Analgesia, Anti-inflammatory, Anticoagulants Drugs Flashcards
0
Q
What would prescribe some for
1) severe acute pain- e.g. Trauma ?
2) mild inflammatory pain?
3) Severe Chronic pain?
A
1) iv strong opioids
2) NSAIDS & weak opioids given orally
3) strong opioids given orally cs or epidural +\~pt controlled analgesic systems
1
Q
What approach is used when deciding on to start analgesia?
A
- A progressive approach starting with SIMPLE ANALGEISA (e.g. NSAIDS) supplemented first by WEAK OPIOIDS and later STRONG OPIOIDS- “analgesic ladder”
2
Q
Name the 4 classes of analgesic drugs?
A
- Opioids
- NSAIDS
- Centrally acting non opioids - paracetamol, amitripylline , carbamazepine
- Local anaesthesics
3
Q
Name some strong and weak opioids ?
A
- Strong- morphine, diamorphine, fentanyl , pethidine, buprenorphine
- Weak- codeine, dihydrocodeine, dextropropoxyphene
4
Q
How do opioids work?
A
- They MIMIC ENDOGENOUS OPIOID PEPTIDES by causing a PROLONGED ACTIVATION OF OPIOID RECEPTORS- usually mu (µ) receptors
- these receptors are disrupted widely thruout the CNS most highly in areas involved in nociception such as dorsal horn of the spinal cord / thalamus
- so facilitating the OPENING OF POTASSIUM CHANNELS ( causing HYPERPOLARIZATION) and CALCIUM CHANNELS ( inhibiting transmitter release) at the NEURONAL LEVEL, acting via G PROTEINS linked to ADENYLATE CYCLASE
5
Q
Where are opioid receptors concentrated?
A
- Most highly in areas involved in NOCICIEPTION e.g. DORSAL HORN of the spinal cord and THALAMUS
6
Q
What are the clinical effects of opioids ?
A
- Analgesia
- Sedation
- Euphoria
7
Q
What are the adverse effects of opioids ?
A
- *Respiratory depression
- removed with naxolone ( short acting) or naltrexone ( long acting)
- * Nausea and Vomiting
- due to stimulation of chemoreceptor trigger zone
-
*Constipation
- require laxatives with strong opioids
-
*Tolerance and Dependance-
- to strong opioids in addicts
-
* Postural Hypotension-
- depression of vasomotor centre
-
*bilary spasm!
- constriction of sphincter of Oddi- esp morphine
- ***Pruritis due to histamine release **
- Bronchoconstriction- due to histamine release
8
Q
What acts quicker morphine or diamorphine?
A
- Diamorphine ( heroin) as more lipid soluble than morphine
- Fentanyl can be given transdermally
- Buprenorphine is effective given sublingually but associated with vomiting
9
Q
Give so examples of NSAIDS?
A
-
Salicylate acid derivates
- aspirin
-
Propionic acid derivates-
- ibuprofen, naproxen ( low incidence of side effects, first line in inflammatory arthropathies)
-
Miscellaneous -
- diclofenac, Indomethacin
-
Selective cox2
- celecoxib, rofecoxib ( few GI side defects but increased risk of cardiovascular morbidity / mortality)
- Oxicams- piroxicam (long t1/2 but assoc with GI bleeding)
- Pyrazolones- azapropazone- potent and high incidence se
10
Q
How do NSAIDS act?
A
- All inhibit CYCLO- OXYGENASE (COX) -> INHIBITION OF PROSTAGLANDIN SYNTHESIS.
- PG sensitize the nociceptive nerve endings to inflammatory mediators like histamine and bradykinine.
11
Q
What is cox1/2?
A
- Cyclo-OXYGENASE exists as a CONSTITUTIVE ISOFORM
- cox1 in most tissues where it has a house keeping function.
- Yet at sites of INFLAMMATION Cox2 is stimulated by cytokines.
12
Q
How do NSAIDS exhibit their an-inflammatory action?
A
- By inhibition of COX2
13
Q
What problems does inhibition of cox1 by NSAIDS do?
A
- Results in gastrointestinal damage-
- dyspepsia , gastritis, nausea
- -as a result of loss of the gastroprotective effects of prostaglandins E2 ( PGE2) and I 2( PGI2) which inhibit gastric acids secretion, increased blood flow thru the gastritis mucosa.
14
Q
What chemical disadvantage does aspirin have? How does it do this? What other actions does it have?
A
- It is an IRREVERSIBLE INACTIVATOR OF COX By ACETYLATING a SERINE residue of the CONSTITUTIVE form of the enzyme
-
ANTIPLATELET effects-
- inhibition of Platelet Aggregation
- Used in prevention of COLORECTAL CANCER/ delaying Alzheimer’s disease
15
Q
What other clinical effects do NSAIDS have? How do they do these things?
A
-
Analgesics
- via inhibition of PG, which sensitize nocipetive nerve endings to inflammation
-
ANTI-INFLAMMATORY
- via inhibition of prostaglandins -> less vasodilation and oedema
-
ANTIPYREXIAL-
- by **inhibition of endogenous pyrogen IL-1 **which acts via PG to elevate the hypothalamic set point for temperature control to fever.
- ** NSAIDS are reversible non selective competitve inhibitors of COX
16
Q
What are the side effects of NSAIDS ?
A
-
GI- Dyspepsia, nausea, gastritis
- inhibition of COX1 due to loss of protective prostaglandins E2 and I2 which inhibit gastric acid secretion, increasing blood thru the gastric mucosa, cytoprotective action
-
RENAL
- prostaglandins are involved in renal blood flow and NA/ h20 excretion.
- pt with cirrhosis, cardiac failure -increase in angiotension 2/ catecholamines-> inhibiting renal PG synthesis -> sodium retention! reduced blood flow- reversible renal insufficiency
- LUNG- bronchospasm in aspirin sensitive asthma, nasal polyposis
- MINOR- rash, urticaria, photosensitivity rxns
17
Q
What is paracetamol ? How does it act?
A
- ACETAMINOPHEN
- A WEAK INHIBITOR OF SYNTHESIS OF PROSTAGLANDIN
- via the production of reactive metabolites by the peroxidase function of COX 2 which could deplete gluthione, a cofactor of enzymes such as PGE synthase
- Central action via descending serotonergic pathways
18
Q
What mode of actions do paracetamol have?
A
- ANTIPYREXIAL
- ANALGESIC
- Weak antiinflammatory
- well absorbed orally
- doesn’t cause gastric irriation
19
Q
What side effects are there of paracetamol?
A
-
ANALGESIC- associated NEPHROPATHY
- may occur follwoing long term high doses of paracetmol
-
HEPATOTOXICITY in OVERDOSE-
- potentially fatal liver damage by saturation of the normal conjugating enzymes causing drug to be converted by mixed function oxidises to N-acetyl-p- benzoquinone imine. If it is not inactivated by conjugation with glutathione it reacts with cell proteins -> hepatic necrosis :(
22
Q
Describe the local anaesthetic molecules?
Why is this Important in their role?
A
- AMPIPHILIC molecules with a HYDROPHOBIC AROMATIC GROUP LINKED by an ESTER or AMIDE bond to a BASIC AMINE GROUP.
- Their activity is strongly pH DEPENDENT-
- being INCREASED in ALKALINE pH - proportion of ionized molecules is LOW- allows them to penetrate the nerve sheath/ axon as the unionized form is more membrane permeant.
36
Q
What is warfarin?
A
- A coumarin derivative
- with a similar structure to vitamin K
- active orally
- blocks vitamin K dependent Gamma carboxylation of glutamine residues on factors II, VII, IX, X -> modified factors known as PIVKA (proteins in vitamin K absence)
- these modified factors cannot bind calcium and so inactive for coagulation
43
Q
How does heparin work?
A
- It forms a 1:1 complex with anti-thrombin III, a protease inhibitor that inactivates thrombin ( factor II)
- also inactivates factor Xa
45
Q
What does low molecular weight heparin inhibit?
A
- LMWH anti-thrombin III complex inhibits factor Xa only
- results in less bleeding
- longer half life and so only single daily doses
- given subcutaneously injection
- doesn’t require monitoring
49
Q
What is rivaroxiban?
A
- An oral active direct factor Xa inhibitor
- max asorbed from but
- action is hours
- effects last 8-12 hours but factor Xa activity does not return for 24 hrs so once daily dosing fine
- Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi.
- Rivaroxaban does not inhibit thrombin (activated Factor II), and no effects on platelets have been demonstrated
