Pharmacology S7 Flashcards
Non Steroidal Anti-Inflammatory Drugs (NSAIDs): Three primary therapeutic effects
Analgesia Anti-Inflammatory Antipyretic
Eicosanoids ?
Prostanoids
Includes Prostaglandins
LTs
TXA2
Prostacyclins
COX isoforms 1
COX-1 Isoform is Constitutively Expressed
- COX-1 expressed in wide range of tissue types
- PG synthesis by COX -1 has major cytoprotective role
Gastric mucosa Myocardium Renal parenchyma Ensures local perfusion – reduces ischemia
- PG t 1/2 short 10 mins - need constant synthesis
- Due to its constitutive expression, most ADRs caused by NSAIDs effects are due to COX-1 inhibition
COX-2 Isoform Expression is Induced by Injurious Stimuli
- COX-2 expression induced by inflammatory mediators such as Bradykinin
- COX-2 appears to be constitutively expressed in parts of the brain and kidney
- Main therapeutic effects of NSAIDs occur via COX-2 inhibition
- COX-1 and 2 not work independently and PG synthesis of both dependent on tissue and organ type
PGE2 يشتغل على يا ريسبتور حتى يسوي بين وعلى يا ريسبتور حتى يسوي حمى
Pain EP1
PYREXIA PE3
NSAIDs : GI ADRs
GI ADRs include stomach pain, nausea, heartburn, gastric bleeding, ulceration
- Gastric COX-1 PGE 2 stimulates cytoprotective mucus secretion throughout GI tract, reduce acid secretion and promote mucosal blood flow
- NSAIDs especialy long term have high incidence of GI ADRs between 10-30%
NSAIDs: Renal/Renovascular ADRs
Renal ADRs in HRH compromised patients due to renal perfusion blood flow
- PGE 2 and PGI 2 maintain renal blood flow
- If reduced by NSAIDs then GFR compromise
further risk of renal
• Na+ /K+ /Cl - and H2 0 retention follow with increased likelihood of hypertension
NSAIDs – Specific COX-2 Inhibitors
Large research effort put into developing highly selective COX-2 inhibitors Rofecoxib, celecoxib,
- Theoretically overcome ADRs due to COX-1 inhibition with equal efficacy to standard NSAIDs
- Not completely free of GI ADRs
- Clinical trials show significant increase of cardiovascular ADRs with long term use
- there approval for short term use only .
NSAIDs: Other ADRs
Vascular
• Increased risk of prolonged bleeding time bruising haemmorhage
Hypersensitivity
- Skin rashes(up to 15% for some NSAIDs) range from mild to rare Stevens Johnson syndrome. Bronchial asthma Anaphylaxis.
- Particular care when prescribing to asthmatics
NSAID protein binding can affect PK/PDs • Highly protein bound drugs affected by NSAIDs include
Sulphonylurea Warfarin Methotrexate
• Competitive displacement of these drugs may require dose adjustment to avoid changes in PK and PD Sulphonylurea - Hypoglycaemia Warfarin – Increased Bleeding Methotrexate – Wide ranging serious ADRs
Aspirin : The First NSAID
Aspirin used as reference NSAID
- The only NSAID to irreversibly inhibit COX enzymes by acetylation
- Unique PK profile. T½ less than 30 minutes rapidly hydrolysed in plasma to salicylate
Salicylate PKs dose dependent. At lower doses first order t½ ≈ 4hrs
- At higher doses ≈ 12x300 mg tablets/day zero order kinetics apply
- Widespread use as cardioprotective (75 mg)
- Increasing trial evidence as prophylactic for GI/breast other cancers –trials continue
Paracetamol: Toxicology
Single doses in excess of 10 g (20 tablets) potentially fatal
- At high doses Paracetamol PKs become zero order
- Elimination involves both Phase I and Phase II metabolism and production of highly reactive intermediate
- The intermediate is conjugated with glutathione and is then made non- toxic
- At very high doses glutathione is depleted
Unconjugated intermediate binds with cellular macromolecules –
- Precipitous loss of function leads to necrotic hepatic cell death
- Treatment for overdose must be given as soon as possible and guided by blood levels of drug
Paracetamol: Pharmacology mechanism of action
Currently unknown mechanism – weak COX-1 / COX-2 inhibitor
- Considered to primarily act in CNS possibly on a COX-3 isoform ?
- PKs in normal healthy patient t½ ≈ 2-4 hrs
- Caution in those with compromised hepatic function or alcoholics.
Endogenous Opioid Peptides
Enkephalins Endorphins (proenkephalin) (pro-opiomelanocortin) Precursors
Dynorphins
(prodynorphin)
ADRs of opioids
nausea, vomiting constipation drowsiness miosis
Dependence Tolerance
respiratory depression (monitoring) hypotension
