene -Morphine

-codeine

-thebaine

2-benzylisoquinoline -papaverine

-noscapine

• SEMISYNTHETHIC OPIODS 1 -Methylmorphine

2 -Codeine

3 -Diacetylmorphine-Heroin

• SYNTHETIC OPIODS 1 -Morphine derivative-levorphanol

2 -Methadone derivative

3 –Benzomorphan derivative-pentazocine

• 4 -phenylpiperidine derivative-Meperidine

-Fentanyl
CLASSIFICATION OF
OPIODS
• OPIOIDS-
- Morphine
- Meperidine - Sufentanil
- Fentanyl - Alfentanil
- Codeine - Hydromorphone
- Oxymorphone - Oxycodone
- Propoxyphene - Methadone
- Tramadol - Heroin
OPIOID AGONIST
ANTAGONIST
• -Pentazocine
• -Butorphanol
• -Nalbuphine
• -Buprenorphine
• -Nalorphine
• Bremazocine
• -Dezocine
• -Meptazinol
ENDOGENOUS PAIN
SUPPRESSION SYSTEM

• Opioid receptors located in brain-periaquiductal gray

matter of brainstem, amygdala, corpus striatum ,
hypothalamus
• Spinal cord –substantia gelatinosa
• These areas are involved in pain perception , integration
of pain impulses .
MECHANISM OF ACTION OF
OPIOIDS

• Opioids act as agonist at opioid receptors at presynaptic &

postsynaptic sites in the CNS and peripheral tissues
• These opioid receptors are normally activated by three
endogenous opioid peptide known as endorphins ,
enkephalins and dynorphins.
• Opioids mimic the action of these ligands by binding to
receptors , resulting in activation of pain modulating system
NEURAXIAL OPIODS

• In contrast to iv opioid neuraxial opioid is not associated

with –symp. Dennervation
-Skeletal ms. Weakness
-loss of proprioception
SIDE EFFECTS OF NEURAXIAL
OPIOIDS

1. Pruritus 8. Neonatal morbidity

2. Nausea & Vomiting 9. Sexual dysfunction
3. Urinary retention 10. Ocular dysfunctions
4. Depression of ventilation
5. CNS excitation
6. Viral reactivation
MORPHINE
• It is prototype opioid agonist.
• Effects of Morphine -Analgesia ,euphoria , sedation
-Nausea , feeling of body warmth
-heaviness of extremities , dryness
of mouth , pruritus
• Continuous dull pain relieved more effectively than sharp intermittent pain.
• It is effective against pain arising from viscera , skeletal muscles ,joints ,
integumental structures.
• Analgesia is more effective when drug is given before painful stimulus .
• In the absence of pain however Morphine may produce dysphoria rather than
euphoria.
PHARMACOKINETICS OF
MORPHINE
• After im inj.onset of effect -15-30min.
Peak effect - 45-90min.
Duration of action -4hrs.
• Morphine, 5mg in saline &inhaled as aerosol act on afferent
pathway in airway relieve dyspnea as associated with lung
cancer & associated With pleural effusion
• Aerosol of morphine produce profound depression of
ventilation.
MORPHINE

• Analgesia , euphoria ,sedation , decrease concentration

• Nausea , feeling of body warmth , dry mouth , pruritus
• Continuous dull pain relieved more effectively than sharp
intermittent pain
• Effective in pain arising from viscera skeletal muscles, joints,
integumental structures
• Analgesia most prominent when morphine is given before painful
stimulus
PHARMACOKINETICS OF
MORPHINE
• After IM – onset 15-30min. Peak-45-90min. Duration 4hrs
• Morphine is inhaled as aerosol relieve dyspnea associated with lung cancer &
pleural effusion.
• Aerosol causes profound depression of ventilation
• Morphine has poor penetration of csf reasons-
• 1.Relatively poor lipid solubility
• 2.high ionization
• 3.protein binding
• 4.rapid conjugation
METABOLISM OF MORPHINE

• Principal pathway –Conjugation with glucucuronic acid in hepatic &

extrahepatic site especially kidney
• 75-85%appear as M-3-GLUCURONIDE
• 5-10% as M-6-GLUCURONIDE
• 5% Morphine demethylated into –normorphine
• Small amount into codeine
• EXCETION- mainly in urine
• 7-10% -biliary excretion
SIDE EFFECT OF MORPHINE

• 1.CVS-In supine normovolumic patients even large dose - no myocardial

depression or hypotensipon
• Pt changing from supine to standing orthostatic hypotension &syncope
• Decrease BP due to drug induced bradycardia or histamine release
• Bradycardia is due to stimulation of vagus
• Morphine has direct depressant effect on SA NODE +slow conduction through AV
NODE

• In contrast to morphine, fentanyl infusion 50µg/kg IV-No histamine release

•2 VENTILATION-µ Opioid agonist - Direct depressant of
brainstem ventilatory centre
• Equialgesic doses of all opioids produce some degree of ventilatory
depression
• Depression of ventilation by Decrease responsiveness of ventilatory
centre to co2 → increase resting paco2 → rightward
displacement of co2 response curve
• Opioid agonist → interfere with pontine & medullary ventilatory
centre that regulate rhythm of breathing → periodic breathing
• High dose opioid → Apnea
• Opioid produce dose dependent depression of ciliary activity in the
airway
• ↑ Airway resistance due to direct effect on bronchial smooth muscle
indirect due to release of histamin

•3. COUGH SUPRESSION-Produced by dextro isomer

of opioids (dextromethorphan) that do not produce analgesia

•4. NERVOUS SYSTEM-↓CBF ↓ICP

• Used with caution in head injury pt.- b/o
- effect on wakefulness
- miosis production
- depression of ventilation with asso. ↑ICP
• Head injury impair BBB--↑sensitivity to opioids
• EEG-replacement of rapid α-waves by slow δ-waves
• Large dose of opioid after rapid IV inj.- skeletal muscle rigidity
• Myoclonus – may resemble grand mal seizure
• Rapid IV opioid → skeletal muscle rigidity-
mc with fentanyl
• difficult ventilation due to closure of vocal cord
• mechanism → ↓ GABArelease +
↑dopamine production ( 84-100%)
• 5. SEDATION

•6. BILIARY TRACT-Spasm of biliary sm. Mus. →

biliary colic → confused with angina
• Naloxone releive biliary spasm pain but not MI
• ↑CBD pressure -Fentanyl 99%
• -Morphine 53%
• -Meperidine 61%
• -Pentazocine 15%
• Glucagon 2mg IV reverse biliary spasm it does not antagonize analgesic effect
• Morphine cause contraction of pancreatic duct-
• ↑Amylase
• ↑Lipase

•7. GIT-Spasm of git smooth muscle

• Constipation
• Biliary colic
• Delayed gastric emptying
•9. GENITO URINARY TRACT-↑ Tone &
peristaltic activity of ureter
• URINARY URGENCY – By opioid ↑ detrsor muscle tone but tone
of vesicle sphinctor is ↑ voiding

•10. CUTANEOUS CHANGE-Dilatation of blood vessel →

due to histamine release → urticaria ------ erythema & pruritus

•11. PLACENTA-Depression of neonate

• TOLERANCE & PHYSICAL DEPENDENCE-
• Tolerance to analgesic, euphoria, sedation, depression of ventilation,
emesis . Not to miosis & constipation
• Physical dependence require 25 days to develop
• Withdrawal Symptoms – Yawning, Lacrimation, Insomnia,
Restlessness, Abdominal Cramps, Nausea & Vomiting, Diarrhoea
• HARMONAL CHANGES-
• ↑ Prolactin
• ↓ LH, FSH, Testosterone, Estrogen
FENTANYL
• Phenylpiperidine derivative synthetic opioid agonist.
• 75-125 times more potent analgesic than morphine
• Greater potency ,more rapid onset reflect greater lipid
solubility which facilitate passage across BBB.
• 75% of fentanyl undergo first pass pulmonary uptake
• Cardiopulmonary bypass causes clinically insignificant
effect on PK of fentanyl
METABOLISM OF FENTANYL

• It is extensively metabolised by n-demethylation producing nor-

fentanyl, hydroxy propionyl nor-fentanyl
• It is excreted by kidney& detected in urine for 72 hrs after single
iv dose
• T1\2 of elimination longer than morphine due to large Vd
• In elderly pt t1\2 prolonged due to ↓CL ,this is due to ↓ hepatic
blood flow ,↓enzyme activity ,↓albumin production as fentanyl
is 80 -87% pp bounds
CLINICAL USES OF
FENTANYL
• Low doses 1-2mcg/kg provide analgesia
• 2-20mcg/kg act as adjuvant to inhaled anaesthetics to blunt circulatory
response to intubation , laryngoscopy , surgical stimulation
• Large doses 50-150mcg/kg iv alone used to produce surgical anaesthesia
• Large doses as a sole anaesthetic have advantage of stable hemodynamics due
to –
1.lack of direct myocardial depressant effect
2.absence of histamine release
3.supression of stress response to surgery
DISADVANTAGES OF FENTANYL

• Failure to prevent symp. Nervous system response to

painful surgical stimulation at any dose
• Pt. awareness
• Post op depression of ventilation
DIFFERENT ROUTES OF
ADMINISTRATION
• Intrathecal fentanyl produces rapid profound labor analgesia with minimal
side effects
• Oral transmucosal fentanyl 5-20mcg/kg
• ↓ pre op anxiety & facilitate induction in children
• This can be used by cancer pt for pain relief
• Transdermal fentanyl deliver 75-100mcg/hr used before induction & left
in place for 24 hrs to provide post op analgesia
• Toxic delirium reported in pt received fentanyl patch for prolonged period
SIDE EFFECTS OF FENTANYL

• CVS-In contrast to morphine even large dose does not

release histamine
• It depress carotid sinus baroreceptor causes bradycardia
• FENTANYL more than 30mcg/kg produce changes in
somatosensory evoked potential
• ICP-In head injury pt it produce ↑ICP ,↓MAP, ↓CPP
SUFENTANYL

• Thienyl analogue of fentanyl

• Analgesic potency is 5-10 times of fentanyl
• Transient skeletal ms. Spasm has been described after
accidental intrathecal inj. Of large dose
CLINICAL USES OF
SUFENTANIL
• Analgesia-0.1-0.4 mcg produce longer period of analgesia
& less depression of ventilation than fentanyl
• Induction-compared with fentanyl or morphine it produce
more rapid induction ,earlier emergence from anaesthesia ,
• SIDE EFFECTS-Use of large dose of sufentanil ,fentanyl to
produce iv induction may cause rigidity of chest &
abdominal musculature.
REMIFENTANIL

• It is selective mu opioid agonist with analgesic potency similar to fentanyl (15-20

times as potent as alfentanil )
• Chemically similar to fentanyl but structurally unique because of ester linkage, ester
linkage render it susceptable to hydrolysis by nonspecific plasma & tissue estrases.
• This unique pathway of metabolism imparts remifentanil –precise & rapidly titrable
effect
• - noncumulative effect
• -rapid recovery
• Combination of propofol & remifentanil is synergistic resulting in severe depression
of ventilation
CLINICAL USES OF
REMIFENTANIL
• In cases where profound analgesia is desired transiently
( retrobulbar block)
• Prompt onset & short duration of action make remifentanil useful
selection for supression of transient sympathetic activity to direct
laryngoscopy & intubation
• It is reliable analgesic during labor & delivery
• It is used for long operation where quick recovery is desired
•s
TRAMADOL

• Centrally acting analgesic that has moderate affinity for mu receptors & weak
kappa and delta opioid receptor affinity
• It is 5-10 times less potent than morphine
• Tramadol is racemic mixture of two enantiomers one of which is responsible for
inhibition of NE uptake whereas other for inhibition of 5-HT reuptake and
facilitation of its release
• Analgesia by Tramadol with absence of depression of ventilation and low potential
for tolerence , dependence and abuse may be result of complementry & synergistic
interaction of two enantiomers .
• Metabolized by hepatic enzyme to desmethyltramadol.
USES OF TRAMADOL

Tramadol 3mg\kg administered orally , im or iv is effective for

Tt of moderate to severe pain
Marked decrease in post op shivering and minimal depressant
effect on ventilation
It is useful for Tt of chronic pain because it does not cause
tolerence or addiction & is not associated with major organ
toxicityor significant sedative effect.
This drug is useful in pt. who do not tolerate NSAIDS
DISADVANTAGE OF TRAMADOL

• It lowers seizure threshold

• High incidence of nausea & vomiting
• Use of ondensetron may interfere with analgesic
componant of tramadol that is due to effect on reuptake
& release of 5-HT
OPIOID AGONIST ANTAGONIST

• PENTAZOCINE
• DEZOCINE
• BUTORPHANOL
• NALBUPHINE
• BUORENORPHINE
• NALORPHINE
• BREMAZOCINE
INTRODUCTION TO OPIOID
AGONIST ANTAGONIST
• Partial mu agonist or antagonist
• Antagonist properties of these drug can attenuate the efficacy of
subsiquently administered agonist .
• Advantages of agonist antagonist are ability to produce analgesia
with limited depression of ventilation and low potential for
physical dependence
• These drug have ceiling effect such that increasing doses do not
produce additional responses
PENTAZOCINE

• It is benzomorphan derivative
• Agonist at delta and kappa receptor
• Antagonist activity is weak being only 1\5 as potent as
nalorphine.
• Antagonist effect are sufficient to precipitate withdrawal
symptoms
• Agonist effect are antagonized by naloxone
PHARMACOKINETICS OF
PENTAZOCINE

• Well absorbed after oral or parenteral administration

• Extensive hepatic metabolism
• Metabolism occur by oxidation of terminal methyl
groups and resulting inactive glucuronide excreted in
urine
• Elimination t1\2 is 2-3hrs.
CLINICAL USES OF
PENTAZOCINE

• 10-30 mg iv or 50 mg orally used most often for relief of

moderate pain
• Placement in epidural space produce rapid onset of
analgesia that is shorter duration than morphine
SIDE EFFECTS OF
PENTAZOCINE
• Sedation
• Diaphoresis
• Dizziness
• Dysphoria-This limits the physical dependence liability
• Increase catecholamine- increases BP & HR
• Crosses placenta causes fetal depression
• In contrast to morphine miosis does not occur& biliary tract pressure
not raised significantly
BUTORPHANOL
• It resembles pentazocine

• Compared with pentazocine agonist effects are 20 times greater ,antagonist effects 10-
30 times greater

• Butorphanol has –low affinity for mu receptor to produce antagonism

• -moderate affinity for kappa to produce analgesia and antishivering

effect

• - minimal affinity for sigma so the incidence of dysphoria is low

• 2-3mg im butorphanol provide analgesia and depression of ventilation similar to 10

mg morphine

• Intranasal butorphanol used for Tt of postoperative pain and migrain

• Inraop use is limited

• Elimination t1\2 2.5 -3.5 hrs

SIDE EFFECTS OF
BUTORPHANOL

• Sedation, nausea ,diaphoresis

• Dysphoria infrequent
• Depression of ventilation
• Increase BP , CO
• Withdrawal symptoms are mild
BUPRENORPHINE

• It is agonist antagonist derived from opium alkaloid thebaine

• 0.3 mg im equivalent to 10 mg morphine
• After im inj. Onset occur in 30 min., duration at least 8 hrs
• Its affinity for mu receptor 50 times greater than morphine & subsequent
slow dissociation from these receptor account for prolonged duration of
action
• It is resistant to antagonism with naloxone
• It is effective for moderate to severe pain & pain asso with cancer , renal
colic , MI
SIDE EFFECTS OF
BUPRENORPHINE

• Drowsiness ,nausea , depressin of ventilation

• It is resistant to antagonism with naloxone
• Pulmonary oedema
• Withdrawal symptoms
 NSAIDS
NON-STEROIDAL ANTI-
INFLAMMATORY DRUGS
CLASSIFICATION
PROPIONIC ACID
DERIVATIVES
• IBUPROFEN

• ANALGESIC, ANTIPYRETIC AND ANTI-INFLAMMATORY EFFICACY IS LOWER THAN

ASPIRIN (LOW POTENCY)
• INHIBITS PG SYNTHESIS
• ADVERSE EFFECTS: BETTER TOLERATED THAN ASPIRIN AND INDOMETHACIN –
• MILDER - GASTRIC DISCOMFORT, NAUSEA, VOMITING,- GASTRIC EROSION
• RARELY- CNS EFFECTS - HEADACHE, DIZZINESS, BLURRING OF VISION, TINNITUS AND
DEPRESSION RASH, ITCHING AND HYPERSENSITIVITY ARE LESS- PRECIPITATES ASPIRIN
INDUCED ASTHMA
PREFERENTIAL COX-2
INHIBITORS
•DICLOFENAC
• ANALGESIC-ANTIPYRRETIC AND ANTI-INFLAMMATORY
• EFFICACY SIMILAR TO NAPROXEN
• INHIBITS PG SYNTHESIS
• SOMEWHAT COX-2 SELECTIVE- REDUCED NEUTROPHIL
CHEMOTAXIS AND REDUCED SUPEROXIDE GENERATION
• NO ANTIPLATELET ACTION (COX-1 SPARING)
• GOOD TISSUE AND SYNOVIAL FLUID PENETRATION
• USES: MOST WIDELY USED DRUG –
• RA, OA, BURSITIS, ANKYLOSIN SPONDILITIS, BURSITIS,
TOOTHACHE, DYSMENORRHEA, RENAL COLIC, POST TRAUMA AND
POST INFLAMMATORY CONDITIONS
• ADRS:
• MILD - EPIGASTRIC PAIN, NAUSEA, HEADACHE, DIZZINESS AND
RASHES
• GASTRIC ULCERATION AND BLEEDING
• RISK OF HEART ATTACK AND STROKE
PARA-AMINO PHENOL
DERIVATIVES

• Paracetamol (acetaminophen)
• Phenacetin 1887 - banned now (Nephropathy)•
• Its de-ethylated active metabolite of Phenacetin
• Analgesic - Like aspirin
• Antipyretic, raises pain threshold but no PG inhibition except COX
inhibition in brain - no peripheral anti-inflammatory action- Good
promptly acting anti pyretic Additive analgesic action with Aspirin
(central + peripheral)-
PARACETAMOL…
PARACETAMOL…
PARACETAMOL…
KETAMINE

• Ketamine is a water soluble phencyclidine derivative

• Ketamine is highly lipid soluble and undergoes rapid
breakdown and redistribution to peripheral tissues
• It is metabolized extensively in the liver by N-
demethylation and ring hydroxylation pathways.
KETAMINE USES :
• As an IV induction agent in the emergency setting in shocked or
hypotensive patients
• Ketamine by virtue of its broncho dilating property and profound
analgesia allowing use of high oxygen concentration is considered
to be the IV induction agent of choice in patients with active
bronchospasm.
• Burns: Analgesia in burn dressing changes, during excision and
grafting and for sedation
• Prehospital and battlefield medicine: Ketamine is the anesthetic of
choice when supplies of oxygen and monitoring and disposable
equipment are limited
ASPIRIN
ASPIRIN : PROPERTIES
THANKS