Lecture 33: Analgesic drugs 2 Flashcards
What are the 3 types of pain?
1) Nociceptive Pain
2) Inflammatory Pain
3) Neuropathic Pain (pain due to damage to the neurons)
What are NSAIDs?
Non-Steroidal Anti-inflammatory Drugs (NSAIDs)
NSAIDs is a large group, has varied activities. This is most frequently prescribed class of medications
It has various routes of administration:
- Oral (most widely used form)
- Parenteral (after surgery): intramuscular, intravenous
- Topical (skin)
- Suppositories
One example is aspirin, prototype (but distinct) is discovered in 1898 as acetyl salicylic acid
Describe the Mechanism of Action of NSAIDs
NSAIDs compete non-specifically to inhibit cyclo-oxygenase enzymes (COX1 & COX2), leading to suppression of prostanoids production (e.g. prostaglandin) in the cells
- Traditional NSAIDs inhibit COX1 and COX2
- Newer agents selectively inhibit COX2
Most inhibitions are reversible and incomplete, except aspirin, which selectively acetylates a single serine residue of the enzyme and inactivates it irreversibly.
COX-1 is present in all cells all the time, which is essential in biological function.
COX-2 is mainly an inflammatory product, which mediates inflammation response such as pain and fever.
Most inhibitions of COX are reversible and incomplete, except __________
Most inhibitions are reversible and incomplete, except aspirin, which selectively acetylates a single serine residue of the enzyme and inactivates it irreversibly.
What are the 4 general effects of NSAIDs?
- Decrease inflammation by ↓PGs
- Relieve mild pain by ↓PGs
- Anti-pyretic ↓PGE2 (prostaglandin E2) (Hypo-thalamus) [pyro=fire]
- Anticoagulation – inhibiting platelets aggregation by ↓TXA2 (thromboxane A2)
NSAIDs decrease inflammation by…
Decrease inflammation by ↓PGs
NSAIDs relieve midl pain by….
Relieve mild pain by ↓PGs
NSAIDs have anti-pyretic qualities by….
Anti-pyretic ↓PGE2 (prostaglandin E2) (Hypo-thalamus) [pyro=fire]
NSAIDs have anticoagulatory properities by….
Anticoagulation – inhibiting platelets aggregation by ↓TXA2 (thromboxane A2
What are prostaglandins?
Prostaglandin is a large group of lipid compounds derived from fatty acids.
- Highly potent with a wide spectrum of biological actions.Very short half-life (seconds to minutes).
- They are produced by almost all cells (except RBCs)
- They are synthesized, released, act and inactivated locally by the same tissues.
There are currently 10 known prostaglandin receptors on various cell types (brief knowledge):
- Sensitize spinal neurons to pain
- Regulate inflammatory mediation
- Constriction or dilation in vascular smooth muscle cells
- Aggregation or disaggregationof platelets
- Induce labor
- Regulate calcium movement
- Control hormone regulation
- Control cell growth
- Acts on thermoregulatory center of hypothalamus to produce fever
- Acts on the kidney to increase glomerular filtration rate
- Acts on parietal cells in the stomach
Describe the pathway involving arachidonic acid
1) AA is synthesized from the essential FFA linoleate or ingested in the diet.
2) AA is esterified to cell membrane phospholipids.
3) Many stimuli _liberate arachidonic acid (AA) from cell membran_e by activating phospholipases (vary with cell type).
* This includes thrombin, bradykinin, 5HT, NO, [Ag-Ab] reaction on the mast cells, general cell damage.
4a) Cyclooxygenase(COX) pathway:
* Involves Cox1 and Cox2
5a) Production of Prostanoids (e.g. prostaglandins, prostacycline, thromboxane)
4b) Lipooxygenase pathway (usually occurs in the white cells)
5b) The Leukrotriens are produced (mediates inflammatory responses/allergy)
What make up prostanoids?
1) Prostaglandins
2) Prostacycline
3) Thromboxane
What are the following collectively called?
1) Prostaglandins
2) Prostacycline
3) Thromboxane
Prostanoids
Leukcotrienes and Prostanoids are collectively called…..
Eicosanoids
Lipoxygenase pathway liberates…..
Leurkotrienes.
Cyclooxygenase pathways liberates…
Prostanoids (prostaglandins, prostacyclins, thromboxane)
Describe the Cyclo-oxygenase pathway
1) Cox 1 Pathway
- Constitutive (always there in the cells)
- This enzyme acts on the free Arachidonic acids and produces various by-products.
- These by-products include (homeostatic functions)
- GIT: Prostaglandin 2
- Renal: Prostaglandin 2-PG12
- PlatletsThromboxane 2
- Macrophage differentiation
- NSAIDs can block this enzyme. This i_nhibition is undesirable_ because it blocks the production of these prostaglandins- which causes the side effects in certain organs.
2) Cox 2 Pathway
- Inducable pathway (induced by cytokines, IL-1, TNF, growth factors)
- COX 2 is normally dormant, when activated produces excess infalmmatory prostaglandins
- (undesirable)- pain and inflammation
- Inhibition desirable
NSAIDs block both Cox 1 and Cox 2
Steroids (glucocorticoids) block Cox 2
What are the Pharmacokinetics of NSAIDs (what the body does to a drug)
Pharmacokinetics Of NSAIDs (What The Body Does To A Drug)
- All NSAIDs are highly lipophilic substances, so rapid and complete absorption after oral administration.
- It undergoes very little first-pass metabolism. Consequently, it has a very high bioavailability (95%)
- It has high degree of protein binding and thus small volumes of distribution.
- Onset of action is slow. Peak plasma concentration is achieved 3-4 hours after initial dose.
- Differences in clearance account for the variability in half-life among these drugs.
- Metabolized by liver through a variety of pathways. Most are metabolized into inactive products.
Describe the drug interactions (pharmacokinetics) of NSAIDs
1) Protein-Binding-Displacement Interactions
The following drugs also bind to proteins, NSAIDs might displace these drugs from proteins (protein-binding-displacement interactions), so increased free drugs in plasma, thus increased effect, which is dangerous!
- Oral anticoagulants
- Anticancer agent methotrexate
- Oral anti-diabetic agents
- Thyroid hormones
- Digoxin
2)Compete For Active Renal Tubular Secretion
NSAIDs can c_ompete fo_r active renal tubular secretion with other organic acids (e.g. uric acid).
3) Enzyme Inhibitors and Inducers
- Enzyme inhibitors (cimetidine, valproic acid) inhibit drug metabolism so enhance anti-inflammatory activity of NSAIDs
- Enzyme inducers (carbamazepine (Tegretol), phenobarbitone) accelerate drug metabolism so decrease activity of NSAIDs.
Describe the excretions of NSAIDs
NSAIDs are excreted in urine as: (don’t need to know detail)
- Phase-II glucouronides
- Sulfate conjugates
- Small percentage is excreted unchanged.
- 10% of acidic drug such as aspirin is excreted unchanged.
- Its rate of excretion is increased by urine alkalinisation (using antacids, aluminium hydroxide and milk of magnesia)
Name 1 traditional NSAIDs?
Aspirin
What are some side effects of NSAIDs?
Usually due to blocking of COX-1 enzyme.
- Bleeding
- GI tract
- Renal
- Water and electrolytes
- Asthma
- Liver
- ↓Immunity?
- Necrotising fasciitis (? impairment of the immune response)
- Pregnancy/lactation
- Reye’s syndrome
- Bones and cartilage (COX-2 inhibitors impair tendon and bone healing)
Describe Aspirin
Aspirin is acetylsalicylic acid, absorbed in the stomach and the upper intestine by passive diffusion. Note that salicylic acid is not taken orally (irritant!), only useful in topical (skin).
- Once in blood, most of it is de-acetylated (hydrolyzed in liver) to salicylic acid (salicylate) which is also responsible for most of anti-inflammatory and analgesic effects
- Salicylate bound to serum albumen (plasma protein)
Salicylate is conjugated in the liver with glycine (mainly) and glucuronic acid and excreted in urine. 10% excreted unchanged. It competes with uric acid secretion in kidneys and exacerbates gout.
Aspirin And Bleeding
Aspirin, irreversibly acetylates platelets COX1:
(1) Inhibit formation of TXA2;
(2) Platelets adhesions
Low Dose*** ***(90-160mg/Day)
Inhibits platelet aggregation (by inhibiting TXA2 production). Partially sparing of endothelial prostacyclin PGI2 (vasodilator).
- ⬇thrombosis (hence ↓coronary thrombosis) (reduce risk of heart attack and stroke)
- ⬇toxicity to kidney and gastric mucosa
- ⬆Vasodilatation
High Dose*** ***Aspirin (And Clinical Doses Of Other NSAID)
Additionally inhibits prostacyclins which are vasodilators (not desirable for IHD patients). More side effects
Explain how Aspirin may cause bleeding
Aspirin And Bleeding
- Aspirin, irreversibly acetylates platelets COX1:
- (1) Inhibit formation of TXA2;
- (2) Platelets adhesions
-
Low Dose (90-160mg/Day)
-
Inhibits platelet aggregation (by inhibiting TXA2 production). Partially s_paring of endothelial prostacyclin PGI2_ (vasodilator).
- ⬇thrombosis (hence ↓coronary thrombosis) (reduce risk of heart attack and stroke)
- ⬇toxicity to kidney and gastric mucosa
- ⬆Vasodilatation
-
Inhibits platelet aggregation (by inhibiting TXA2 production). Partially s_paring of endothelial prostacyclin PGI2_ (vasodilator).
-
High Dose Aspirin (And Clinical Doses Of Other NSAID)
- Additionally inhibits prostacyclins which are vasodilators (not desirable for IHD patients). More side effects
Describe NSAIDs and Bleeding
Bleeding time increases in patients on aspirin or other NSAID
- May ↑__operative blood loss (risk)
- Epidurals (for pain relief e.g. labour) may be at risk of developing haematoma (compress on spinal cord, emergency!).
What is a haematoma?
a solid swelling of clotted blood within the tissues.
Describe the effects of NSAIDs on the GI tract
Gastric epithelium produces gastric cytoprotective prostanoid (PG) protecting from acid damage. However, gastric cytoprotective PG synthesis is inhibited by aspirin (& other NSAIDs).
The production of this PG is increased by mucosal injury and irritants (e.g. ethanol). It:
Effects of this prostanoid:
- ↓ gastric acid secretion
- ↑ bicarbonate secretion, therefore, _↑ pH gradient b_etween epithelial cell surface and lumen
- _↑mucus synthesis (_carbohydrate polymer acts as an endogenous cytoprotective substance against the digestive effects of trypsin [duodenum] and HCl [stomach])
- ↑ mucosal thickness
- Dilates gastric blood vessels and ↑ mucosal blood flow
So NSAIDs reduces the prostanoid effects.
Other GIT Side Effects Of NSAIDs
Being organic acids, they irritate gastric mucosa (nausea, vomiting, diarrhoea)
Compare to oral NSAID, injectable one will not reduce side effect (still block PG production), may reduce some local effects.
Compare injectiable NSAID to oral NSAID,
injectable one will not reduce side effect (still block PG production), but it may reduce some local effects.
Describe the interaction between Aspirin and Asthma
Aspirin-induced asthma (AIA) due to cross-sensitivity with other NSAIDs
- Symptoms appears at an average age of 30 years (rare in children).
- May be severe and life threatening
Asthma triggered within 1-3 hours of ingestion of aspirin or other NSAIDs
(Samter’s triad)
Aspirin and Asthma Mechanism
Inhibition of COX1 and COX2 enzymes leads to:
- ↓PGE2 (bronchodilator) (NSAID may precipitate bronchoconstriction in any asthmatic patient)
- Activation of lipoxygenases → ↑inflammatory mediators (leukotrienes) → bronchospasm
What is the Aspirin/Samter’s triad?
Aspirin Exacerbated Respiratory Disease (AERD), also known as Samter’s Triad or Aspirin Sensitive Asthma, is a chronic medical condition that consists of asthma, recurrent sinus disease with nasal polyps, and a sensitivity to aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs).
Aspirin (or Samter’s) Triad
1) Aspirin intolerance (1) manifested by:
- Rhinitis (nasal obstruction, rhinorrhea and sneezing)
- Facial flushing.
These symptoms continue for few days then progress to:
2) Severe asthma (2)__.
3) Nasal polyps (3) will then appear at a later stage.
What is the mechanism of negative side effects of aspirin on asthamtic patients?
Aspirin and Asthma Mechanism
Inhibition of COX1 and COX2 enzymes leads to:
- ↓PGE2 (bronchodilator) (NSAID may precipitate bronchoconstriction in any asthmatic patient)
- Activation of lipoxygenases → ↑inflammatory mediators (leukotrienes) → bronchospasm
NSAIDs may precipitate broncho-constriction in any asthmatic patients
Describe Reye’s syndrome and aspirin
Reye’s Syndrome And Aspirin
Reye’s syndrome is an acute metabolic encephalopathy (following aspirin administration in children).
It can affect brain (encephalopathy); liver (fatty), ↑ammonia, ↑liver enzymes.
- Rare with 40% fatality. Infants and young children more prone after a viral illness (e.g. chicken pox)
- The role of aspirin remains very controversial. Avoid aspirin use in children with viral illness!!
What is Reye’s Syndrome?
Reye syndrome is a rapidly progressive encephalopathy.[2] Symptoms may include vomiting, personality changes, confusion, seizures, and loss of consciousness.[1] Even though liver toxicitytypically occurs, yellowish skin usually does not.
The cause of Reye syndrome is unknown.[2] It usually begins shortly after recovery from a viral infection, such as influenza or chickenpox.[1] About 90% of cases in children are associated with aspirin(salicylate) use.[2]
Describe NSAIDs and the kidney
- Effects are relatively mild and rare in healthy individuals.
- In compromised patients, NSAIDs are associated with renal failure:
- papillary necrosis,
- interstitial nephritis,
- acute tubular necrosis.
- This is called “analgesic nephropathy.” (mainly due to inhibition of COX1 enzyme)
Describe NSAIDs, pregnancy and lactation
NSAIDs, Pregnancy and Lactation
NSAIDs c_ross the placenta_, and excreted in milk.
Prostaglandins in pregnancy:
- Establishing and maintaining labor.
- ↑Uterine smooth muscle contraction
- Maintains patency of the ductus arteriosus in utero
NSAIDs (usually indomethacin) used for:
- Premature labor (inhibits labour)
- C_losure of patent ductus arteriosus_ in premature infants.
Describe Paracetamol
Paracetamol
Paracetamol is analgesic and antipyretic
- Mechanism of analgesic action unknown, may involve central ↓prostaglandin (?COX3 inhibition)
- Metabolism is via liver cytochrome P450
It is weak anti-inflammatory (weak COX inhibitor), but not considered NSAID because it does not exhibit significant anti-inflammatory activity.
Side Effects (Few)
Acute overdose causes fatal hepatic damage due to metabolite N-acetyl benzoquinone (normally conjugated with glutathione)/
Toxicity antidote is N- acetyl-cystiene (augments glutathione reserves in body and, together with glutathione, directly bind to toxic metabolite)
Routes Of Administration
- PO
- PR
- IV (perfalgan) (good analgesic for mild pain after minor surgery to avoid opioid)
Paracetamol Combinations
- Paracetamol + Codeine
- Paracetamol + NSAID
