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  • pg 1
									        Birmingham City University

Prescribing from the Community Practitioner
          Formulary (V100 & V150)

              Roger McFadden
              Pharmacology II
   Analgesia and Anti-constipation drugs

   Click mouse to begin
                 Part I
              Inflammation

  The inflammatory response occurs
  immediately
  after trauma and…

• prevents the spread of pathogens
• minimises further damage to tissues
• promotes repair and healing
         The Inflammatory Response

The inflammatory response involves two key processes…

1. Vasodilation resulting in increased blood flow

2. Increase vascular permeability – plasma leaks from
   blood vessels into the damaged area
    Inflammation – signs and symptoms

Redness and Heat…

• Inflammation results in vasodilation
• More blood flows to the damaged area
• Blood makes the area red and warm

We will see later what causes vasodilation
   Inflammation – signs and symptoms 2

Swelling and Pain

• Chemicals released in inflammation cause small blood
  vessels to „leak‟
• Plasma enters interstitial fluid
• Plasma causes swelling in tissues
• Pressure on nerves causes pain
• Inflammatory chemicals also cause pain

We will discuss inflammatory chemicals later
macrophage
Mast cells


               Injury and
             immune system
                 proteins
             stimulate mast
             cells to release
             their mediators
                Inflammatory Pain

Swelling puts pressure on pain receptors causing pain

Prostaglandins produced in inflammation make the pain
receptors more sensitive to pain




                                         Pain neuron
                            Pain
                          receptors
                  Prostaglandins

Prostaglandins are members of a large family of
chemical mediators derived from arachidonic acid (a
fatty acid) and are found in all tissues of the body.

Prostaglandin biochemistry is complex, as are the
actions of prostaglandins themselves.

Prostaglandins belong to a family that includes
prostaglandins, thromboxanes and leukotrienes.
There‟s a whole journal
     dedicated to
  prostaglandins and
leukotrienes (and fatty
       acids) …!!!

 Good for insomnia…!!!
                Prostanoids - function
Prostanoids have many housekeeping roles unconnected with
inflammation, including…

Prostaglandin E2 (PGE2) – promotion of gastric mucus secretion and
inhibition of gastric acid secretion
Prostaglandin I2 (PGI2) - inhibition of platelet aggregation in the
clotting process, vasodilation

Prostaglandin D2 (PGD2) – inhibition of platelet aggregation in the
clotting process, sleep regulation
Thromboxane A2 (TXA2) – (produced in platelets) promotes their
aggregation in the clotting process
Plus many, many more useful functions
       Prostaglandins in Inflammation

Prostaglandin E2 (PGE2) main prostaglandin involved in
  inflammation
Secreted by mast cells and macrophages. PGE 2 acts
 synergistically with histamine and other mediators
Resulting in…
• vasodilation
• increased vascular permeability
• Make pain receptors more sensitive to stimuli
• pain transmission in dorsal horn of spinal cord
• pyresis (fever)
         Prostanoids in Inflammation

Mast cells and macrophages produce large amounts of
PGE2 that is released into the inflamed area

Increased synthesis of PGE2 results from the
upregulation of an enzyme – cyclo-oxygenase 2 (COX-2)

COX-2 is part of a family of cyclo-oxygenase enzymes
(isozymes)

COX-1 is perhaps the most common, being produced
constitutively in most cells of the body and producing
the prostaglandins involved in normal homoeostasis
Constitutive “housekeeping”        Inflammatory prostaglandin
  prostaglandin pathway                    pathway

Membrane phospholipid               Membrane phospholipid

                               NSAIDS
                                Target
      Intermediate                        Intermediate

                  COX-I            COX-II

      Intermediate                        Intermediate
                              NSAIDS
                                Hit


     Prostaglandins                      Prostaglandin E2
     “housekeeping”                       “inflammatory”
                NSAIDs - Effects

NSAIDs target COX II

They reduce the production of inflammatory
  prostaglandin E2 and so reduce inflammatory
  effects…

• reduction in oedema reduces dull pain
• reduction in allodynia (tenderness of skin)
• reduction in fever (anti-pyretic effect in
  hypothalamus)
           Modern NSAIDs include

Aceclofenac           Ketoprofen
Acemetacin            Mefenamic acid
Azapropazone          Meloxicam
Dexibuprofen          Nabumetone
Dexketoprofen         Naproxen
Diclofenac sodium     Piroxicam
Etodolac              Sulindac
Fenbufen              Tenoxicam
Flurbiprofen          Tiaprofenic acid
Ibuprofen           Differences in anti-inflammatory activity
Indometacin         between NSAIDs are small (BNF 2010)
                      NSAIDs

Which drug is suitable for which patient must be made
by the clinical practitioner but around 60% of patients
will respond to any NSAID (BNF 2009)

Anti-inflammatory action may take longer to become
effective than the analgesic action

Note that NSAIDs give continuous anti-inflammatory
action – not just pain relief
            NSAIDs – side effects

COX-1 and COX-2 are isozymes – very similar in
structure

Anti-inflammatory drugs that target COX-2 are thus
likely to bind to COX-1

Inflammatory PGE2 prostaglandin levels are reduced

Unfortunately, so are the prostaglandins produced by
COX-1 – the non-inflammatory “housekeeping”
prostaglandins
             NSAIDs – side effects

Inhibiting COX-I reduces levels of “housekeeping”
prostaglandins and can produce disturbances in
homoeostasis – side effects

The most common side-effect is…
GI discomfort (remember PGE2 protects the stomach by
promoting gastric mucus secretion and inhibiting gastric
acid secretion)

NSAIDs are contra-indicated in patients with peptic
ulcers, hypersensitivity reactions to aspirin, coagulation
defects, severe heart failure etc. (refer to BNF for full
list)
         Selective COX-2 Inhibitors

These drugs are highly specific for COX-2 enzyme and
do not inhibit COX-1 produced prostanoids
Long-term use is possible with less chance of side-
effects, particularly GI problems

Selective COX-2 inhibitors have been useful in the
treatment of chronic inflammatory diseases such as
rheumatoid arthritis.

At the time of writing (November 2010) celecoxib
(Celebrex) and etoricoxib (Arcoxia) appear in the BNF
plus parecoxib (Dynastat) – post-operative pain only
                         Paracetamol
                       (US – acetaminophen)

Paracetamol is a non-anti-inflammatory analgesic that has mainly
anti-pyretic and analgesic properties

Its mechanism of action is subject to much pharmacological
speculation but somehow it reduces prostaglandin synthesis

A reduction in prostaglandins in the hypothalamus reduces pyresis

The short-term usage of paracetamol at therapeutic doses
produces relatively few side effects

Hepatotoxicity can occur at only 2-3 times the therapeutic dose.
The toxic metabolite (N-acetyl-p-benzoquinoneimine) accumulates
causing necrosis in the liver

Acetylcysteine is used to treat paracetamol overdosage
             Part II
The Digestive System and Related
         Pharmacology
             Principles of Digestion

The digestive system is basically a tube that runs from
the mouth to the anus

During the passage of food along this tube, various
chemicals and enzymes are added to break down the
food into its component parts

The muscular walls of the gut squash and squeeze the
food along the system which aids the process of
breakdown
     Disorders of the Gastro-intestinal
           system - indigestion
Vague feeling of abdominal discomfort - possibly
involving pain and a feeling of fullness.

Rarely a serious health problem, unless accompanied by
other symptoms.

May be triggered by eating particular foods or drinks.

Symptoms may be worsened by anxiety and depression.

Treatment is usually by OTC preparations, antacids,
alginates or combinations of both.
Disorders of the Gastro-intestinal system

Gastro-oesophageal reflux disease - GORD (heartburn
& dyspepsia)

Discomfort caused by the reflux of acidic chyme from
the stomach into the oesophagus which can become
inflamed

Causes of GORD are various but commonly it is the
inappropriate relaxation of the gastro-oesophageal
sphincter that allows chyme to enter the oesophagus.

The symptoms may be worsened by coughing, lifting or
by certain foods.
   Drugs used in the treatment of GORD
Antacids - these usually contain aluminium or magnesium
compounds that increase the pH of chyme, making it less
acid and reducing its irritating effect on the oesophagus.

Simeticone acts as an anti-foaming agent

Alginates - form a raft that floats on top of the stomach
contents that reduces reflux and protects the
oesophageal mucosa. They are usually combined with an
antacid.
Most are available OTC such as Gaviscon (sodium
alginate, sodium bicarbonate, calcium carbonate)
H2 receptor antagonists and Proton-pump
            inhibitors (PPIs)
H2 antagonists include; cimetidine, famotidine,
nizatidine and ranitidine.

H2 antagonists block the H 2 receptors from the
stimulatory effect of histamine and thus reduce gastric
secretions

PPIs include; esomeprazole, lansoprazole, omeprazole,
pantoprazole and rabeprazole.

These drugs irreversibly inhibit proton pumps in the
parietal cells of the mucosa and so reduce stomach acid
                         Diarrhoea
Diarrhoea is the frequent passage of liquid faeces. It
can range from minor discomfort to emergency
requiring fluid and electrolyte replacement.


                               fluid secretion
                         GUT
              motility

                               fluid absorption




Diarrhoea involves either an increase in fluid secretion
into the gut, a reduction of fluid absorption from the
gut or an increase in motility
              Anti-diarrhoea drugs

First there is a need to identify and remedy the cause
of the problem, not just to relieve the symptoms. For
example, in the case of bacterial infection, an antibiotic
may be required plus any necessary rehydration.

Anti-diarrhoea drugs can either –

• reduce motility eg. opiates
• absorb excess fluid eg. kaolin
                   Constipation

Difficult or infrequent defecation that can have many
  causes including…
• abdominal muscle weakness eg. from surgery
• pain eg. from haemorrhoids
• low fibre diet
• sedentary lifestyle
• depression
• antidepressants (anticholinergics block
  parasympathetic system)
• opiates
• dehydration
              Treatment - laxatives
Treatment is primarily directed at cause e.g. diet
Bulk forming laxatives - increases faecal mass and
stimulates peristalsis eg. ispaghula husk,
methylcellulose and sterculia

Osmotic laxatives - pulls water into gut and softens
stools and increases faecal mass eg. lactulose,
magnesium hydroxide and macrogols (polyethylene
glycols)

Stimulant laxatives - increases fluid secretion into gut
and stimulates peristalsis eg. bisacodyl, docusate
sodium, sodium picosulfate & senna
End of presentation


                      That‟s all
                       Folks

								
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