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 :(
20
Q
Name some type of local anaesthetics?
A
- ESTERS- COCAINE, PROCAINE
- AMIDES- Lignocaine, buprivacaine, prilocaine
21
Q
What is the action of local anaesthetics?
A
- They BLOCK the **ACTION POTENTIAL INITIATION and PROPAGATION in NEURONS **By physically PLUGGING THE TRANSMEMBRANE PORE OF NA CHANNELS
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.
23
Q
What is the order of the nerves local anesthetic block first?
A
- Small myelinated axons- NOCICIEPTION and sympathetic transmission in** A delta/C** fibres first
- Unmeylinated axons
- Large myelinated axons
24
Q
How can local anesthetic be given?
A
- Direct infiltration
- Intravenously
- Nerve block
- Spinal
- Epidural
25
Q
What is the max dose of lignocaine , bupivicaine, Levobuvicaine and prilocaine that can be given to an adult?
A
- Lignocaine 4mg/kg , w adrenaline 7mglkg (90-200mins)
- Bupivicaine 2mg/kg , w adrenaline 3mg/kg (180-300 mins)
- Levobupivicaine 2mg/kg , w ardrenaline 3mg/kg (180-300mins)
- Prilocaine- 7mg/kg (w adrenaline 10mg/kg ( 60-90 mins)
- To calculate the maximum recommended dose, the weight of the patient must be known.
- A maximum dose of 4 mg/kg of lidocaine can be used per 90-200 minutes. In a 10 kg patient, this means that: 4 mg/kg x 10 kg = 40 mg total can be used. As 1% Lidocaine contains 10 mg of Lidocaine per mL, this means that we can use a total of 4 mL.
26
Q
How are the ester and AMIDE local anaesthetics broken down?
A
- Esters- rapidly hydrolysed by plasma cholinesterase
- Amides-metabolised in the liver
27
Q
What are the adverse effects of local anaesthetics?
A
- CNS
- agitation, confusion, tremors -> CONVULSIONS, RESPIRATORY DESPRESSION
- CVS-
- MYOCARDIAL DEPRESSION, VASODILATION-> HYPO BP
- HYPERSENSITIVITY REACTIONS
28
Q
What are glucorticoids and name some examples?
A
- a class of steriod hormones that bind to the glucocorticoid receptor ( present in every cell)
- glucocorticoids are part of the feedback in the immune system to turn down immune activity ( inflammation)
- Mild potent ( class I) - hydrocortisone
- Moderately potent ( class 2)- triamcinolone
- Potent ( class III)- methylprednisolone
- very potent ( class iv)- betamethasone diproprionate
29
Q
What are the effects of glucocorticoids?
A
- Anti-inflammatory
- Immunosupressive
30
Q
How do glucocorticoids act?
A
- Act on all phases of inflammatory response
- interact with intracellular receptors forming steroid-receptor complexes that modify gene transcription at the DNA level-> induction or inhibition of protein synthesis
- e.g. inhibition of genes for COX-2, phospholipase A2, cytokines such as IL
- Glucocorticoids also directly depress monocyte/macrophage function, decrease T cell levels and directly inhibit lymphocyte transport to the site of antigenic stimulation and antibody production
31
Q
How can glucocorticoids be given?
A
- Orally
- topically
- parentenally
32
Q
How are glucocorticoids carried in the blood?
A
- Bound to corticosteriod binding globulin
- enter cells by diffusion
- metabolised in liver
33
Q
What are the effects of glucocorticoids?
A
“I WAS HOPPING MAD”
- Infection
- Wasting of muscles ( due to protein loss)
- Adrenal insufficiency
- Sugar disturbances ( hyperglycaemia/diabetes)
- Hypotension
- Osteoporosis
- Peptic ulcer
- Pancreatitis
- Proximal myopathy ( due to protein loss)
- Incidental ( moon facies/orange on a stick- central obesity, easy bruising, hirstism
- Necrosis of femoral head
- Glaucoma
- MAD- psychological cahnges- europhia/depression/psychosis/emotional lability)
34
Q
When are anticoagulants used?
A
- Prophylaxis
- tx of thromboembolism
35
Q
What are the different classes of anticoagulants?
A
-
Vitamin K antagonists
- Warfarin
-
Inhibitors of thrombin
- unfractionated heparin
-
low molecular weight heparins (LMWH)
- enoxaparin/dalteparin
- Fondaparinux
- oral thrombin inhibitors
- melgatran
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
37
Q
How long does it take for warfarin to achieve it full anticogulant effect?
A
- 2-3 days
- as inactive factors replace active ones
38
Q
How is the effect of warfarin measured?
A
- Prothrombin time
- expressed as the internatinal normalised ratio (INR)
39
Q
What is the half life of warfarin?
A
- 40 hrs
- 5 days for INR to return to normal after cessation of tx
40
Q
How is warfarin metabolised?
A
- by hepatic microsomal enzymes to inactive 7 hydroxywarfarin
41
Q
What are the adverse effects of warfarin?
A
-
Haemorrhage
- in overdose - acutely reverse with clotting factors, if severe consider vitamin K
-
Drug reactions
- induce- Barbiturates/ carbamazepine
- Inhibit- ethanol/metronidazole
- **Teratogenicity **
42
Q
What is heparin?
A
- A naturally occuring glycosaminogylcan
- vary molecular weight (5000-15000)
- given by injection
- subcutaneous/ IV
- Short acting
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
44
Q
How is heparin effects measured?
A
- Activated partial thromboplastin time - APTT
- heparin has short duration of action ( 4-6 hours)
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
46
Q
What are the adverse effects of LMWH?
A
-
Haemorrhage
- less with LMWH than heparin
- stop in bad cases, give protamine sulphate
- Allergic reaction
- Heparin induced throbocytopenia ( HIT) - monitor platelets, less with LMWH cf heparin
- Osteoporosis when used long term
- Thrombosis- rare
47
Q
what is fondaparinux?
A
- A pentasaccharide
- inhibits factor Xa
- Reduce thromboembolism more effectively than LMWH in hip/knee arthroplasty and fx of hip
- Given 6h after surgery and at least 12h after removal of spinal/epidural catheter
48
Q
What is melagatran?
A
- Newer direct oral thrombin inhibitor
- wide therapeutic and safety window
- lack of need for monitoring no reported interactions with drugs
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
