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
Mechanism of Action of Opioid Receptors
All GPCRs
outward flux of K+ excitability
k binding ➔ influx of Ca 2+ via channels
ميو and d binding ➔ reduce cAMP synthesis
Opioid Receptors
Evidence in CNS for: - analgesia (supraspinal)
k - analgesia (spinal cord)
d - enkephalins (widely distributed)
Receptor Subtypes
Receptor Subtypes
µ1 µ2
1 - main effect – analgesia 2 - ADRs:
nausea, vomiting constipation drowsiness miosis
Dependence Tolerance
respiratory depression (monitoring) hypotension
k - pentazocine - dysphoria
Agonist of opioids
morphine
Methadone
Codiene
Antagonist of opioids
naloxone
Naltrexone
Partial agonist of opioids
buprenorphine
Agonist/antagonist
nalbuphine excellent analgesia without euphorea
Antagonist at meo receptor
Agonist at delta
Partial agonist at kappa receptor
Which opioids analgesic has longest half life
Methadone
15-30h
Opioid Analgesics
Give examples
Drug Morphine Diamorphine Methadone Buprenorphine Codeine Dihydrocodeine Fentanyl Pethidine Nalbuphine Tramadol
Half-life (T½) (h)
- 3 - 6.7
- 08 15-30 2–4
- 9 – 3. 9
- 4 – 4.5 3 – 12 2–5
- 9 – 7.7
- 3 - 6.7
Morphine
‘Gold standard’ opioid analgesic
Metabolism ?
Oral bioavailability
Plasma protein binding
Metabolism: glucuronidation
Morphine – 6 – glucuronide Morphine – 3 - glucuronide
Diamorphine اشرحي الخطوات حتى يتحول الى مورفين مع ذكر ال خالف لايفز
Diamorphine (Diacetyl morphine)
T½ = 5 min
Hydrolysis
Monoacetyl morphine
Morphine
T½ ~ 4 h
الأنزيم اسمه pseudocholin Estrase enzyme
Clinical Uses of Opioid Drugs
Analgesic - chronic visceral pain
Clinical Uses of Opioid Drugs
Morphine
Diamorphin
analgesic (terminal illness) diarrhoea Diamorphine – analgesic (terminal illness) epidural analgesia
Clinical Uses of Opioid Drugs
Codeine
Methadone
Codeine - mild analgesic (oral) (metabolised to morphine) Methadone - post-operative analgesia maintenance in dependence
Clinical Uses of Opioid Drugs
Fentanyl Alfentanil Remifentanil
Pethidine
Anaesthetics Alfentanil Remifentanil (can cause histamine release)
analgesia in labour (im) sickle-cell crisis (norpethidine (metabolite) ➔ convulsions) Do not give frequent repeat doses
Opioid Agonists-antagonists
Pentazocine Nalbuphine -
analgesic “
e.g. antagonist at µ, partial agonist at k, weak agonist at d
Opioid Antagonists
When they use
μ receptor antagonists Naloxone T½ 1 – 1.5 h Naltrexone T½ 4 h opioid toxicity reverse respiratory depression treatment of dependence
New Endogenous Opioid Peptides and Receptor
Peptides – Nociceptin
Nocistatin - blocks effects of nociceptin Endomorphin-1 Endomorphin-2
Receptor - ORL1 (opioid receptor-like 1)
