Analgesic Drugs

28.4.06

Not covered:
• Opiates.
• Disease-modifying drugs for rheumatoid arthritis.
• Drugs for neuralgic pain.

Pain
• Somatic.
-Inflammation of epithelial surfaces, trauma, sepsis.
-Felt at site of pathology.
• Visceral.
-Eg. myocardial ischaemia, colic.
-Poor localisation, often "referred."
• Neurogenic.
-Eg. neuralgia.
-No response to analgesics.

Osteoarthritis
• Common.
• Disease of cartilage.
• Big weight-bearing joints: knees and hips.
• More likely if there is joint insult eg. trauma.
• Congenital component: "primary familial osteoarthritis."
• Heberden's nodes, distal interphalangeal joints.

Rheumatoid arthritis
• Common.
• May commence at any age.
• Inflammatory condition: joints commonest "tissues" involved, but also inflames arteries etc.
• Small joints: hands and feet.
• Hands: metacarpal phalangeal joints and primary interphalangeal joints.

Gout
• Common.
• Paroxysmal arthritis, with quiet joints between attacks.
• Any joint, excepting axial skeleton.
• Uric acid crystals in joint fluid.
• Most commonly, first metatarsal phalangeal joint.

Ankylosing spondylitis
• Less common.
• Around 20% people with HLA B27.
• Low back pain in early 20s, leading to variable degrees of spinal deformity.
• Also, arthritis of hips and knees.
• Other tissues: iritis.

DRUGS
Paracetemol
• Mechanism pf analgesic activity not fully understood: ? decreased prostaglandin synthesis in CNS.
• Mechanism of antipyretic activity: decreased PG-E2 in hypothalamus.
• Safe, effective analgesic used OTC:
-Analgesia.
-Lowering elevated temperature.
-No anti-inflammatory effect.
• Dangerous in overdose.
• Main problem: hepatotoxicity.
• Takes around 24-36 hours to become apparent.
• Antidote: n-acetyl cysteine, but use in first 24 hours.
• Damage correlates with paracetemol concentration.
• Measure concentration - no earlier than 4 hours.

NSAIDs
Aspirin
• Acetylsalicyclic acid.
• Analgesic/antipyretic at low dose.
• Anti-inflammatory at high dose.
• [Anti-platelet activity at low dose.]
• Upper GI irritation and bleeding.

Aspirin overdose
• Partly eliminated unchanged in urine.
• Strong acid, lipid soluble at acid pH (remember Henderson-Hasselbach).
• "Alkaline diuresis": iv bicarbonate to yield alkaline urine.
• Hence, water soluble aspiring and higher aspirin clearance.
• Dialysis in most serious cases.

Other NSAIDs
• [Ibuprofen: OTC as analgesic.]
• Naproxen.
• Diclofenac.
• Useful in inflammatory arthritis.
• Use adjunct to opiates in terminal care.

COX-II inhibitors
• Anti-inflammatory, useful for Rh-D.
• Much more expensive than older NSAIDs.
• Reserve for selected patients with PUD or GORD.
• Rofecoxib withdrawn for SAEs - may prove to be class effect.

NSAID adverse effects
• GI.
• Salt and water retention.
• Renal impairment.
• Asthma may be precipitated.

DRUGS FOR GOUT
Acute gout
• Commonly precipitated by diuretics (especially thiazides).
• May be very severe and resemble septic arthritis.

Treatment
• Rest.
• NSAID until arthritis settles.
• Worst cases merit prednisolone.
• If prophylactic drug (eg. allopurinol) to be used, then NSAID "cover."

Allopurinol
• Purine bases metabolised via xanthines to uric acid.
• Xanthines water soluble.
• Uric acid pretty insoluble.
• Allopurinol inhibits xanthine oxidase.
• Used to decrease frequency of paroxysms.
• May precipitate acute gout when first started: NSAID "cover."

Acute drug reactions and interactions
• GI upset.
• Rash.
• Azathioprine - potentiated.
• Warfarin - potentiated.

The Rise Of The "Nanny State"

27.4.06

• Increasing state responsibility for health.
-Vaccination.
-Health of infants.
-Health "protection" and "promotion."
• Risk and responsibility in health.

Why introduce state medicine?
• Threat theory.
-Provoked by epidemic diseases - cholera.
-"Urban penalty" of high mortality rates.

Contagious Diseases Acts
• Passed in 1864, 1866, 1869.
• Women with disease could be detained and forcibly treated.
• Acts suspended in 1883, repealed in 1886.

Compulsory Disease Notification
• 1889 Act.
• Permissive, not compulsory.
• Limited to certain infectious diseases.
-Smallpox, diphtheria, scarlet fever, typhoid.
-Later, tuberculosis.

• Improvement theory.
-Fear of national deterioration.
-Increasing competition with German and USA.
-Poor health of Boer War recruits.
-1904 - Report on Physical Deterioration.

19th Century medical care
• Piecemeal, un-integrated network.
• Three types of hospitals.
-Voluntary (including cottage).
-Poor Law.
-Municipal (isolation).

• Primary care.
-Private physicians for wealthy.
-Dispensaries for working classes.
-Increased use of friendly societies, clubs.

Health visiting
• Voluntary middle class movement.
• Salford - 1870s.
• Targeting mothers.

Political pressure
• Enfranchisement of working classes (and women!)
• Rise of Labour Party.

Liberal Welfare Reforms
• 1905-1911 - "a welfare state in embryo."
• School medical service.
• Free school meals and milk.
• Infant and maternal welfare clinics.
• Health visiting.
• 1911 - National Health Insurance Act.
• Established panel doctors (state paid).
• Only covered working men.
• Limited medical treatment.

Enough to eat?
• 1930s.
• Evidence of malnutrition in working class communities.
• Government attitude.
• Politicisation of health research.

1948 - new expectations
• 5 July 1948 - formation of NHS.
• Further shift in responsibility from individual to state.

Role of medicine
• Central to new NHS.
• Aneurin Bevan's attitude to engaging doctors: "If necessary, I will stuff their mouths with gold."

Smoking and lung cancer
• 1950s.
• Richard Doll and Austin Bradford Hill.
• Study of doctors' smoking habits.
• Government response.

Duty to inform?
• 1962 - Royal College of Physicians report on smoking and health.

Duty to promote?
• Exercise and healthy eating.
• Family planning.

Duty to protect?
• Public expectations.
• 1970s whooping cough vaccine problems.
• AIDS.
• BSE.
• Passive smoking.

Community Perspectives On Early Childhood Development

26.4.06

There was also a handout to go with. The notes below are just the slides that weren't included on the handout.

Why screen children?
• To detect remedial condition.
• To check growth.
• To check developmental milestones reached.
• To support parents - give information, address concerns.
• To address public health issues.

Neonatal examination
• Hospital-based, within first 24 hours.
• Check weight and head circumference.

Major disorders
• Down's syndrome (1 per 600).
• Congenital hypothyroidism (1 per 5,000).
• Phenylketonurea (1 per 13,000).
• Congenital heart disease (7 per 1,000).
• Congenital dislocation of the hip (1 per 1,000).
• Undescended testes (60 per 10,000).

6-8 week check
• Done by GP in specific baby clinics.
• Developmental milestones.
• Measure and plot weight, length and head circumference.
• Top-to-toe examination.
• Ask about parental concerns and address issues.
• Discuss feeding, parental coping, smoking, prevention of cot death, immunisations.
• Screen for post-natal depression.

6-9 month check
• Done by health visitor.
• GP only involved if problems.
• Looking for:
-growth;
-squint - cover test;
-hearing - distraction test;
-developmental milestones.
• Check for parental concerns.
• Ask specifically about hearing and vision concerns.

3 year check often by questionnaire.

5 year check
• Done by school nurse.
• Children with special educational needs - followed up annually.


Growth problems
Failure to thrive:
• Failure to gain weight at normal rate.
• Commonest cause: inadequate dietary intake.
• Further investigation - CF, coeliac disease.

Short stature:
• Short parents = constitutional short stature.
• Height below 3rd centile.
• Causes: chromosomal abnormalities, poor gestational nutrition etc.

Normal hearing
• Not turning to sound <6 months old.
• Ignoring being called at 3-4 years.

Walking
• Normal late walking up to 18 months.
• Often familial.
• Bottom shufflers - 10% of population - often familial.
• Hypotonia.

Referrals to community paediatric units
• Hearing problems.
• Speech and language problems.
• Visual problems.
• Developmental delay.
• Behavioural/psychological problems.

Important issues to cover in child health promotion clinics
1. Immunisations
• Explore parental attitude to immunisations.
• Address parental concerns.
• Check immunisations up-to-date.

2. Universal advice
• Cot death prevention.
• Smoking cessation etc.

3. Parental issues
• Contraceptive advice.
• Post-natal depression screening.
• Support of good parenting skills.
• Parental concerns.

4. Child protection issues.
• Four types of abuse:
(i) physical;
(ii) emotional;
(iii) neglect;
(iv) sexual.
• Watch out for:
-mental health problems of carers;
-previous history of neglect;
domestic violence.

If child abuse suspected
• Consider whether child needs immediate removal.
• Other cases: refer to social services.
• Patient confidentiality can be breached in child's best interests.

Cystic Fibrosis: From Laboratory To The Clinic

25.5.06

Short history
• Dorothy Andersen - pathologist with special interest in children - carried out post-mortems on children - start of last century - coeliac disease (gluten insensitivity) - found not coeliac disease: "cystic fibrosis of the pancreas" - associated respiratory symptoms.
• Paul di St Agnisi, 1950s New York City.
• High sweat salts - drawing on Medieval folklore - became diagnostic test for CF - pylocarpin applied topically and charge applied to stimulate sweat glands.
• Holistic care:
-chest;
-nutrition;
-social.

Why do children with CF have problems with chest infection?
• Salt transport.

CFTR gene makes ion-transporting protein pore - pores situated in apical surface of epithelium. Lungs sterile due to "mucosillary escalator" - cilia - periciliary aqueous layer helps cilia to beat - mucous layer on top of this - absorbing liquid in respiratory epithelium via sodium transport (ENaC) - water pulled through via osmosis.

CFTR protein:
• 12 transmembrane domains.
• Large R domain.
• 2 NBFs.
• Cl- out of cell, Na+ into cell through difference channel.
• CFTR not Na+ - only regulates Na+ channel - acts as brake on Na+ channel.
• No CFTR protein in CF - lose brake on Na+ channel - increased Na+ absorption - dehydrated periciliary aqueous layer - cilia clamped down - problem with mucosillary clearance.
• Body can form mucosillary transport through other mechanisms - more mucous formed, but becomes dehydrated also - prime breeding ground for bacteria - form chronic infection.

• Difficult bacteria.

• Inflammation - neutrophils enter lungs and become stuck in mucus - explode - release lots of DNA - very sticky.

Paediatric clinic
• Multi-disciplinary team.
• CF nurse specialist.
• Dietician.
• Physiotherapist.
• School teacher.
• Social worker - disability living allowance.
• Psychologist.
• Physicians.

Hope 1: ion transport modulators
• Amiloride - clinical trials - only works for 30 minutes.
• Long-acting Na+ channel blockers.
• Chloride secretagogues.
• Problems:
-dynamic;
-early;
-mucus.

Hope 2: gene therapy
• Somatic gene transfer.
-Replication-deficient viral vector.
§Integrating.
§Non-integrating.
-Liposome vectors.
• Systemic gene transfer.
• Stem cell.
• Foetal gene transfer.

Hope 3: modulators of inflammation
• Steroids.
• NSAIDs - ibuprofen.
• Azithromycin.
• Newer compounds.

Module 1.10

Going to Nursery School.
24.4.06 - 5.5.06.

Functional Significance Of The Mouth

31.3.06

The oral cavity
Tissues
• Bone.
• Joint(s).
• Epithelia.

Borders
• Lips.
• Palatoglossal fold.
• Palate.
• Cheeks.
• Floor of mouth.

Lips
• Muscular structures.
• Non-keratinised oral mucous membrane.
• Angle of mouth.

Cheeks
• Muscular structures.
• Non-keratinised oral mucous membrane.
• Buccinator muscle.

Tongue
• Dorsum.
• Ventral (inferior) surface.
• Lateral borders.

Dorsum of tongue
• Anterior two-thirds - sensory (V), taste (VII).
• Posterior one-third - IX.

Tongue muscles
• Extrinsic - genioglossus, hyoglossus, palatoglossus.
• Intrinsic - superior longitudinal, inferior longitudinal, vertical, transverse.

Functions
• Mastication.
• Speech.
• Taste.
• Oral hygiene.
• Communication (gestures).
• Sensory (infant).

Hard palate
• Maxilla and palatine bones.
• Thick keratinised epithelium.

Soft palate

Salivary glands
• Minor salivary glands - everywhere.
• Major salivary glands.
-Parotid (25% - mainly serous).
-Submandibular (70% - mixed saliva).
-Sublingual (5% - mainly mucous).

Muscles of mastication
• Temporalis.
• Masseter.
• Medial pterygoid.
• Lateral pterygoid.
• Accessory muscles of mastication.

Temporomandibular joint
• TMJ = synovial joint with intervening disc.
• Disc divides joint ccavity into 2.

Nerve supply to muscles of mastication
• All V apart from buccinator (VII).

Nerve supply to oral cavity
• V (trigeminal).
-Ophthalmic branch.
-Maxillary branch.
-Mandibular branch.

Blood supply to oral cavity = internal carotid and its branches.

Saliva
Protective functions
• Lubrication - mucins, glycoproteins, water.
• Antimicrobial.
-Amylase - breaks up starch.
-Complement.
-Lysozyme.
-Secretory IgA.
• Contains growth factors - healing.
• Maintains mucosal integrity.
• Lavage/cleansing/clearance of sugars and acids.
• Buffering.
• Remineralisation.

Food- and speech-related functions
• Food preparation - water, mucins.
• Digestions - amylases.
• Taste.
• Speech.

Considerable volume produced each day: 0.5-0.75l.

Salivary gland anatomy

Secretory unit
• Acini.
• Ducts.

Parotid gland
• VII branches divide gland into superficial and deep lobes, while moving from stylomastoid foramen to muscles of facial expression.

Salivary constituents
• Ions - Na+, K+, Ca2+, PO4-, Fl-, Cl-.
• Miscellaneous.
-Blood and blood-derivative compounds.

Factors contributing to saliva content
• Normal human variability.
• Unstimulated versus stimulated saliva.
• Ageing (not per se, but medications of ageing do).
• Medications - 500 that cause dry mouth (xerostomia).
• Disease.
• Circadian rhythms.

Factors affecting salivary production
• Local diseases.
• Systemic diseases.
• Medication.

Salivary dysfunction and oral sequelae
• Dental caries.
• Mucositis.
• Oral ulceration.
• Taste.
• Swallowing.
• Dentures - loose and painful.
• Infections.

Dental anatomy
Human dentition
• 32 permanent, 20 primary.

Incisors
• Straight edges.
• Designed to cut through food.

Canines
• Function: pierce and hold food.
• Located at corners of mouth.

Premolars
• Some characteristics of both canines and molars.
• Located between canines and molars.

Molars
• Crush and grind food.
• Located at back of mouth.
• First, second and third molars.

Tooth surfaces
• Proximal.
• Lingual.
• Facial.
• Incisal/buccal.

Enamel
• Covers crown.
• Hardest substance in human body.
• Highly mineralised.
• Brittle.
• After initial completion, new enamel cannot be formed.

Dentine
• Largest component of tooth.
• Contributes to tooth colour.
• Can form throughout life - reparative dentine.
• Structure: dentinal tubules.

Cementum
• Covers root.
• Formed continuously throughout life.

Dental pulp
• Soft tissue.

Supporting structures (periodontium)
• Cementum, periodontal ligament, gingivae, alveolar bone.

Dental x-rays
1. Bitewing - check for dental caries in back teeth.
2. Periapical - whole-tooth radiograph.
Panaramic view (orthopantomogram - OPG) - plan view of all teeth - MOST IMPORTANT.

Formation of teeth
• Entire primary dentition begins at 6-8 weeks in utero.
• Successional secondary dentition begins at ≈20 weeks in utero.
• Stages of crown development.
• Dental lamina/tooth bud.
-Extends in from lamina.
-Enamel organ formation - will mineralise.
-Cap stage.
• Initial amelo- and dentinogenesis.
• Ameloblasts and odontoblasts.

Tooth eruption dates

And bytheway, I have complete faith in Paul Collingwood.

Foetal circulation

30.3.06

Cardiovascular system
• Vasculogenesis.
• Early circulation.
• Foetal circulation.

Vasculogenesis
• Day 17.
• Wall of yolk sac.
• Splanchopleuric mesoderm form aggregations of cells.
• Blood islands.
-Core of haemoblasts.
-Surround of endothelial cells.
-Haemoblasts - embryonic blood cells.
-Endothelial cells - blood vessel endothelium.
-Blood vessel endothelia elongate.
-Interconnected mesh.
-End week 3: vascular network around yolk sac, connecting stalk and chorionic villi.
• Angioblastic cords - throughout germ disc.
• Angioblastic plexuses.

Growth of circulatory system
• Continued formation and fusion of angiocysts.
• Angiogenesis - budding and sprouts of new vessels.

Cardiogenic area

Heart development
• Two tubes.
• Fusion.
• Single chamber.
-Sinus venosus.
-Atrium.
-Ventricle.
-Bulbus cordis.
-Truncus arteriosus.
• Chamber elongates - restricted by volume of primitive pericardial cavity.
• Develops kink.

Circulation
• Blood from placenta → primitive heart → dorsal aortae → umbilical arteries → tertiary villus → umbilical veins → sinus venosus → primitive heart.
• Vitelline vessels give rise to portal vein.

Placental structure
• Blood pumped in spurts into intervillous space.
• Vessels on maternal side separate entities that pump maternal blood to placenta.
• Branches increase surface area - each branch contains mesh of capillaries.
• Embryonic tissue forms septa - strengthen placenta (cotyledons) - seen on maternal side.

Foetal haemoglobin - hypoxia countered by
• γ chains in haem.
• Carry more O2 - greater affinity for O2.
• 180gl-1.
• Greater cardiac output.

Umbilical cord
• Begins as connecting stalk.
• 2 arteries, 1 vein (right umbilical artery disappears).
• Set in gelatinous substrate - mucoid connective tissue.
• → ductus venosus.
• Bowels herniated into umbilical cord, then come back into abdomen later in development.
• Umbilical vein → north towards liver → shortcut: ductus venosus → inferior vena cava.

Veins

Portal vein

Bilateral symmetry and regressions
• Arterial system - regresses on right.
• Venous system - regresses on left.

Limb vessels
• Primary - axial artery.
• Axial artery rearranged into minor vessels.
• Secondary vessels form major vessels - new development from primary vessels.

Arch arteries
• Trucus arteriosus → 6 arch arteries (number 5 doesn't develop in humans) → aortic trunk → divides into 2 flows.
• Give rise to adult vessels.
-IV and VI important.
-I = maxillary artery.
-IV = arch of aorta on left, subclavian on right.
-VI = ductus arteriosus on left (shunt between pulmonary circulation and systemic circulation).

Foetal circulation
• IVC.
• Right atrium.
• Foramen ovale (shunt between right and left atria).
• Left side.
• Head and brain.
• Right side.
• Pulmonary trunk.
• Ductus arteriosus.

Infant circulation.

Auscultation.

Introduction To Antibiotics

27.3.06

What?
• Compounds that act against bacteria (antimicrobials - against parasites, fungi).
• Kill (bacteriocidal) or inhibit (bacteriostatic) - not useful distinction nowadays.
• Administered orally, parenterally or topically.
• Resistance may rapidly develop.

Complex relationship
• Drug ⇔ [potency versus resistance] ⇔ Bug.
• Bug ⇔ [virulence versus immunity, attack versus defence] ⇔ Host.
• Host ⇔ [metabolism versus toxicity] ⇔ Drug.
• Balance makes outcome good or bad.

How are bacteria classified?
• 2 ways - colour on staining or shape.
• Gram staining - gram + (purple) or gram - (pink).
• Shape - coccus (round) or bacillus (rod).

Some medically important bacteria
Gram +
• Cocci (generally throat).
-Staphylococcus.
-Streptococcus.
• Rods.
-Clostridia - cause of antibiotic diarrhoea - antibiotics kill colonic flora and new ones recolonise.

Gram -
• Cocci.
-Neisseria - neisseria meningitidis causes meningitis, neisseria gonorrhoea.
-Haemophilis - also slightly bacillus with capsule - more virulent - meningitis in <4 years, swells without capsule, troat infection, epiglottis - HiB vaccine, haemophilius, influenza B vaccine - capsule.
• Rods - generally gut/abdomen.
-E. coli.
-Proteus.
-Klebsiella.
-Salmonella.

• Important: gram + cocci and gram - rods.
• Anaerobic bacteria - strep faecalis etc.
• Human bites dirtier than dog bites.
• Staphylococcus aureus - boils - druggies get most often.

Infections
Is there infections? Take culture. Fever? Pain, swelling, redness, tachycardia, sweats, pus, toxaemia.

Where is site? What are likely organisms?

What antibiotics are likely to be effective?
• β lactams.
-Penicillins (amoxycillin, flucoxacillin, benzylpenicillin)
-Cephalosporins (cephtriaxone).
-Others.
• Aminoglycosides.
-Gentamycin.
• Macrolides.
-Erythromycin, clarithromycin.
• Quinolones.
-Ciprofloxacin against gut rot/diarrhoea.
• Tetracycline.
• Glycopeptides.
• Metronidazole.

Is there likely to be resistance?

Will the antibiotic penetrate to the site?

Route of administration?

What is the toxicity and cost?

Likely resistance?
• Community acquired or hospital acquired?
• Previous antibiotics?
• Travel history?
• Nasocomial infections - hospital acquired - tend to be resistant eg. MRSA, clostridium difficile.
• Preventable - hygience, antibiotic control.
• Broader spectrum used.

Penetrating to site? Route? Consider
• Very sick?
• Serious infection?
• Barrier to drug absorption?
• Malabsorption - post-surgery?
• Vomiting or swallowing problems?
• Poor bioavailability.

Common mistakes
• Often not effective.
-Tonsillopharyngitis (viral).
-Gastroenteritis (self-limiting usually).
-Colonisation versus infection.
• No prior culture obtained.
• Inappropriate dose/route.
• Continued for too long.

Change And Choice In Childbirth

24.3.06

• Places of birth and choices of support.
• Medicalisation of pregnancy and childbirth.
• Maternal mortality - the silent crisis.
• Choice and rights.

Changing place of birth
• 1927 ~ 85% home births.
• 1961 ~ 32% home births.
• 1980 ~ 1.3% home births.
• Hospital birth increasingly synonymous with "safe birth."

Man-midwives
• Exploiting medical knowledge.
• AKA "accoucheurs."
• William Smellie (1733-1815).
• 3 stages of labour.
• Rise of the surgeon - apothecary - general practitioner.

18th Century
• 1730s - increased use of forceps.
• More anatomy, physiology and pathology knowledge.

But…
• Limited obstetric teaching.
• No successful caesareans before 1890s.
• Despised by physicians and surgeons.
• No Royal College of Obstetricians until 1929.

Reducing the risks of childbirth
• James Young Simpson - anaesthesia in childbirth 1849.
• Queen Victoria's "blessed chloroform" 1851.
• Management of complications.
-Placenta praevia.

Puerperal "childbed" fever
• Streptococcus pyogenes.
• Ignaz Semmelweis (1818-65).
• Vienna Maternity Hospitals.
• Proved medical students carried infection to maternity wards from mortuary.
• Introduced carbolic hand wash.
• Semmelweis ridiculed.
• Louis Pasteur (1822-95).
• Joseph Lister (1827-1912).
-Antisepsis technique.
• Single Causation theory.
• 1880s - obstetric antiseptic practice.

Medicalisation of childbirth
• Increased use of anaesthesia.
-"Twilight sleep" fiasco.
• Western women "all have difficult labours."
• GPs applied forceps under general anaesthetic in 50% of normal deliveries.
-For doctor's convenience?

The backlash?
• Grantley Dick Read (1890-1959).
• "Natural Childbirth" published 1933.
• Stressed the "psychosomatic" as opposed to "mechanistic" approach.
• "Fear-tension-pain" syndrome.
• Advocated more relaxation and less drugs.

Professionalisation of midwifery
• Pre-20th Century image: "drunken old hags."
• 1902 Midwives Act.

Maternal mortality
• 1890s ~ 13 maternal deaths a day.
• 1990s ~ <1 maternal death a week.
• 1920-1929 ~ 25,000 maternal death in UK.
-Puerperal infection, toxaemia, haemorrhage.

Statistical black spot - Rochdale
• Most dangerous place in Britain to give birth in 1930.
• 90 maternal deaths per 10,000 deliveries.
• Government inquiry.

"Magic bullets"
• Gerhard Domagk (1895-1964).
• 1935 - developed first sulphonamide.
-Prontosil.
-Led to almost 100% recovery from puerperal fever.

Reversing the trend
• Ergometrine.
• Blood transfusions.
• Penicillin (1945).
• NHS (1948).
• Improved medical education.

Liverpool's contribution
• Robert Minnitt (1889-1973).
-Developed self-administration of obstetric anaesthesia "gas and air" machine.

New issues
• Increasing rates of medical intervention.
• Episiotomy rare before 1970s.
• Caesarean rates.
-1950s ~ 2%.
-2000s ~ 20%.
• Screening and monitoring.

Birth, The Neonate And Growth

Another of Dangerfield's.

23.3.06

• Pregnancy.
• Skull shape.
• Anthropometry.
-Techniques.
-Growth charts - centiles.
-Longitudinal growth charts.
• Scoliosis.
• Influence of parents.

Growth variations of foetus
• Smoking.
• Poor nutrition/poverty.
• Diabetic mother.
-Obese child, but soon normalises.
• Low birth weight.
-Preterm versus light for dates.
• Poor lactation and failure to thrive.
• Neglect.
-Abuse.
• Hospital.

• Bone growth.
• Ossification.
• Growth plate.
• Foetal skull.
• Foetal skeleton.

• Ability.
• Motor development milestones.
• Walking.
-Gluteus maximus (gluteal region).
-Ilio-tibial tract.
-Upper outer quadrant for IM injections.
-Achilles tendon.
-Calf.
• Reflexes.
-Grasp.
-Moro.
-Stepping.
• Bony landmarks.
-Bones of forearm.
-Extensors of forearm.
-Surface markings of hand.
-Surface landmarks of wrist.
• Growth influences: hormones.
• Determinants of growth/determinants of health.

"Mothers, Babies and Disease in Later Life" - Barker.

Birth And The Post-Natal Period

22.3.06

"Childbirth itself is a natural phenomenon, and the large majority of women need no interference whatsoever - only close observation, moral support and protection."
-Klooserman, 1972.

Antenatal
• Scans.
• Clinics.
• Groups.
• Birth plan.
• Waiting.

Onset of labour
• Spontaneous rupture of membranes.
• Cervical changes.
• Change in contractions.

Spontaneous rupture of membranes
• "Waters break."
• Regular observations of mother and foetus.
• If >24 hours to deliver - paediatric care for infant.
• If >72 hours to delivery - induce.

Cervical changes
• Hormonal effects thin cervix (effacing).
• The show.
• Mechanical effects cause cervix to dilate.
• Dilates up to 4cm in early (latent) phase of labour).
• Dilation of >2cm considered "in labour."

Changes in contractions
• Natural rhythmic smooth muscle contractions through late pregnancy.
• Hormonal and mechanical changes cause alteration to contractions.

Remember!
• Pregnancy, labour and birth are normal.
• Physiology, not pathology.

Where to now?
• Home versus hospital.
• Individual decision.
• Majority of babies delivered in hospital.
• ≈30 home births per year in Liverpool region.
• Philosophical, resource, midwifery and legal issues.

Home births
• Ante-natal preparation and perinatal monitoring.
• Uncomplicated pregnancies with expected normal labour and delivery.
• Primiparous women accepted.
• Patients given information on safety of home births.
• Initial home visit in second trimester to check environment.
• Second visit at 35+ weeks to ensure equipment delivered and confirm birth plane.
• Patient contacts delivery suite as normal at onset of labour.
• Two midwives at birth.
• Problems lead to 999 transfer to hospital.

Pain relief in labour - non-pharmacological methods
• Support.
• Position.
• Mobilisation.
• Complementary therapies - massage, acupressure, aromatherapy, music etc.
• Water.
• TENS.

Pharmacological methods
• Paracetemol.
• "Gas and air" (nitrous oxide and oxygen in 1:1 ratio).
• Opiates - pethidine (less crosses into foetal circulation).
• Epidural (not home births).

Progression of labour
Stage 1
• Latent phase - up to 8 hours, gradual increase in strength of contraction.
• Active phase - up to 6 hours, contractions become more painful.
• Transitional phase - ≈1 hour, painful contractions.
• Progression from latent to active phase heralds time to call delivery suite.
• Progression variable, but overall labour 12-14 hours for primiparous women (6-7 hours for multiparous women).

Stage 2 - delivery
• Vaginal canal fully relaxed, cervix fully dilated.
• Frequent and strong prolonged contractions.
• Irresistible urge to push.

Stage 2 - birth
• Perineal bulging - emptying of residual bowel/bladder contents.
• Crowning of baby's head.
• Check cord position.
• Two midwives attend birth.
• Head delivered, followed by shoulders.
• Baby delivered in ≈1 hour from start of second stage.

In-patient care and support - paediatricians
• APGAR scores at 1 and 5 minutes (and 10 minutes if problems).
-Pulse.
-Breathing.
-Movements.
-etc.
-7-10 normal, 4-7 resuscitative support, 0-3 emergency resuscitation.

Episiotomy
• Some controversy, less common now.
• Performed to prevent uncontrolled tearing/need for caesarean section.
• Indication - large head, need for forceps.

Stage 3 - placenta
• 20-25cm, 500g.
• Smooth with central cord on uterine cavity (baby) side.
• Uterus relaxes after stage 2 for 10-15 minutes.
• As contraction restart, placenta shears away from uterine wall.
• Delivered via gentle consistent pressure on cord with above pressure to control descent.
• Must examine placenta to ensure intact.
• Post-partum haemorrhage - >500ml blood loss.
• Medical emergency usually due to failure of uterus to contract or placenta remnants.
• Risks reduced by routine syntocinon.
• Vaginal tears/episiotomy should be repaired immediately after delivery.

Caesarean section
• Non-cephalic presentations.
• Multiple pregnancies.
• >1 previous caesarean section.
• Suspected/previous problems in delivery.
• Foetal distress.
• Failure to progress.

Midwives
• Baby care information.
• Feeding support - breast versus bottle.
• Maternal rest and support.
• Advice wrt wound care, cord care, lochia etc.
• Early signs of problems.
• Labour "debriefing."
• Administration advice.

Paediatrics
• Second check within 24 hours,
• Weight, height, head circumference.
• Face.
• Back.
• Digits.
• Genitals.
• General appearance and behaviour.

Going home
• Discharge.
• Midwife visits on first day at home.
• Further visits as needed, up to 28 days post-delivery.
• Eighth day visit for heel prick test.

Health visitor
• Statutory visit 10-14 days post-delivery.
• Establish relationship.
• Support feeding.
• Baby routine and ailments.
• Weight/growth monitoring.
• Depression monitoring - Edinburgh Post-Natal Depression Score (EPNDS).
• Subsequent visits as indicated.
• Open access clinics every 2 weeks.
• Post-natal groups.
• Positive parenting groups.
• Ongoing growth/development monitoring.
• Ongoing maternal support and monitoring.
• Open dialogue.

Post-natal depression
• 10% of women.
• Weeks or months post-delivery.
• Symptoms of depression.
• Poor bonding with baby.
• Feelings of failure and guilt.
• Lasts for months.

"Baby blues"
• 50% of women, 4-10 days post delivery.
• Tearful and irritable.
• Rapidly resolves.

Puerperal psychosis
• 1 in 500 women within 2 months of delivery.
• Personality change, agitation, depression.
• Threaten suicide or harm to baby.
• Requires prolonged in-patient treatment.

GP's role
• Massively reduced - post-natal role only.
• Contact parents after delivery.
• Support/advice as needed.
• Part of health care team.
• 6 week check.

6 week check
• Parental concerns and questions.
• Weight and head circumference.
• General behaviour and appearance.
• Palate and fontanelles.
• Motor tone, reflexes.
• Eyes, hearing and vocalisation.
• Cardiovascular system.
• Spine, hips, feet.
• Hernias, testes, genitalia.
• Health education and advice.
• Contraception.
• Parental/family support.

What Has Blood Got To Do With Babies?

21.3.06

Normal haemostasis
• 3 players:
1. Blood vessel.
2. Platelets - form initial plug.
3. Coagulation factors - form fibrin clot.

Bleeding from injured vessel will cease if
1. Internal pressure = external pressure
eg. increased blood surrounding tissue → increased vasoconstriction → increased hypotension (blood pressure decreased).
2. Hole blocked by solid material
ie. platelet plug → fibrin clot.

Coagulation of blood
Essential reaction: Soluble fibringogen I ==> [Prothrombin IIa] ==> Fibrin clot Ia

Physiological changes in coagulation in pregnant women
Increased clotting factors
• Including Factor VIII.

Reduced coagulation inhibitors
• Protein S.
• Activated protein C resistance.

Factors unchanged
• Antithrombin.
• Protein C levels (functional impairment).

Blood transfusion - haemolytic disease of the newborn.

Blood group systems
• ABO antigens.
-Glycoproteins.
-Same protein backbone (15 amino acids).
-Variable terminal sugars:
§L-fucose "H."
§L-fucose + N'acetyl galactosamine "A."
§L-focose + D galactose "B."
• A and B genes code transferases for sugar addition.
• ABH antigens increase in strength from 0-3 years.
• Isoagglutinins (anti A, anti B) present from 6 months.

Mortality and morbidity of ABO incompatibility - intravascular haemolysis
• Death ~ 10%.
• Irreversible renal failure ~ 30%.
• Renal failure ~ 30%.
• Asymptomatic ~ 30%.

Rhesus system
• Rh antigens are proteins in red cell membranes. ? Function.
• 3 closely-linked genes.
-D (d).
-C (c).
-E (e).
• Most immunogenic and clinically significant = D.
• Haemolytic disease of newborn (HDN) - delayed transfusion reaction.
• Rh (D) group (anti-D and red cells) SPIN.
Positive }
} control
Negative }

Antenatal screening
• Booking clinic (12 weeks).
-ABO.
-Rh (D).
-Antibody screen (indirect).
• Third trimester (28 weeks).
-Repeat for all.
• More frequently for some.

Anti-D prophylaxis
• Offered to all Rh (D) negative women.
• 500 IU anti-D immunoglobulin at 28 weeks.
• 500 IU anti-D immunoglobulin at 34 weeks.
• 500IU anti-D immunoglobulin after delivery.

Red cell transfusion indications - avoid wherever possible
• Peri-operative loss >1,000ml.
• Depends on haemoglobin (Hb) pre-op.
• Depeneds on cardiovascular status.
• Tx Hb at 10G/dl - WRONG!

Pre-compatibility testing - electronic crossmatch
• ABO/Rh (D) group patient (recipient) red cells.
• Antibody screen patient plasma (IAT + enzyme).
• ABO/Rh (D) group red cells.
• Major crossmatch (IAT).

Module 1.09

A New Arrival.
20.3.06 - 31.3.06.

Genetic Variation Of Immune Disorders

17.3.06

Disregulated, excessive or absent immune responses → pathology.

Excessive: allergies eg. asthma, hay fever.

Autoimmune diseases eg. diabetes, rheumatoid arthritis.

Immunodeficiencies.

Immunoproliferative disorders.

CD4+ helper T lymphocytes provide cytokines and growth factors that serve as (usually) essential costimulants for B cell (antibody) and CD8+ cytotoxic T cell responses.

2 types of antigen receptor
1. Surface immunoglobulin on B cells.
-Recognise intact antigens outside cell, where most bacteria found.
2. Antigen receptor on T cells: T cell antigen receptor (TCR).
-Detect peptide antigens generated inside cell eg. viral and bacterial peptides.

Function of HLA molecules
• Originally identified as histocompatibility antigens in context of transplantation and pregnancy.
• Now know: main function to sample antigenic peptides and present them for screening by T cells.

HLA molecules
• Encoded on short arm of chromosome 6.
• Human major histocompatibility complex (MHC) gene complex contains 264 genes/pseudogenes.

MHC
1. Class I HLA
• Expressed on virtually all nucleated cell types.
-Not trophoblast.
-Not sperm.
• 3 important genes - HLA - A, B, C; multiple "alleles."
• Binds small peptides (form cytosol) and "presents" them to CD8+ (cytotoxic) T cells.

2. Class II HLA
• Expressed on antigen - presenting cells (APC) - macrophages, dendritic cells and B cells.
• 3 gene products, HLA - DR, DP, DQ; multiple "alleles."
• Binds peptides (from intracellular vesicles) and presents them to CD4+ (helper) T cells.

CD4 activation necessary for virtually all immune responses, so APC play pivotal role.

Each HLA allele (tissue type) binds different repertoire of antigenic peptides fo presentation to T cells.

Frequency of immunogenic peptides
• Average-sized protein of 60,000 molecular weight contains ≈ 500 amino acids.
• From defined anchor residues for each class I/II HLA molecule in any individual, would be (at best) only a few peptides that could be bound.
• Hence, low frequency of immunogenic peptides in any typical protein - immunogenic peptides will vary between individuals.

How is HLA polymorphism maintained?
1. Non-pathogen-driven mechanisms
• Spontaneous mutation and gene conversion rates?
• Maternal-foetal incompatibilities??
• Mating preferences?

2. Pathogen-driven mechanisms
• Heterozygote advantage.
• Rare allele advantage.

HLA and HIV
• Frequently-exposed HIV-negative individuals:
-HLA-A2, -A28; -DR13.
-Higher occurrence of cervical IgA anti-HIV.
• Fast progressors:
-HLA-A1, -A9, -A11, -A23, -A24; -B8, -B-35.

HLA-B53 and malaria
• Frequency of allele is ≈ 1% in Caucasian populations, but >50% in Gambians.
• HLA-B53 can bind peptide from malaria parasite that is a target for cytotoxic T cells.
• Selective advantage of allele in malaria-endemic regions.

HLA-A11 and EBV
• European EBV strains recognised by HLA-A11 restricted CD8+ cytotoxic T cells.
• In New Guinea (where HLA-A11 more frequent), EBV has mutated - no longer recognised by HLA-A11-restricted CTL.
• Here, parasite one step ahead of host.

EBV, HSV and certain adenoviruses can persist harmlessly after primary infection (illness), because they interfere with the cellular mechanisms of production, processing or presentation of antigenic peptide fragments of viral proteins.

HLA polymorphism important in humans.

Pregnancy: The Obstetrician's View

16.3.06

Causes of improved mortality
• Improved medical care
-Infection control.
-Medical knowledge.
-Anaethetics.
-Drugs (antibiotics, oxtocins, antihypertensives, MgSO¬4).
-Diagnostic ability.
• Availability of care (NHS/transport).
• Improved maternal health.
• Education.
• Audit.
• Changes in parity.

International situation
• Huge disparity in health outcomes.
• Worst in sub-Saharan Africa.

Causes of maternal mortality (global)
• Haemorrhage ~ 25%.
• Sepsis ~ 15%.
• Unsafe abortions ~ 15%.
• Hypertension/eclampsia ~ 12%.
• Prolonged labour ~ 8%.
• Pre-existing disorders ~ 20%.

Africa's problems
• Delays in treatment.
-Women do not seek care.
§Traditional treatments used.
-Transport.
§Inadequate.
§Huge distances.
-Delays at institution.
• Organisation.
-Work overload.
-Low morale.
• Lack of facilities and supplies.
-Finance.

Goal: access to quality care when needed.

Worst case - Sierra Leone
• Worst health indicators - UN WDI.
• Life expectancy = 37 years.

Work experience - South Africa
• 1998-1999.
• Obstetrics and gynaecology.
• Eastern Cape.
-Old "white" and township facilities.
• High-risk obstetrics.
-Eclampsia/antipartum haemorrhage/postpartum haemorrhage.
-High maternal mortality.

Philosophy of care
• "Pregnancy is a physiological process."
• WHO objectives for maternity care:
1. Healthy mother.
2. Healthy baby.
3. Good experience.
• Reality: "Pregnancy is only normal in retrospect."
• Risk assessment unhelpful.

Midwives see normal, obstetricians see abnormal
• Midwives better at screening.
• Gives obstetricians biased view.
• Labour becoming medicalised.

Medicalisation of birth
• Global rise in C-section rates.
• 90% in Brazil.
• At some time in some places, normal to have general anaesthetic to give birth.
• Upper class 30s women more at risk.
• Intervention leads of intervention.
• Academics tend to be medics not midwives.
• Power held with medical profession.
• Medics only see abnormal/complicated.
• Drives medicalisation and patient preference.

Reasons for caesarean section increase
• Society trends - convenience, control.
• Low threshold if foetal concerns.
• Safety of procedure.
• Patient preference.
• Medical ease.
• Litigation.
• Declining skills - complex vaginal deliveries.

Alternatives
• Hospital midwifery-led units.
• Community birth centres.
• Home birth.
• Birth Choice UK.
-Information on birth statistics.
-Different units.
Intervention rate.
• National Childbirth Trust.
-Established 1957.
-Independent.

Obstetrician's role in pregnancy
1. Pre-conceptual
• Counselling.
• Optimise medical conditions.
• Advise against pregnancy.
-Severe renal disease.
-Pulmonary hypertension.

2. Pre-natal
• Screening issues.
• Down's/spina bifida.
• Invasive testing.

3. Antenatal
• General obstetrics.
• Medical disorders.
• Foetal medicine.

4. Delivery
• IOL decisions.
• Manage abnormal labour.
• Operative delivery.
• HDU care.

5. Post-natal
• Counselling.
-Problems.
-IUFD.
-Referral.
• ?? Ongoing care eg. hypertension.

Liverpool Women's Hospital labour ward - tertiary care
• 24-hour cover.
• Multidisciplinary team.
-3 obstetricians.
-2 anaesthetists.
-12 midwives.

The future?
• Pre-natal implantation diagnosis.
• Non-invasive diagnosis.
-Genetic conditions.
-Free foetal DNA in maternal blood.
§Molecular genetics.
§Endless possibilities.
• Earlier identification of problems - USS 11-14 weeks.
• Effective interventions for:
-PET, preterm labour.
• Foetal surgery - spina bifida, diaphragmatic hernia, twin laser.
• Delivery by caesarean section??

Job in obstetrics?
• Recruitment crisis.
• Poor work-social balance.
• Consultant resident on-call.
• Fear of litigation.

Genetic Screening... But Why?

15.3.06

Many questions, information needed
• What happened, why, what caused it?
• Whose fault was it? What can I/we do?
• Will it get better, is there a treatment?
• Will it happen again? Worse next time?
• What are our options? Are there any tests?
• Who else it at risk? Can they be tested?
• What can I do? Who can help us?

Clinical genetics package
• Genetic nurses/counsellors, MDT, medics.
• Home visits, pre-clinic contact, family history.
• Information gathering and consent; set them at ease.
• Genetics clinic - investigation, assessment.

Autosomal recessive
• Affected siblings [males] = [females].
• Parents usually unaffected carriers.
• 25% recurrence risk.
• Syndromes tend to breed true.
• Consanguinity, isolated populations.
• Founder effect versus selective advantage.
• Very, very low mutation rate.
• Non-paternity more likely.

Autosomal recessive conditions
• Cystic fibrosis.
• Sickle cell, thalassaemia - contiguous.
• Albinism.
• Hunter syndrome.

CF and carriers
• Everyone carries ≈5 recessive genes.
• Eg. sickle cell, thalassaemia, CF, Tay-Sachs.
• Consanguinity, making people aware.
• Population screening? When? How?

Genetic screening programmes
• During antenatal care, Down's screening.
• Haemoglobinpathies.

What are we going to do?
• Do nothing.
• Denial, hope for best.
• Public Health agenda, ££ costs.
• Eugenics.
• Give people choices and chances.

Population screening programmes
• Guidelines for new programmes. Who decides?
• Impact of genetic screening on extending family.
• Public Health agenda? Eugenics, ethical issues.

Types of genetic disease
• Chromosome disorders.
• Structural re-arrangements, translocations.

How important are genetic diseases?
• Individually rare, collectively common.

Influence of nature and nuture
• Multi-factorial.

Objectives of medical genetics
• 1X, specialist opinion, syndrome diagnosis.

Variation in human genome
• Single nucleotide polymorphism (SNP).
• Highly polymorphic markers.
• Anonymous sequences.
• Not causing disease, simply genetic flags.
• Frequent SNPs every 500-1,000 base pairs.
• Makes us varied and interesting.

Human Genome Project - deliverables
• Pharmacogenetics.
• Decreased toxicity/tailor therapy.

Applying new technologies
• Diagnostic testing.

Perinatal Epidemiology

14.3.06

Definitions
Perinatal period
• From 24th completed weeks' pregnancy until end of 6th day of life.
• Includes stillbirths.
-Child which has issued forth from mother after 24th weeks of pregnancy.
-Did not at any time after being completely expelled from mother breathe or show other signs of life.

Epidemiology
• Study of distribution and determinants of health-related states/events in specific population.
• Application of study to promote, protect and restore health.
• Person, place, time.

Birth, fertility, mortality
• Crude birth rate.
-Total population.
• Fertility rates.
-Women 15-44 years.
§General.
§Age-specific.
§Total (period).
• Mortality rates.
-Live and stillbirths.
§Still birth.
§Perinatal.
-Live births.
§Neonatal (28 days).
•Early/late.
§Post-neonatal.
§Infant.

Sources of data
• Routine data collection (descriptive epidemiology study).
-Birth registration.
-Death/stillbirth registration.
-Birth notification.
• "Special" data collecting.
-Hospital audit.
-Special studies.
§Cross-sectional.
§Cohort.
§Case control.
§RCTs.

Registration and notification processes
Birth registration
• LEGAL DUTY to register birth within 42 days.
• Usually by parent.
-Infant: name, sex, weight of infant (from notification [record linkage]), plurality.
-Mother: name, address, date and place of birth, occupation.
-Father (if joint-registered or married): as with mother.
-If married: date of marriage, number of previous children (live and stillborn).
• International variations.

Birth notifications
• Responsibility of persons delivering infant.
-Within 36 hours of birth.
• Alerts NHS to birth and hence need for services, triggers NHS number.
-Linked to immunisation and screening in childhood.
• Includes birth weight, gestation and foetal anomalies.
-Record linkage with registration (birth weight).

Birth and infant mortality rates
Headline figures (England and Wales, 2001)
• How many births annually?
594, 634 live births.
-304,635 male (51.2%. F:M ratio = 1:1.050)
-356,548 "within marriage" (60%).
• How many stillbirths?
3,159 stillbirths.
-5.3 per 1,000 live and still births.
-1,725 male (F:M ratio = 1:1.203).
-1, 771 "within marriage" (56%).
• How many deaths?
3,240 deaths under 1 year.
-5.4 per 1,000 live births.
1,420 deaths aged 1-14 years.
-15 per 100,000 population of same age.

So what?
• Time, person, place.
• Descriptive epidemiology study.

Implications and consequences
• Declining birth rate.
-17% fall in crude birth rate in 11 years, compared with 13% fall in general fertility rate.
• Increasing maternal rate.
-18 months in 10 years.
• 7% fall in stillbirths.

Teenage pregnancies
• Peak of 9.5 (1996), trough 8.1.

Drug Safety In Pregnancy

13.3.06

Primum non nocere ("First, do no harm").
• Mother.
• Child.

Adverse drug reactions
• Appreciably HARMFUL of UNPLEASANT reaction, resulting from intervention related to USE of medicinal product, which predicts hazard from future administration and warrants prevention or specific TREATMENT, or ALTERATION of dosage regimen, or WITHDRAWAL of product.
• Common.
• 6.2% of all hospital admissions.
• Occupy seven 800-bed hospitals in UK.

Drug safety in pregnancy
• Pre-existing disorders eg. epilepsy.
• Infections eg. urinary tract infections.
• Disorders of pregnancy.
• Treatment of foetus.

Physiological changes in pregnancy
Absorption…
• Decrease in intestinal motility.
• Decreased gastric emptying.
• Emesis/reflux - decreased absorption.

Distribution…
• Increased plasma volume by 45% (32 weeks).
• Total body fat increased.
• Protein concentration decreased.
• Uterine blood flow increased (<1% to 16-25%).

Excretion…
• 50% increase in glomerular filtration rate by mid-pregnancy.
• Increased excretion of drugs, increased dose requirements.

Bacteriuria in pregnancy…
• 6% of normal pregnant women have asymptomatic bacteriuria.
• 23-40% of these will develop acute pyelonephritis.
• Screening at initial test.
• For E. coli, commonly.

Treatment…
• Asymptomatic.
-Trial of single-dose therapy.
-If fails, 7-day course.
• Safe: penicillins and nitrofurantoin.
• Contraindicated: quinolones, tetracycline and trimethoprim.
• Symptomatic UTI: 1-2% pregnant women.
• Prevent complication to mother and foetus.
• Prevent recurrence.
• Ampicillin 10-14 day course.

Adverse effects of penicillins
• Nausea.
-Pregnancy can cause nausea.
-UTI may cause nausea.
-Drug can cause nausea.
• Diarrhoea.
-Vary in severity.
-Mild to fulminant colitis.
• Rash.

Causality
• Pregnancy-related?
• Disease-related?
• Drug-related?
• Temporal relationship.
• Rechallenge.
• Exclusion of other causes.
• Previous reports.
• ALWAYS CONSIDER DRUGS IN DIFFERENTIAL DIAGNOSIS OF NEW SYMPTOMS.

Placental circulation

Placental transfer
• Molecular weight of drug <500 daltons.
• Lipid solubility.
• Degree of ionisation of drug.
• Extent of plasma protein binding.
• Type I (intermediate).
-Equal concentrations.
-Complete transfer profile.
• Type II (most unsafe for foetus).
-Higher foetal than maternal plasma concentrations.
• Type III (safest for foetus).
-Higher maternal concentrations.
-Incomplete transfer profile.

Teratogenicity
• Regard every drug as being potentially teratogenic.
• 1-5% all congenital anomalies caused by drugs.
• Thalidomide disaster.
• Yellow card adverse drug reaction reporting scheme.

Yellow cards
• Introduced in 1964.
• 500,000 reports.
• ≈20,000 reports per year.

Screening for teratogenicity…
• Animals used as models for man.
• 2 species (rat/mouse + rabbit).
• 3 dose levels.
• Period of organogenesis.
• Males tested for effect on fertility.
• Females administered drug in third trimester to assess effects on foetal growth.

Stage of pregnancy…
• Period of organogenesis.
• Late stages may lead to foetal growth retardation and/or mental retardation.

Most teratogenic drugs during pregnancy:
• Alcohol.
• Anticonvulsants.
• Thalidomide.
• Corticosteroids.
• Vitamin A and derivatives.

Sources of information
• BNF.
• Drug information centres.
• National Teratology Information Centre, Newcastle.

Prescribing in pregnancy
• Disease pre-pregnancy.
-Does drug therapy need to be continued?
-Does it need to be altered?
• Try non-drug treatment first.
• Avoid multiple drugs.
• Select safest and most efficacious drug.
• Dose changes may be necessary.

Adverse drug reactions in pregnancy
• Consider stopping drug.
• Treat mother.
• If harm to foetus suspected, get specialist advice.
• Communication with mother.
• Report adverse reaction.

Complementary Medicine In The Community

Okay, now Flintoff's holed out to deep mid-wicket. It just gets worse and worse. I think I'm going to cry. This is all too much, coupled with yesterday's "history-making" first UK number 1 on downloads only. So says the England cricket-supporting, vinyl-loving plenary-goer.

8.3.06

Why complementary medicine?
• Patients ask for information and referral.
• Should understand patients' choices.
• To broaden scientific horizon.
• Part of medical curriculum, so subject is assessed.

Conventional medicine
• Disease focus: organ.
• One local cause → specific symptoms.
• Mind and body = separate entities.
• Treatment = eliminating symptoms.

Complementary medicine
• Complex system.
• Multiple factors → systemic symptoms.
• Mind and body = two sides of one coin.
• Treatment = reinforcing the system.

Conceptual link: complexity
A complex system
• Contains many elements: multifactorial.
• Non-linear dose-response effects.
• Emerging properties unexplainable from properties of each element.
• Adaptative, self-organising.
• Memory established [Plesk and Greenhalgh, 2001].

Why do people use complementary medicine? They have:
• Poorer health.
• Higher education → autonomy for treatment choice.
• Profound life experiences transformed their world view: "Illness is part of my existence, rather than a disturbing factor" [Astin, 1998].

Main complementary therapies
• Acupuncture - traditional Chinese medicine.
• Homeopathy - within NHS (since 1948).
• Herbal medicine.
• Manipulative therapies: chiropraxy, osteopathy.
• Smallwood report (2005):
Complementary therapies → £480million possible savings on drugs prescriptions.

Referral pattern
Referral initiated by
1. GPs.
2. Patients.
3. Hospital doctors.
4. Others.

Reasons for choice of complementary medicine
• Conventional treatment not effective.
• Worries about side effects.
• Personal preference.
• Problems with side effects.

Changes other aspects
• Satisfaction ~90%.
• Secondary problems better ~ 33%.
-Mental: anxiety, depression.
-Pain, arthritis.
-Skin.
-Digestive.

Effect of RCT in homeopathy
• Otitis media.
• Osteoartritis.
• Childhood diarrhoea.
• Fibrositis.
• Hayfever, flu.
• Pain.

Evidence for acupuncture
• Conclusive.
-Dental pain.
-Nausea, especially postoperative.
-Migraine.
• Nonconclusive.
-Asthma.
-Back pain.
-Drug dependency.
-Tension headache, neck pain.
-Osteoarthritis.
-Stroke.

Integrative medicine
Organ and system approach combined
Type I → Type II ← Type III
Illness Reaction Person

Antenatal Care In The Community

I'm currently feeling very depressed about the cricket. Matt Prior has just run himself out and I'm really regretting getting up at 4.30am (again!) to listen to a losing cause.

"I'm so glad to have you and it's getting worse/I'm so mad to love you and your evil curse..."

7.3.06

Community?
• "Shared care" - package of care carried out in community and secondary care - determined by clinical need.
• "Shared" notes - kept by patient.

Low-risk pregnancy: mainly midwife-/GP-led in the community.
High-risk pregnancy: mainly specialist-led in secondary care.

Why?
• Reduce maternal mortality and morbidity.
• Reduce neonatal mortality and morbidity.

What is it?
• Means of trying to ensure physical and emotional well-being of the pregnant woman.
• Ensure baby is in best physical health following delivery.
• Combination of screening and surveillance - designed to detect problems/abnormalities which might increase maternal and/or neonatal mortality and morbidity.
• Also seeks to address need to health promotion, information and choice for pregnant women.

Low-risk pregnancy
• Use specific criteria (16• Can move from low-risk to high-risk at any time in pregnancy.

History
• Confirm pregnancy - β hCG - early-morning urine sample.
• Age.
• Past menstrual history.
• Past gynaecological history.
• Past obstetric history.
• Medication.
• Social history.
• Family history.

Nice guidelines: www.nice.org.uk ~ 2003

Lifestyle advice
• Smoking - cigarettes/cannabis.
• Alcohol.
• Exercise.
• Travel - seatbelts/deep vein thromboses.
• Prescriptions.
• Complimentary therapies.
• Sexual activity.

Diet and food
• High fibre, low fat.
• Supplements: folic acid 400 mcg per day until 12 weeks.
• Avoid vitamin A supplements and liver.
• Avoid:
-Mould-ripened cheese eg. brie.
-Pate.
-Uncooked/undercooked ready-made meals.
-Raw/partially-cooked eggs and mayonnaise.

Toxoplasmosis
• Avoid contact with cat faeces and soil that may have traces of cat faeces in it.

Advice
• Screening and surveillance (main condition = Down's syndrome).
• Antenatal and parentcraft classes.
• Options wrt place of delivery, pain relief.
• National Childbirth Trust (NCT).

Overview Of Embryology

Another of Dangerfield's, I'm afraid.

6.3.06

• Ovarian cycle and ovulation.
• Post-fertilisation to implantation.
• Blastocyst.
• Implantation.
-Epiblast (ectoderm) and hypoblast (endoderm).
• Bilaminar disc.
• Implantation and placenta.
• Primary villus formation.
• Secondary villus formation.
• Tertiary villus formation.
• Intervillus space.
• Placental structure.
• Cotyledons.
• Early foetal circulation.
• Late foetal circulation.
• Placental growth.
• Umbilical cord.
• Twins.

Gastrulation
Third week of gestation
• Establishes three germ layers:
1. Ectoderm.
2. Mesoderm.
3. Endoderm.
• Involves formation of primitive streak.

• Trilaminar disc formation.
• Primitive streak.
• Notochord and neuroenteric canal.
• Neural tube and mesoderm.
• Somite and mesoderm.
• Migration of sclerotome.

Module 1.08

An Uncomplicated Pregnancy.
6.3.06 - 17.3.06.

Hospitals, Health Centres and History

3.3.06

Pre 19th Century
• Hospitals marginal to medical care.
• "Gateways to death."
• Limited range of patients.
• Very few hospitals.

19th Century developments
• Increase in number of hospitals.
• Linked to population and urban growth.
• Still don't treat the rich.
• Primarily social institutions - respectable working classes.

Types of hospitals
1. Workhouse infirmaries.
2. Voluntary hospitals.
3. Specialist hospitals.
4. Cottage hospitals.

Revolution in hospital care
• 1830s - crises over "hospital diseases."
• 1840s - anaesthesia - safer operations.
• 1867 - Lister publishes on antisepsis.
• 1880s - most hospitals had asepsis/antisepsis regimes.

Late 19th Century
• Sophistication of medical testing.
• Impact of germ theory of disease.
• New bacteriological laboratories.
• Rich people forced to hospitals.
• Wilhelm Roentgen (1845-1923) - x-rays.
• Willem Einthoven (1860-1927) - ECG.
• Charles Sherrington(1857-1927) - nervous system.

The Cell Cycle And Early Embryonic Development

As with all of Dangerfield's plenaries, there aren't any proper notes per se, but here's just a list of stuff he thinks we should read up on. I realised that I haven't any of these for last term because I couldn't be bothered to go to any of his anatomy plenaries at any point before Christmas apart from The Brain For Beginners, which wasn't as useful as everybody thought it would be. Anyhow...

2.3.06

• The start - the ovum and sperm.
• Morula.
• Somites and the early nervous system (18-21 days).
• 3-4 weeks into development - structures appearing.
• 5- and 6-week embryos - more "human."
• 7 and 8 weeks into pregnancy - foetus, not embryo.
• 22- to 25-week foetuses - prematurely-born babies able to survive with intensive care - sufficiently-developed respiratory system.
• Term - note vertex position.
• Anthropometry.
• Ultrasound.
• Cell cycle.
-Cell division.
-Mitosis.
-Meiosis.
-Growth.
-Cancer.
• Maturation of ovum and ovulation.
• Fertilisation.
• Morula.
• Blastocyst.
• Implantation.
• Amniocentesis.
• Chorionic villus sampling.
• Spina bifida.
• Anencephaly.
• Hydrocephalus.
• Postmaturity and eczema.
• Birth trauma: forceps.

An Introduction To Family Planning?

That's a rhetorical question mark, not just because I wasn't quite sure what the plenary title was.

1.3.06

Sexual health: The enjoyment of sexual activity of one's choice without causing/suffering physical/mental harm.

Contraceptive consultation - different?
• Clients, not patients.
• Discussing intimate details.
-Embarrassed/confused/worried/afraid.
• Legal and ethical aspects.
-Privacy/confidentiality/consent/abuse.
• Non-judgemental.
• Informed choice.

Access to services
• Own GP.
• Any other GP.
• Community-based service/clinics.
• Some hospital-based services - genito-urinary medicine, accident and emergency.

Fully integrated sexual health service
• Contraception.
• GUM.
• Gynaecology.
• GP.
• Infectious diseases.

Ideal contraceptive method.
• 100% effective.
• 100% safe.
• Easy to use - minimal medical intervention.
• Readily/easily available.
• Effective immediately.
• Rapidly reversible.
• No side effects.
• Not coitus-related.
• Protection against STIs.
• Cheap.

Condoms - male/female.

Contraceptive pills
• "The pill" - combined oral contraception.
• Progesterone-only contraception.
• Emergency hormonal contraception.

Progesterone-only methods
• Sub-dermal implants.

Male contraception
• Spermatogenesis.
-Hypothalamus - anterior pituitary - testes.
-Sperm production versus testosterone.
• Hormonal: oral/injectable.
• Non-hormonal: gossypol, tripterygium wilfordii.
• Other methods:
1. Heat.
2. Ultrasound.

Sterilisation
• Female.
-Variety of methods of tubal occlusion.
-Crest study - ?efficacy.
• Male.
-Advantages.
-Methods.

Websites
• www.ffprhc.org.uk
• www.fpa.org.uk

How Drugs Get To Where They're Going (Pharmacokinetics)

27.2.06

Why do you need to know?
• Duration of drug action.
• Impact of disease on drug levels.
• Basis of many drug interactions.
• Management of overdoses.

Routes of drug administration
• Systemic.
-Oral.
-Parenteral (subcutaneous, intra-muscular, intra-venous).
-Rectal and transcutaneous.
• Topical.
-Skin preparations.
-Inhaled medications.
-Rectal and vaginal formulations.

Processes relevant to systemic use of drugs
• Absorption (not relevant to IV use).
• Distribution.
• Metabolism (biotransformation).
• Excretion.

Absorption
Lipid solubility
• Most drugs weak acids/bases.
• Drugs cross membranes when unionised.
• Look up Henderson-Hasselbach equation.

Other major factors
• Surface area: small bowel >> stomach (surface area).
• Blood flow: relevant to IM route.

Bioavailability = Proportion of a dose that gets from point of delivery unaltered to systemic circulation (metabolites reduce bioavailbility).

Benzyl penicillin falls apart in extremes of pH.
Amino glycosines are lipid insoluble - not absorbed.
Lygeryl trinitrate metabolised by liver - sublingual administration.

FIRST-PASS METABOLISM.

Distribution
Plasma protein binding
• α-1 acid glycoprotein - plasma protein to which drugs bind (+ albumin, ionically).
• Less albumin, drug more potent.
• Common cause of nephritic syndrome (kidney loses albumin) is diabetes mellitus → drop in plasma albumin concentration → toxic drug may cause adverse effects; extreme effects, both therapeutic and toxic.
• Acute phase reactant - group of proteins - concentration increases in inflammation, infection eg. α-1 acid glycoprotein.
• Drugs bound to α-1 acid glycoprotein less potent.
• Diffusion down concentration gradients.
• Changes in plasma protein concentration affects distribution.

Tissue distribution
• Blood-brain barrier junctions, active pumping (ability to keep things out of brain water), increased water solubility (polar eg. penicillin), decreased lipid solubility.
• Muscle - leaky junctions.
• Thiopentone - anaesthetic induction agent.

Metabolism - biotransformation
Principles of hepatic drug metabolism
• Most drugs relatively lipid-soluble.
• Readily absorbed, but more difficult to eliminate.
• Metabolism converts lipid-soluble drug to more water-soluble molecule.
• Usually terminates biologic activity.
• …But sometimes, the reverse.

Hepatic drug metabolism
• Phase I (decreasing weight).
-Oxidation, reduction, deamination, hydrolysis.
-Can be INDUCED and INHIBITED (look up - p. 450 of Walley/Winstanley).
-Metabolite may retain biologic activity.
• Phase II (increasing weight).
-Conjugation.
-Usually with glucoronate, acetate or sulphate.
-Metabolite lacks biologic activity.
• Pro-drug - no effect, needs Phase I to produce metabolite that has desired effect.

Excretion
• Mostly via kidney.
• Entereohepatic circulation - oestrogens.

Irreversible elimination
• Mainly kidney.
• Glomerular filtration.
• Tubular secretion.
• Tubular re-absorption.

LOOK UP ASPIRIN OVERDOSE.

Pharmacokinetic parameters
• Essentially, use of maths to describe drug disposition.
• Half-life.

Volume of distribution
• Measure of degree to which drug in circulation or tissues.
• Drugs with high VD mainly in tissues.
• Practical implication: such drugs cannot be easily removed from body (eg. by dialysis) after overdose.

Clearance
• Volume of blood completely cleared of compound per unit time.
• Units = L hr-1.
• Clinical relevance includes effect of liver/renal disease of drug elimination.

Reading
• Henderson-Hasselbach ~ p.8.
• Aspirin ~ p.200.
• p. 10, p. 231.

Normal Menstrual Cycle

23.2.06

Female patient: check menstrual history.

Menstrual cycle
• Dynamic relationship between hypothalamic, pituitary and ovarian hormones.
• Hypothalamus-pituitary-ovarian axis.
• Uterine changes.
• End result - menses/pregnancy.

Hypothalamus
• GnRH - pre-optic area.
(Kallman syndrome - anosmia/hypogonadotrophic hypogonadism.)
• Nutrition (amino acid level/anorexia).
Stress (CRH/beta endorphins).
Light (serotonin/melatonin synthesis).
• Ventromedial/arcuate nucleus of medio-basal hypothalamus may be pulse generator.
• GnRH - peptide hormone - receptors in anterior pituitary gonadotrophs.
• Pharmacology.
-Analogues = high affinity/longer binding.
-Stimulation > desensitisation.
• Artificial menopause.
-Pre-follicle stimulation in IVF.
-In hypogonadotrophic hypogonadism.

Pituitary
• FSH/LH.
• Feedback regulation with E2/progesterone/inhibin.
• Pulsatile production in response to GnRH pulses - frequency/amplitude.
• Tumours.

FSH
• Antrum formation.
• Gonadotrophin-dependent phase.
• Induce oestrogen production by dominant follicle.
• Induce LH receptors in granulosa cells.
• Used to induce follicle in IVF.

LH pulses - frequency/amplitude
• Pre-ovulatory - highfrequency/low amplitude.
• Mid-cycle - ovulation induction.
• Post-ovulatory - low frequency/high amplitude - ?needed for normal corpus luteal function.
• Used as depot, inhibits ovulation.
• Injection in late follicular phase induces ovulation.

Ovarian hormones
• Theca (LH) and granulosa (FSH) cells - "two cells theory."
• Theca cells produce androgens.
• Granulosa cells = oestrogen, progesterone, inhibin, activins, IGF.

Ovary
• Oestrogen.
• Progesterone.
• Inhibin (inhibits FSH)/activins (stimulates FSH action).
• IGF.
• Chromosome XO (Turners).
• Deletion of part of X → premature menopause.
• PCOS (theca cell hyperplasia) → high androgens, small follicles.

Oocytes
• Dorsal aspect of yolk sac.
• Primordial follicles - 5x106.
• Intermediary/primary follicles - 1x106 at birth.

Secondary follicles
• Antral stage/recruitment.
• Selection of dominant follicle (most sensitive to FSH).
• Ovulation.
• Corpus luteum.
• Corpus albicans.
• Menopause.

Ovulation
• Trigger LH surge (38 hours preceding ovulation).
• Pre-ovulatory E2 surge induces LH surge.
• LH → LHR → second messenger systems.

Puberty
1. Breast growth.
2. Pubic hair growth.
3. Axillary hair growth.
4. Growth spurt.
5. Menarche.

Precautious puberty - primary amenorrheoea.

Endometrium
• Functional layer and basal layer.
• Glandular/stromal/leucocytes/blood vessels.
• Progesterone and oestrogen receptors.
• Prostaglandins/cytokines/chemokins.
• Proliferative phase.
-Oestrogen dominant.
-Stromal and glandular mitosis.
• Secretory phase.
-Progesterone dominant.
-Decidualisation of stroma.
• Menstrual shedding and regeneration.
-Vascular regeneration.

• Menorrhagia - endocrinological/anatomical/iatrogenic.
• Oligomenorrhoea - endocrinological/PCOS/pituitary tumours.
• Amenorrhoea - chromosomal/anatomical/weight/physiological.
• Dysmenorrhoea - endometriosis.
• Pre-pubertal - low oestrogen/no follicular growth.
• Menopause - increased gonadotrophins.

Module 1.07

The Positive Test.
20.2.06 - 3.3.06.