Download Aspirin Resistance in Cardiovascular Disease

Analgesic???????
 An
agent that subdues pain by acting
in the CNSor on peripheral pain
mechanism
Classification of Analgesics
a)
Opioid Analgesics
b)
Non – opioid Analgesics
NON-STEROIDAL
ANTI-INFLAMMATORY
DRUGS
What are NSAIDs?
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Non- opioid; non-narcotic analgesics
Analgesic, antipyretic, anti- inflammatory actions
Weaker analgesics than morphine
Do not depress CNS
No dependence
Acts primarily on peripheral pain mechanisms
Weakly acidic compounds
Highly protein bound
Orally absorbed
The major pharmacological actions
of these drugs are due to their
ability to inhibit the synthesis of
prostaglandins
Beneficial actions due to PG
synthesis inhibition:
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Analgesia
Antipyretic
Anti-inflammatory
Antiplatelet
Closure of ductus arteriosus
Toxicity due to PG synthesis
inhibition:
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Gastric mucosal damage
Bleeding
Na+ and H2O retention
Prolongation of labour
Asthma
History
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The medicinal properties of willow bark (salix
alba) was known since centuries
In the 5th century, people used the bitter powder
extracted from willow bark to relieve pain
Salicilin  salicylic acid
In 1897 aspirin was discovered by Felix Hofmann
1949: phenylbutazone
1950: paracetamol
1963: indomethacin
I) Non-selective COX inhibitors:
1.
Salicylates: Aspirin, Diflunisal
2.
Paraaminophenol derivatives: Paracetamol
3.
Pyrazolone derivatives: Phenylbutazone
4.
Indole acetic acid derivatives: Indomethacin, Sulindac
5.
Aryl acetic acid derivatives: Diclofenac, Tolmetin
6.
Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen
7.
Antranilic acids: Mefenamic acid, Flufenamic acid
8.
Oxicams : Piroxicam, Tenoxicam
9.
Alkanones : Nabumetone
10.
Pyrrolo-pyrole derivative: Ketorolac
II) Selective COX-2 inhibitors
Nimesulide, Celecoxib, Rofecoxib
ASPIRIN
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One of the oldest drugs
Acetylsalicylic acid
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Rapidly converted in the body to salicylic acid
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Aspirin: Mechanism of Action
Membrane Phospholipids
Arachidonic Acid
Cyclooxygenase
Lipooxygenase
PGH2
Prostaglandins
PGG2
Thromboxanes
Leukotrienes
Aspirin: Mechanism of Action
Membrane Phospholipids
Aspirin
Arachidonic Acid
Cyclooxygenase
Lipooxygenase
PGH2
Prostaglandins
PGG2
Thromboxanes
Leukotrienes
COX-1
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Continuously stimulated by the body
Its concentration in the body remains stable
Creates PGs used for basic housekeeping
through out the body
PGs stimulate normal body functions such as
stomach mucous production, regulation of
gastric acid secretion, Na+ & water excretion…
COX-2
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Induced
Stimulated only as apart of immune
response
Used for signaling pain & inflammation
Produces PGs for inflammatory response
Pharmacological actions
1.ANALGESIA ( 0.3- 1.5/day)
Good analgesic, but weaker than morphine
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Relieves non-visceral pain such as
inflammatory, tissue injury related etc…
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Relieve pain from integumental structures
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No Euphoria & No Tolerance
Analgesic effect is due to:
1. Inhibition of PG synthesis
2. ↑ the threshold to pain perception at central
subcortical level
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2. Antipyretic action:
 ↓ body temperature of patients having
pyrexia
 Inhibits PG synthesis in hypothalamus
 Promotes heat loss by peripheral
vasodilatation & sweating
3. Anti-inflammatory action
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Occurs at high doses ( 3-6 g/day)
Potent anti-inflammatory agent
Signs of inflammation are suppressed
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Inhibition of PG synthesis
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Antagonizes the action of bradykinin
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4. Respiration
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Respiration is stimulated
Anti-inflammatory dose
↓
↑ O2 consumption by skeletal muscles
↓
↑ CO2 production
↓
Respiratory stimulation
↓
Removal of plasma CO2
↓
Respiratory Alkalosis
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High dose : Respiratory centre depression
5. Acid- Base & Electrolyte balance
Anti-inflammatory doses
↓
Alkaline pH
↓
↑ Excretion of HCO3 ,Na+,H2O
↓
Normal pH
↓
Compensated Respiratory Alkalosis
5. Acid- Base & Electrolyte balance
Toxic Doses
Depress VMC
Depress
Respiratory centre
Impairs
Renal Function
↑↑ CO2
Accumulation of
strong acids
↓ pH
Respiratory Acidosis
Uncompensated Metabolic Acidosis
6. Metabolic Effects
Anti-inflammatory doses
↓
Uncoupling of oxidative phosphorylation
↓
↑ Cellular Metabolism
↓
↑ Heat production
↓
↑ Utilization of glucose
↓
↓ Blood sugar level
Large Dose:
a) Negative nitrogen balance
b) Hyperglycemia
7. G.I.T
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Gastric irritant: epigastric distress; Nausea; Vomiting
High Doses : Gastritis; Gastric ulceration; GI bleeding
Salicylic Acid
Adhere to gastric mucosa
Inhibit PGE synthesis
Irritation
Gastritis; Peptic Ulcer
How to avoid GI irritation & Ulcer ?
Aspirin should be administered
1. With plenty of water
2. With an alkali
3. With misoprostol, a PGE analogue
8. CVS
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High dose : depress VMC  ↓ BP
9. Uric Acid Excretion
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Therapeutic doses: ↓ urate excretion
High doses : ↑ urate excretion
10. Blood
Prostaglandins
Thromboxane synthetase
TXA2
Inhibit
Adenyl cyclase
↓ Platelet cAMP
↑ Platelet aggregation
10. Blood
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ASPIRIN
Prostaglandins
Thromboxane synthetase
TXA2 is not synthesized
No Inhibition
Adenyl cyclase
↑ Platelet cAMP
↓ Platelet aggregation
Pharmacokinetics
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Absorbed from stomach & upper intestine
Rapid deacetylation→ salicylic acid
80% plasma protein bound
Crosses BBB & placenta
Metabolism : glycine conjugation
Excretion : kidney
Half life: 3-5 hours
Adverse Effects
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Nausea, vomiting, epigastric distress, occult
blood loss
Rashes, urticaria, rhinorrhea,angioedema,
asthma
SALICYLISM
dizziness, tinnitus, vertigo
reversible impairment of hearing & vision
excitement, mental confusion
Liver damage: Reye’s syndrome
Nephrotoxicity
Acute salicylate intoxication
(15- 30g)
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Manifestations
dehydration, GI irritation, vomiting
acid- base imbalance
hyperpyrexia
restlessness, delirium, hallucination
tremor, convulsions
haematemesis
respiratory failure
Treatment of Acute salicylate
Intoxication
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Gastric lavage
IV fluids
External cooling
Vit K & blood transfusion
Alkaline diuresis
CONTRAINDICATIONS
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Peptic ulcer
Children suffering from influenza
Chronic liver disease
Diabetics
Pregnancy
prolongation of labour
greater postpartum blood loss
premature closure of ductus arteriosus
Stopped 1 week before surgery
Drug Interactions
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Displaces Warfarin, Sulfonylureas, Phenytoin,
Methotrexate from their protein binding sites.
Antagonizes the action of probenecid
Blunts the action of diuretics
Therapeutic Uses
Head ache, back ache, myalgia, joint pain
pulled muscle, neuralgia, dysmenorrhoea
 Fever
 Acute Rheumatic fever
first choice
4-6g/day
 Rheumatoid arthritis
relieves pain, swelling, morning stiffness
3-5 g/day
 Osteoarthritis
 Patent ductus arteriosus
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Therapeutic Uses
Myocardial infarction
 Low dose aspirin started immediately after
MI prevents reinfarction and reduce
mortality.
 Use with or with out Heparin
 Clopidogrel/Ticlopidine are alternatives
Therapeutic Uses
Unstable Angina
 Aspirin (100- 150 mg/day) given along with
Heparin followed by Warfarin decreases risk
of MI & sudden death in patients with
unstable angina.
 Clopidogrel/Ticlopidine are
alternatives/adjuvant to aspirin.
Therapeutic Uses
Cerebrovascular disease
 Aspirin has been used to prevent transient
ischemic attacks of stroke in patients with
cerebrovascular disease, although aspirin
do not alter the cause of stroke
Aspirin considered a wonder drug for
>50 years (1899-1950), inhibit Cyclooxygenase, . . . but found to cause
gastrointestinal ulcers and bleeding,
to cause CNS “salicylism,” altered
acid-base balance (respiratory
alkalosis), Reye’s syndrome in
children with viral infections. . .
MORPHINE
1. Basic drug
2. Potent analgesic
3. Relieves visceral pain
4. Removes the associated
reactions to intense pain
ASPIRIN
1. Acidic drug
2. Potent analgesic
3.Relieves inflammatory,
tissue injury related pain
4. Does not remove the
associated reactions to
intense pain
5. No anti-inflammatory/
antipyretic action
5. Potent anti-inflammatory/
antipyretic action
6.Produces sedation
6. No sedation
MORPHINE
7. Produces euphoria
8. Depress respiratory centre
9. Depress cough centre
10. High dose ↓BP
11.Do not cause acid- base imbalance
12.No GI irritation; bleeding
13. Produce constipation
14. Produces miosis
15. Causes tolerance & dependence
16. Precipitate asthma
17. No Salicylism
18. No antiplatelet action
19. Pre- anaesthetic medication
ASPIRIN
7. No euphoric effects
8. Stimulates respiratory centre
9. No effect
10. High dose ↓BP
11. Produce acid- base imbalance
12.Cause GI irritation; bleeding
13.No constipation
14.No miosis
15. No tolerance & dependence
16. Precipitate asthma
17. Causes Salicylism
18. Antiplatelet action
19. Not a pre- anaesthetic
medication
PARACETAMOL
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Acetaminophen
De-ethylated active metabolite of
PHENACETIN
Commonly used drug
Over The Counter (OTC) drug
Potent antipyretic & equianalgesic with
Aspirin
Weak/no anti-inflammatory action
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More active on COX in brain
Poor inhibitor of PG synthesis in peripheral
tissues
No GI irritation, acid-base imbalance
No affect on blood
No respiratory stimulation
Not uricosuric
Pharmacokinetics
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Well absorbed orally
Metabolism : liver
i) glucuronide conjugation
ii) sulfate conjugation
Excretion: kidney
Half life: 2-3 hours
Adverse Effects
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Safe & well tolerated
Nausea, rashes, anemia
Nephropathy
Acute Toxicity(>150mg/kg)
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Early manifestations
nausea, vomiting, liver tenderness
After 12-18 hours
centrilobular hepatic necrosis
renal tubular necrosis
hypoglycemia
coma
After 2 days
jaundice, hepatic failure, death
Mechanism of toxicity
Paracetamol (150mg/day)
Saturation in glucuronidation
capacity
↑ NABQI
(minor metabolite)
Binds to proteins in liver
NECROSIS
Treatment
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Gastric lavage
Activated charcoal
Specific antidote: N-acetylcysteine
Replenishes glutathione stores of liver
150mg/kg IV for 15 min; followed by
same dose IV over the next 20 hours
Therapeutic uses
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Headache, musculoskeletal pain
Dysmenorrhoea
OSTEOARTHRITIS
Fever
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ASPIRIN
Potent analgesic
Good antipyretic
Potent anti-inflammatory agent
Inhibits COX even in presence of
peroxides
Stimulate respiratory centre
Alter acid- base balance
Increase cellular metabolism
Produces GI irritation
Inhibit platelet function
Metabolism: glycine conjugation
SALICYLISM
Reye’s syndrome
Nephropathy
No specific antidote for acute
poisoning
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PARACETAMOL
Potent analgesic
Good antipyretic
No anti-inflammatory action
Do not inhibit COX in presence of
peroxides
Do not stimulate respiratory centre
Do not alter acid- base balance
Do not increase cellular metabolism
Do not produce GI irritation
Do not inhibit platelet function
Metabolism: glucuronide conjugation
No SALICYLISM
No Reye’s syndrome
Nephropathy
Specific antidote for acute poisoning :
N- acetylcysteine
Ibuprofen
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Introduced in 1969
Analgesic, Antipyretic & Anti-inflammatory
activity similar to aspirin
Better tolerated orally
Inhibition of synthesis of PG
92-99% bound to plasma albumin
Adverse Effects
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Nausea, Vomiting
Gastric discomfort
Headache, Dizziness, Blurred vision
Tinnitus
Edema
Therapeutic uses
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As an analgesic
Fever
Dysmenorrhoea
Rheumatoid arthritis
Tooth extraction, Fractures, Soft tissue
injuries
Indomethacin
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Potent anti-inflammatory agent
Promptly acting antipyretic
Good analgesic action
Inhibit PG synthesis
Suppress neutrophil activity
Well absorbed orally
Metabolism: liver  glucuronide conjugation
Half life: 2-5 hours
Adverse Effects
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Gastric irritation, gastric bleeding, diarrhea
Nausea, anorexia
Head ache, Giddiness, Mental confusion
Blurring of vision
Therapeutic uses
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Ankylosing spondylitis
Acute Gout
Closure of patent ductus arteriosus
Diclofenac
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Analgesic, antipyretic, anti-inflammatory agent
Inhibit PG synthesis, neutrophil chemotaxis,
super-oxide production
Well absorbed orally
Accumulates in synovial fluid
GI distress, epigastric pain, nausea, dizziness
Therapeutic uses
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Rheumatoid arthritis
Ankylosing spondylitis
Dysmenorrhoea
Post-operative inflammatory conditions
Wound edema