Analgesia, Anti-inflammatory, Anticoagulants Drugs Flashcards
(50 cards)
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
How can local anesthetic be given?
* Direct infiltration
* Intravenously
* Nerve block
* Spinal
* Epidural
25
What is the max dose of lignocaine , bupivicaine, Levobuvicaine and prilocaine that can be given to an adult?
* 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
How are the ester and AMIDE local anaesthetics broken down?
* **Esters**- rapidly hydrolysed by **plasma cholinesterase**
* **Amides-**metabolised in the **liver**
27
What are the adverse effects of local anaesthetics?
* CNS
* **agitation, confusion, tremors -\> CONVULSIONS, RESPIRATORY DESPRESSION**
* CVS-
* **MYOCARDIAL DEPRESSION, VASODILATION-\> HYPO BP**
* **HYPERSENSITIVITY REACTIONS**
28
What are glucorticoids and name some examples?
* 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
What are the effects of glucocorticoids?
* **Anti-inflammatory**
* **Immunosupressive**
30
How do glucocorticoids act?
* 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
How can glucocorticoids be given?
* Orally
* topically
* parentenally
32
How are glucocorticoids carried in the blood?
* Bound to **corticosteriod binding globulin**
* enter cells by **diffusion**
* **metabolised in liver**
33
What are the effects of glucocorticoids?
"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
When are anticoagulants used?
* **Prophylaxis**
* **tx of thromboembolism**
35
What are the different classes of anticoagulants?
* **Vitamin K antagonists**
* *_Warfarin_*
* **Inhibitors of thrombin**
* *_unfractionated heparin_*
* _low molecular weight heparins_ (LMWH)
* *enoxaparin/dalteparin*
* *Fondaparinux*
* oral thrombin inhibitors
* *melgatran*
36
What is warfarin?
* 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
How long does it take for warfarin to achieve it full anticogulant effect?
* 2-3 days
* as inactive factors replace active ones
38
How is the effect of warfarin measured?
* **Prothrombin time**
* expressed as the **internatinal normalised ratio (INR)**
39
What is the half life of warfarin?
* **40 hrs**
* **5 days** for INR to return to normal after cessation of tx
40
How is warfarin metabolised?
* by **hepatic microsomal enzymes** to **inactive 7 hydroxywarfarin**
41
What are the adverse effects of warfarin?
* **Haemorrhage**
* in overdose - acutely reverse with clotting factors, if severe consider vitamin K
* **Drug reactions**
* induce- Barbiturates/ carbamazepine
* Inhibit- ethanol/metronidazole
* **Teratogenicity **
42
What is heparin?
* A **naturally occuring glycosaminogylcan**
* vary molecular weight (5000-15000)
* given by injection
* subcutaneous/ IV
* Short acting
43
How does heparin work?
* It forms a **1:1 complex with anti-thrombin III,** a **protease inhibitor that inactivates _thrombin ( factor II)_**
* also inactivates factor Xa
44
How is heparin effects measured?
* Activated partial thromboplastin time - **APTT**
* heparin has short duration of action ( **4-6 hours)**
45
What does low molecular weight heparin inhibit?
* _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
What are the adverse effects of LMWH?
* **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
what is fondaparinux?
* 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
What is melagatran?
* Newer direct oral thrombin inhibitor
* wide therapeutic and safety window
* lack of need for monitoring no reported interactions with drugs
49
What is rivaroxiban?
* **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
