Patient semester 1

Homeostasis: Stops bleeding ASAP via: platelets which recognises exposed collagen and releases thromboxane for platelet aggregation. Activated platelets release serotonin which causes vasoconstriction. Damaged tissue releases thromboplastin which combines with Calcium  to form an insoluble fibrinn. Insoluble fibrin and the platelets: trap RBC, form a cloth i.e. The first step forms a scab.

Inflammatory stage: Cleans the wound for healing. Langerhans cells release inflammatory mediators: bradykinin (pain), leukotriene (blood flow). Neutrophyls appear which digest bacteria, then monocytes which develop into macrophages. 

Proliferative stage: Healing stage. The dermis is repaired and the epidermis is regenerated. Macrophages continue their healing work. If low 02 levels: they release angiogenic growth factors (new blood vessels). They also release chemicals to attract granulation tissue for new connective tissue. Fibrolasts: when activated i.e. myofibrolasts produce a collagen network, and can also contract to close the wound. Epithelial cells also move over moist granulation tissue until contact inhibition. 

Maturation stage: Scar forming stage. Can take up to 2 years. Collagen is realligned to improve strength, and pull the wound inwards. Extra blood vessels close. 

Epidermis vs dermis: laceration vs incision. Lacertaion involves keratinocytes and contact inhibition.                                                   HIPMan

Necrotic wounds: Dead tissue exposed to a drying atmosphere, therefore chars, shrinks and dehydrates. Eschar delays autolysis, and shrinking causes pain. 

Necrotic digits: unlike other necrotic tissues, rehydration must be avoided! Rehydration = infection. Expose to air for optimal conditions for auto-amputation or surgical amputation. 

Sloughy wounds: Complex mixture of fibrin, leucocytes, exudates, protein and bacteria. Need to support the normal processes which debride slough and manage the exudate, resulting from the inflammatory stage of wound healing. Important not to overrehydrate the wound, to avoid maceration. 

Infected wounds: wounds which are infected.

Granulating wounds: Granulation tissue is a complex mixture of proteins, polysacharides and collagen, which have a red gel like appearance. Need to be kept warm and moist, to manage exudate.

Epitheliaising wounds: Proliferative stage of wound healing. Need to keep wound moist until it closes. 

Necrotic wounds: Hydrogel dressings are available as amorphous gels, impregnated non-woven dressings and sheets. White soft parafin can be used on borderline healthy skin to protect from maceration. Secondary dressings: perforated plastic flim and vapour permeable films. NB hydrogel contain propylene glycol, toxic to larvae if need to be used in sloughy wound stage. Other option is hydrocolloid dressings: occlusive and waterproof: prevent water evaporation and promote moisture. If there is exudate: alginate dressing: derived from seaweed, absorb exudate but maintain moisture. 

Necrotic digits: If edges of wound are moist use iodine and a secondary dressing to fight infection and reduce pain. 

Sloughy wounds: Alginates or hydrocolloids. Moderate or heavy exudate: Hydrofibre dressings which can absorb a high amount of exudate with a secondary dressing. Larvae therapy: release enzymes which combat bacteria and odour. Use a secondary dressing to absorb exudate and keep larvae in place. 

Infected wounds: Systemic antibiotics and antibiotic dressings which contain: Iodine (CI in hypertensive, pregnant, renal impairement or hyper/pothyroidism patients), Silver ( antimicrobial and antifungal, avoid in allergic or impaired patients), Honey ( maintain moist environment, eliminate odour, stimulate tissue growth and aids debridement). 

Granulating wounds: For low depth wounds: Hydrocolloids, especially occlusive ones which create a hypoxic environment. Heavy exudates: use alginated. Change as infrequently as possible. For deeper wounds: polyurethane foam dressing. NB dont overpack the wounds: wound distortion, ischaemia, necrosis etc

Epithelialising wounds: Superficial wounds: hydrocolloid dressings. Others: silicone dressings, nylon and viscose preparations. Check for allergies first.

• Alcoholic cleansers: will delay wound healing.
• Cetrimide: toxic to fibrolasts.
• Na hypochlorite: toxic to capillary network and cells. Painful during treatment and removal. 
• Topical antibiotics: to minimise resistance. Use systemic antibiotics or oral / gel metronidazole if fungal infection. 
• Topical deslouging agents: discontinued, ineffective. 
• Combining hydrogels with an alginate, hydrofibre or polyurethane foam: hydrogel absorbed. 
• Excessive wound cleansing: routinely is never necessary. If needed use room temperature Na Cl, as cooled preparations slow down healing by reducing skin temperature. (remember wound healing notes i.e. proliferatve stage. 
• Excessive dressing changes: can damage the skin / traumatic, usually weekly, except for infected wounds: 2-3 days. 
• Meds which delay healing: corticosteroids, sedatives, hydroxyurea, nicorandil and anticoagulants. 

• Patient nutrition: Protein needed for antibodies, leukocytes, collagen and fibrolasts. Vitamin A, E, B, C, zinc and iron for the healing process. 
• Skin perfusion: Oxygen and nutrients are needed for the wound to heal. Compromised blood supply from disease such as peripheral vascular disease can delay wound healing. 
• Age: Younger patients have less comorbities, better blood perfusion and nutrition. 
• Weight: BMI 30-40, alters the collagen structure and reduces tissue perfusion. 
• Co-morbidity including medication: Hypoglycaemia affects leukocytes phagocytosis. Anaemia and ischaemia = reduced perfusion. Jaundice and malignancy = cancer. 
• Corticosteroids = prostaglandin inhibitors. 
• Cytotoxic drugs = prevent healing.
• Nicotine, cocaine, adrenaline and ergotamine = vasoconstrictors which cause tissue hypoxia. 
• Smoking: impairs wound contraction, reduces oxygen and causes platelet aggregation. 
• Moist wound: needed for epitheliasitation. Not too moist: maceration and infection.
• Wound temperature: faster healing at body temp.
• Tissue oxygenation: granulation phase less oxygen is required, epithelialisation needs more oxygen.
• pH: if 02 drops, lactic acid increases = dropped pH = 02 dissociating from haemoglobin.
• Need no infection and a clean wound surface so that healing isnt delayed. i.e. proliferative stage.

• 3 layers: epidermis, dermis and hypodermis aka subcutis. 
• Epidermis: outermost layer. Main function is to replace damaged cells to maintain the skins protective properties by continually producing keratinocytes. Can take about 28 days. Melanocytes produce melanin which protects the body from UV radiation. Langerhans cells for immunity. Has no blood vessels, therefore nutrients are diffused from the dermis. 
• Epidermis has 4 layers: Stratum basale ( single layer of keratinocytes and melanocytes). Stratum spinosum ( Anchored prickle cells which are held together by interlocking cytoplasmic processes). Stratum granulosum ( cells undergo enzyme induced destruction loosing their nuclei and cytoplasmic organelles, also has a lipid rich secretion which acts as the skin sealant, finally keratin laid down to mesh up the structures). Stratum corneum ( dead  flattened cell layer packed with keratin aka corneocytes which are shed).
• Dermis: strengthens the skin via collagen and fibrolasts. Provides elasticity via elastin. Has specialised structures including sweat glands, hair, sebaceous glands, smooth muscle for goose bumps, cuteaneous lymphatics and nerves. 
• Hypodermis: nerves, blood supplies and fat. For insulation of the tissue beneath it. 

• Vitamin D production: 7-dehydrocholesterol in the skin produces cholecalciferol in the presence of UV. This vitamin D3 is then converted to calcidol in the liver, and then hydroxylated to calcitriol in the kidneys, to produce an active form of vitamin D. Vitamin D raises calcium plasma levels by increasing the number of carrier protein molecules for its transport. Lack of vitamin D can lead to rickets and osteomalacia. 10-15 minutes of sunlight a few times a week is enough to prevent vitamin D defficiency. 
• Sensory organ for touch, pain and temperature: Mechanoreceptors detect light touch or deep pressure. Thermoreceptors detect warmth and cold. Nocireceptors respond to pain stimuli. Large numbers of receptors and overlapping receptors make the skin more sensitive. 
• Controls body temperature: via vasoconstriction, vasodilation (of capillaries), smooth muscle, sweat glands activated when body temp. is above 37. 

NB the skin is a weak insulator. In new borns, there is brown fat which is oxidised to produce more heat than ATP by the mitochondria. 

• Barrier protecting the tissue and organs from: bacteria, toxins, dehydration, UV, mechanical damage and trauma. 

Emollients: regular use to restore pliability to the skin and reduce shedding, cracking and bleeding. Less effective with psoriasis, more effective with other dry and scalling conditions. 

Vitamin D analogues i.e. calcipotriol and calcitriol: may clear in 6-8 weeks in mild-moderate conditions. They dont smell or stain. Calcitriol less irritant: can be used on the face. Apply thickly = 1 FTU to 100 cm2. Cream and oitment to be prescribed: use ointment at night. Inhibit keratinocytes differentiation and proliferation, as well as anti-inflammatory. 

Topical corticosteroids: Dont smell stain or are irritant. Reduce flare ups, as an anti-inflammatory drug. SE: include skin atrophy, rebound psoriasis risk, taxhyphylaxis. Mild one: face, flexures and genitalia. Potent: trunk and limbs. Moderate clobetasone butyrate isnt used. 1 FTU. 

Tazarotene: topically active retinoid which has anti-proliferative and anti-inflammaroty effects, which normalises keratinocytes differentiation. Use limited due to skin irritation, therefore use with corticosteroids. NB systemic retinoids are teratogenic. 

Tar preps: keratolytic, anti-P and anti-I. Stains and smells, may also contain a number of carcinogens and mutagens. Also used with UVB phototherapy. 

Dithranol: aka anthralin, yellow powder which is profoundly irritant to the skin causing blistering and inflammation. Also, stains purple and brown. Avoid healthy skin and flexure psoriasis. Micanol is a temp. sensitive drug which releases Dithranol. Must be washed with cold water to avoid future release. 

Vitamin D synthesis: 7-dehydrocholesterol, into cholecalciferol. Converted to calcidol in the liver, and hydroxylated to calcitriol in the kidneys. Tazarotene: related to vitamin A.

• Mention that it can not be cured, only managed.
• Psoriasis is a chronic immune mediated inflammatory skin disorder, where there are red raised plaques on the skin where keratinocytes are replaced faster than usual: turnover is 10* more than healthy skin. 
• It isnt infectious.
• It doesnt develop into skin cancer.
• It can not be spread via topical treatment. 
• Relapsing can occur as a result of precipitation factors such as trauma, infection esp. streptococcus, hormonal events, sunlight, drugs ( such as beta blockers, ACE, antimalarial, lithium) , alcohol and smoking. 
• Mention that the tar preparations and dithranol can stain and are smelly.
• Explain that the tazarotene is a retinoid drug which is teratogenic. 
• Explain that emollients need to be applied liberally but corticosteroids need tobe apply thinly.
• No topical corticosteroid should be used regularly for 4 weeks without a monthly review.
• potent corticosteroids should not be used regularly for more than 7 days.
• No unsupervised repeat Rx should be made- patients should be reviewed every 3 months.
• No more than 100 grams of moderate or potent per month.
• Try and rotate topical corticosteroids with other topical preparations.
• Potent or v. potent should be under dermatological supervision. 

MILD: Hydrocortisone 0.1-2.5%. Availabe as cream and ointments.

MODERATE: Clobetasone butyrate 500 microgams per 1 gram or 0.05%. Fludroxycortide 125 micrograms per 1 gram. Betamethasone 0.025%. All available as creams and ointments. 

POTENT: Beclometasone dipropionate 0.025% or 250 micrograms per 1 gram. Betametasone valerate 1mg per 1 gram (liquid). Mometasone furoate 0.1% or 1 mg per 1 gram. Rest are available as creams and ointments. 

VERY POTENT: Clobetasol propionate 500 microgram per 1 gram. Available as liquid, ointments, creams, foam and shampoo. 

NB not to confuse clobetasole for clobetasone. As well as, concentrations and potencies. 

• Should be applied no more than twice daily. OD is often sufficient. 
• Should be spread thinly on the skin, but in sufficient quantities to cover the affected area.
• One finger tip unit is sufficient to cover an area that is twice that of a flat adult handprint. 
• Mixing of topical preparations on the skin should be avoided: allow several minutes in between before the next application. 
• Advice that PIL may contain wrong information or misunderstood information. 
• Reassure patients that the side effects such as thinning, and systemic effects rarely occur when topical corticosteroids are used appropriately. 
• However, children and infants are especially susceptible to side effects. 
• The aim of treatment is to control the condition, inadequate treatment will perpetuate the condition. 
• Important to reinforce the fact that corticosteroids arent to be used as emollients. 
• The difference between potency and concentration.
• Important not to confuse clobetasone and clobetasol. 

Lightest to  Heaviest

• E45 liquid: Lightest moisturiser P: Methyl and propyl parabens 
• Aqueous cream: Quite watery texture P: Phenoxyethanol 
• Double base gel: Very light and moisturising P: Phenoxyethanol
• Diprobase cream: Very strong smell P: Chlorocresol
• Dermol cream: Took a while to rub into skin. Antimicrobial for itchy skin and psoriasis P: Phenoxyethanol
• Liquid paraffin WSP: Oily texture P: None 
• Hydromol Ointment : Wax like texture P: None 

• They soothe, smoothen and hydrate the skin fo all sorts of dry and scaling disorders: but they are short lived, and thus need to be applied as frequently as possible even after improvement occurs. 
• Emollient bath additives are added to water and patient must soak in it for 10-20 minutes. 
• Parafin based emollients are flammable: no smoking, or the use of naked flames. 
• Can be used as both a bathing subsituent and topical moisturising agent. 
• Emollients need to be smoothed over the skin, instead of rubbing them in. 
• If emollients are used with other topical preparations: leave several minutes in between applications. 
• Emollients are available as lotions, creams and ointments.
• Lotions: have more water, spread easilly and are absorbed quicker. Prefered for hairy areas, but isnt great at moisturising. 
• Creams: Mixture of water and oil. Absorbed and light on the skin. Cosmetically acceptable.
• Ointments: oily preparations, cosmetically unacceptable. But highly occlusive and moisturising. Usually preservative free. 
• Treatment usually started with lighter emollients. 

• Cream / ointment: use liberally and frequently (500 grams a week for an adult). Apply gently but quickly. Warm before use for an easier application. Cool before use for cooling sensation. 
• Soaps: Applied to dry skin then rinsed off. Doesn't foam, but as effective at cleansing. 
• Bath: as a means of moisturising as well as, bath additive in a warm bath (15 vs 5 ml). After bathing, pat the skin gently. 
• Lanolin: good emolient, newer versions have lower sensitivity issues. 
• Humectants: attract water from dermis into epidermis, useful for rehydrating dry, flaky skin. e.g. urea, glycerine, polyethylene glycol and lactic acid. 
• Colloidal oatmeal and lauromacrogols: soothing and antipruritic. 
• Antiseptics: help control flares.
• Benzyl alcohol: one of several ingredients found in some emollients which can cause irritation.
• Aqueous cream: contains anionic surfactant sodium lauryl sulphate and phenoxyethanol: are irritants, and therefore unsuitable as a leave on treatment. Used as a wash off subsitute instead. 
• Emollients can be used for their steroid-sparing effect, if used efficiently and liberally. 

• A stepped-care plan is recommended by NICE for the management of atopic eczema.
• Complete Emollient therapy: emollients penetrate deep into the stratum corneum and fill the intercellular gaps between the corneocytes (terminally differentiated keratinocytes), as well as may limit the barrier effect of lipids. Therapy involves frequent application of emollients as creams, ointments, bath additives and soap substitutes. Richer emollients: limbs, trunk, winter, at night etc.
• Topical corticosteroids: For flares: inhibit the action of inflammatory mediators to reduce inflammation and itching. Thin skin i.e. face, genital and flexures use a mild treatment e.g. hydrocortisone. Moderate clobetasone butyrate can be used for mild-moderate eczema, for 1-2 weeks. Potent mometasone furoate are used in thicker skin areas e.g. scalp, palms, soles. Used once or twice a day. creams: oozing or infected skin (isnt occlusive like ointments). Infants younger than 1: only hydrocortisone. 

NB pharmacists can provide OTC hydrocortisone for flares, but not for more than 1 week without medical advise. Corticosteroids shouldnt be used OTC for children under 10 or pregnant women. Clobetasone butyrate 0.05% can be used OTC for over 12's for short term treatment. 

• Infected eczema: usually by a staphylococcus aureus infection (identified by broken and weeping skin): use a 7 day course of oral antibiotics such as flucloxacillin and eryhtromycin. 

• Sedatives: effective at reducing itching at night. Promethazine isnt licensed for children under the age of 2. Hydroxyzine can be used at 6 months +. 
• Severe atopic eczema: those patients who do not respond to emollients and corticosteroids must be referred to specialists for the following:
• Topical immunomodulators: (e.g. tacrolimus and pimecrolimus, can also be used if there is a risk of serious SE with corticosteroids, or as an alternative for sensitive areas such as the face, when there is evidence of corticosteroid induced skin damage, or when potent corticosteroids would need to be used most of the time.) P. is used for mild-moderate and T is used for moderate-severe. They inhibit calcineurin phosphatase which is a key enzyme in the activation of T cells.  Tacrolimus can also be used for maintainance treatment to prevent flare ups for up to 12 months- used twice a week. Only SE is a burning sensation which lasts for a few days. Only used in children over 2. 
• Systemic immunosuppression: Severe atopic eczema e.g. cyclosporin, azathioprine, methotrexate and systemic corticosteroids. AKA immunomodulatory treatment (dose used is lower compared to those used after transplants). 
• Phototherapy: Controlled exposure to UV for immunosuppresion. 
• Wet-wrapping: Younger children. Corticosteroids and emollients, avoiding scalp area. 
• Behavioural therapy: e.g. hypnotherapy, cognitive behaviour therapy etc. 

• Irritation: soap, detergents, abrasive clothing and extremes of temperature of humidity.            ( remove lipids and activate proteases, direct physical irritation, drying effect on skin).  
• Psychological stress: some people respond with habitual scratching. 
• Food hypersensitivity: milk, eggs, soya, fish, wheat, nuts. (usually in children under 3- rare).
• Allergens: house dust mites, animal dander, toiletries and cosmetics, moulds and pollens.       ( faeces, saliva, perfume, plants). 

• How to recognise a flare up: increased dryness, itching, swelling, irritation, redness. 
• How to manage a flare up according to the step care plan: usually start with a milder corticosteroid and an emollient, but also depends on how severe the flare up is. match the corticosteroid to the severity of the eczema. 
• Important to start treatment for flares as soon as signs and symptoms appear: and continue treatment for 48 hours after the symptoms have subsided. 

• What are complex therapies?

They have a high risk of toxicity, high cost, intensive monitoring is required, usually prescribed by a specialist i.e. not a GP and finally they arent for first line treatments: used if at least 2 other treatments have failed. 

• ISOTRETINOIN: severe acne, where tropical treatments and antibiotics have failed. 16 week course clears the skin. 13-cys-retinoic acid, has at least 5 active metabolites. causes apoptosis in sebocytes in 6 weeks. decreases hyperkeratinisation, due to lack of sebum. anti-inflammatory as well. Teratogenic (PPP: 1 month before and 1 month after). Depression, anxiety and suicidal (stop treatment). Impaired night vision because of its connection to vit. A (inform DVLA). Dry skin and mucous membranes (joint pain). Skin is made very fragile ( sun protection even in october, no epilation or dermabrasion even for 6 months after). 
• Psoralen and UVA: aka PUVA for psoriasis: oral 8-methoxysporalen. Drug given 2 hours before UVA exposure, which then activates the drug. Disrupts DNA synthesis (basal cell turnover, slows it down to normal). 3 times a week treatment. Usually clears in 5-6 weeks. SE: teratogenic, premature skin ageing, skin pigmentation, cataract formation. (effective contraception, UVA protection, skin and eye examinations). 

• ACITRETIN: psoriasis. retinoid chemically related to aciteronin. Decreases hyperkeratinisation. SE: similar to isotretinoin, but a longer half life and a prolongued therapy is needed in psoriasis. Usually a treatment for older men and women. PPP programme for 3 years after taking the drug. Hyperlipidaemia (CVD risk assesment needed).  Hepatotoxic        ( LFT's every 3 months and keep drinking to the bear minimum i.e. 1-2 pints a week). 
• METHOTREXATE: psoriasis and eczema. 10-25 mg once weekly. Folic acid antagonist, therefore disrupts DNA synthesis and slows basal cell proliferation. Enzyme inhibition also increases adenosine which has anti-inflammatory effects for eczema. Liver cirrhosis (LFT's every month and then every 3 months). Blood disorders ( FBC every week, then monthly, then every 3 months). GI: stomatitis and nausea (folic acid weekly). Infection risk (immune system is dampered). Family planning (contraception 3 months after).
• CICLOSPORIN: psoriasis and eczema. 2.5-5 mg/kg daily, split into 2 doses. blocks calcineurin dependent factor, which prevent T cells proliferation. Blocks keratinocytes proliferation.  Nephrotoxic (monitor renal function). Hypertension (monitor BP). Teratogenic and immunosuppressant. 

• BIOLOGICAL AGENTS: last step in psoriasis treatment is: infliximab, adalimumab, ustekinumab, secukinumab, etanercept. They are all anti-TNF monoclonal antibodies except for etanercept which is a genetically engineered fusion protein. Response seen in 6 weeks: continued for 6 months-2 years. They are all subcutaneous injections exceptfor infliximab which is an iv infusion. Increased risk of infection (reactivation of TB and salmonella and listeria food poisoning). CVD risk (do not use in patients with heart failure, and monitor those with re-existing CV disease). Worsens neurological disease (dont use in demyenilating disease). Conflicting evidence about malignancy risk. 

• Glucose: ubiquitous energy source. CNS cant substitute glucose. 
• Hyperglycaemia: Food or endogenous glucose production by the liver causes insulin release by the beta cells (islet of langernas in the pancreas). Insulin has an action on the liver, muscles, adipocytes and CNS: to take up glucose into their tissues and to stop the endogenous production of it (liver and adiocytes) or its reabsorption (via the kidneys). 
• Hypoglycaemia: A fasting state can lead to hypo's. Glucagon is thus released by the alpha cells (pancreas too), and has an endogenous effect on the liver and adipocytes to increase the production of glucose by the breakdown of glycogen to glucose. Glucose is also reabsorbed by the kidneys. 

NB glycogenolysis: breakdown of glycogen to glucose in the liver. gluconeogenesis: is the manufacture of glucose using amino acids, fat by products etc.by the liver. Adipocytes release fatty acids to be used by the liver for gluconeogenesis. 

• Hypoglycaemia: <2.5 mmol/l
• Normoglycaemia in the fasted state: 3-5 mmol/l
• Normoglycaemia in the fed stae: 7-8 mmol/l
• Hyperglycaemia: >10 mmol/l

• Insulin is a protein hormone with 51 aa. 20 +31 aa
• Proinsulin gene makes insulin via the cleavage of the C peptide molecule, in the GB by endopeptidases. C peptide molecule and insulin are then both stored in the liver. 
• Insulin release occurs as a result of glucose uptake by the beta cells. Potassium channels close which causes a depolarisation, and then calcium influxes. Furthermore, the gut hormone GLP1(incretin hormone) is released and this binds to a receptor on the beta cells which causes cell signalling. This hormone is inactivated by DPP4. 
• Insulin has an anabolic effect as it stores energy. It forces cells, primary muscle and fat to take up glucose via the GLUT4 transporter and endocytosis (insulin binds to a TK receptor which causes GLUT4 to fuse with the PM). Skeletal muscle AMPK also stimulates glucose uptake. 
• Insulin also drecreases glycogen breakdown, increases fat stores and increases protein production. 

NB glucagon like peptide 1 and glucose uptake transporter 4. 

Activated protein kinase 

• This term refers to inappropriate low blood glucose levels i.e. <2.5 mmol/l. 
• This can be due to irregular food intake, insulin overdose, sulphonylurea overdose, insulinoma, hyperinsulinism, T1D nocturnal, post gastric bypass, transient neonatal hypoglycaemia. 
• It can result in autonomic symptoms such as: hunger, sweat, shaking, increased HR, headache, nausea. 
• It can also result in neuroglycopaenic symptoms such as: confusion, drowsiness, odd behaviour, poorcoordination, coma and death. 
• If it is a emergency give GLUCAGON IM, SC or IV.
• Or give an oral drug known as DIAZOXIDE (potassium chanel activator): this reduces insulin release.        

NB insulinoma: tumour in the pancreas

hyperinsulinism: high insulin secretion

post gastric bypass: post operation: low blood glucose levels. 

transient neonatal hypoglycaemia: metabolism problem in neworns. 

• Beta cells in the islets of langerhans are destroyed due to genetic susceptibility which results in an autoimmune disease, triggered by an environmental trigger. Insulitis occurs which is when T lymphocytes invade the beta cells. It is usually presented by the 4 T's: polyuria, polydipsia, weight loss and fatigue. i.e. thirst, toilet, tired, thin.
  
• Diabetic ketoacidosis: diabetic emrgency. >11 mmol/l. This occurs during very low insulin concetrations in the body and a high glucagon concentration which results in the liver producing glucose at a highly fast rate, causing acetyl-coa to be converted into ketones. Ketone lowers the pH of the plasma, which results in the kidneys excreting acidic urine. Acidosis: <7.4 usually <7. 
• Symptoms of DKA include: nausea, vomitting, dehydration, tachychardia, coma and death. 
• First 4 hours: fluid resuscitation (0.9% NaCl Hartmann's solution). 1-2 hours after give insulin (0.05-0.1 unit/kg/hr). this stops the lypolysis and gylcogenolysis. Monitor cBG hourly until <15 mmol/l, then move to maintainance. 
• Adults maintenance: 2L/day max of 0.9% NaCl, glucose 5%, KCL . Continue the insulin sliding scale and titrate to ketones depending if its < or > than 3mmol/l. Once they are ready to eat: feed them, and given the SC 30 minutes before removing the IV insulin, and then stop the glucose solution.  
• Childrens maintenance: 50% normal adult maitenace over 48 hours. 10 kg (2ml/kg/hr) 10-40 kg (1ml/kg/hr) >40 kg (4 ml/kg/hr). Start the SC insulin when cBG is <14 mmol/l, ketones are <3mmol/l and acidosis is resolved. 

Complications of DKA:

• Cerebral oedema: which is more common in children than in adults. Occurs as a result of too much fluid moving rapidly into brain cells i.e. >4ml/kg/hr and hypotonic fluids i.e. <0.9% NaCl. 
• Bradycardia
• Dilated pupils
• Altered mental state

• Keep blood glucose level as close as possible to that of a healthy patient.
• However, consider what is realistic for an individual. 
• Dieting advice: short term diet 5-10% of their weight. long term diet should be a normal BMI.
• Good food choices: high fibre, low GI sources of carbs i.e. low score on the glycaemic index means sugar levels can be steady, low fat dairy products, oily fish. Avoid food aimed at diabetics, trans fat and simple carbs. 
• Exercise: active daily. 150 minutes weekly of moderate exercise or 75 minutes of intense exercise. Include weight bearing activities too twice a week.
• Reduce long term complications such as macrovascular ( premature CVD, cerebrovascular disease, peripheral vascular disease) and microvascular (retinopathy, neuropathy, nephropathy).  
• Aim to understand the patient's experience. 
• Use evidence based medicines when making a choice for treatment.
• Ensure medication use is as safe as possible and is tailored for the patient. 
• low cBG and HbA1c.
• minimal episodes of hypos/hyper.
• no hospitalisation and lack of complications 
• SICK DAY RULES: check cBG every 2-3 hours (even more for children and pregnant women), always take your insulin, eat enough and drink fluids, check blood/urine ketones every 4 hours. 
• Retinopathy: high blood sugar levels damage the retina, can lead to blindess.
• Nephropathy: high blood sugar levels affecting the arteries in the kidneys, thus leading to a deterioration in kidney function.
• Neuropathy: high blood sugar levels result in nerve damage, which causes a loss of sensitisation i.e. desensitisation: this can be dangerous due to the high risk of ulceration, foot damage and thus infections. 

• Islets of langerhans are destroyed as a result of a genetic susceptibility, which is followed by the onset of autoimmune destruction triggered by some environmental factor. This results in insulitis, which decreases insulin production. insulitis: T lymphocytes invade the islets of langerhans beta cells.
• Patients need to depend on a lifelong exogeneous source of insulin. 
• Peak age of diagnosis 10-14 years old. Usually as a chidld or adult. 
• Renal complications: pyelophritis (UTI: where one or both kidneys are affected) due to a bacterial or fungal infection.
• Occular complications: Retinopathy (proliferative or non-proliferative). Severe retinopathy (neovascularisation: adhesions between the cornea and lens, iris and lens: leads to 2 glaucoma). Cataracts may also occur: sorbitol accumulates and results in osmotic damage to the crystalline lens. 
• Atherosclerosis: have early and accelerated atherosclerosis resulting in heart and renal disease, as well as a myocardial infarction. 
• Mucormycosis: DKA potentiates the growth of mucor in the nasopharyngeal region. 

• FIRST LINE: BASAL bolus: this is one/two intermediate/long acting insulin given in the morning and in the evening. As well as, 3 doses of short/rapid acting insulin analogues with meals. NB after meals means there is a lesser likelihood of hypos. Alongside the BASAL bolus regimen, is the DAFNE ( dose adjustement for normal eating: where the short acting doses are calculated based on the meal sizes). 

NB long acting insulin analogue: OD at night (glargine for <12 or detemir 12-18) BD at night and in the morning (detemir for adults). 

• SECOND LINE: BIPHASIC: this is a mixture or rapid acting and intermediate acting insulin. One taken in the morning and one at teatime. Humulin m3
• THIRD LINE: ultra long acting insulin ANALOGUES: this is when other long acting analogues have failed (such as detemir BD). taken OD: degludec (42 hours) or glargine (36 hours). This may benefit non-compliant patients or patients with nocturnal hypos. 

NB adjusting regimens: this is done via cBG monitoring: finger ***** test, which gives the current blood glucose [ ]. Prelunch for the breakfast. Pre tea for the lunch. Before bed for teatime. pre breakfast i.e. FBG. If it is low at pre lunch, reduce the breakfast dose. If it is high in the morning: increase the evening long acting dose. 

• Short acting: onset is within an 1 hour. duration is for 8-10 hours. e.g. insuman rapid
• Rapid acting: onsent is within 15 minutes. duration is for 4-6 hours. e.g. insulin lispro
• Intermediate acting: Isophane i.e. neutral protamine hagedorn. onset is withing 4 hours. duration is 12-18 hours. e.g. humulin 1. 
• Long acting insulin analogues: onset within 4 hours. duration usually 24 hours. gives a flat insulin profile. less risk of hypo's. mirrors non-diabetic patients. e.g. glargine OD or detemir BD. 
• Insulin administeration is usually via a subcutaneous pen: short acting (30 minutes before meals), rapid acting (5 minutes before meals). IV insulin infusion are reserved for hospital use under specialist care (using special insulin syringes). 
• Continuous subcutaneous insulin infusion: when the patient has poor control with the 4 times daily regimen i.e. when the patient has disabling hypos on the multiple daily injections or when the HbA1c levels have remained high despite the use of long acting insulin analogues i.e. >69 mmol/l. 

NB HbA1c: measures the [ ] of the glucose attached to haemoglobin in red blood cells. Usually done every 3-6 months. 

• T2D is chronic hyperglycaemia due to insulin resistance and impaired insulin secretion. Patients will have different degrees which will change over time. Hyperglycaemia itself can impair beta cell function and exacerbate the insulin cycle. 
• Those at a high risk include: genetics (1st degree relatives / epigenetics ), ethnicities ( south asian, chinese, black african), increased age, females (more likely to have a raised waist circumference), obesity (mean are more obese), poor food choices, sedentary lifestyles and smokers. 
• It is usually asymptomatic but some patients may have increased thirst, increased urination and blurred vision. 
• Diagnosing: FBG >7 mmol/l and a HbA1c >48 mmol/l DIABETIC 
• prediabetic or impaired glucose tolerance: FBG <7 mmol/l and 2 hour venous plasma glucose [ ] between 7 mmol/l and 11 mmol/l. 

• FIRST LINE: Metformin 
• SECOND LINE: Metformin + DPP4 inhibitor, sulfonylurea, SGLT2 inhibitor, pioglitazone.
• THIRD LINE: still not controlled add another drug.
• FOURTH LINE: Insulin or GLP-1. 

• METFORMIN: biguanide family. inhibit gluconeogenesis and increase insulin mediated glucose utilisation. Severe SE: GI irritation (take with food). Rare SE: lactic acidosis. weight neutral. low hypo risk. CI if eGFR <30, caution if <45. short half life (take TDS). 
• DPP4 inhibitor: newer drug. dipeptidyl peptidase inhibitor. blocks the rapid degradation of GLP1. e.g. linagliptin. weight neutral / weight loss. low risk of hypos. can be used in renal impairement with dose adjustement. Rare SE: pancreatitis. 
• Sulfonylurea: directly stimulates insulin release, therefore requires some pancreatic function to work (quickly lower cBG). inhibits the ATP sensitive potassium channel. short acting: gliclazide. long acting: glibenclamide. take with meals. can cause hypos. weight gain. fewer GI side effects than metformin. Monitor LF (rare SE hepatitis). unpredictable in renal impairement. OD or BD. 

• SGLT2 inhibitor: sodium dependent glucose co-transporter 2. blocks the reabsorbtion of glucose from the kidneys i.e. blocks active transport from the glomerular filtrate (requires good kidney function for effect). weight loss (2-3 kg over 3 months). reduce BP (by 1.3-7.3 mmHg). low risk of hypos. Not to be given if eGFR<60 and stop if its <45. e.g. canagliflozin. Increased urination (first few weeks) and increased UTI and thrush (on treatment starting). Risk of AKI, DKA and amputations. 
• THIAZOLIDINEDIONES: e.g. pioglitazone. increase insulin sensitivity. decreases glucose production in the liver, and increases glucose uptake by muscle and adipose tissue. low risk of hypos. OD. suitable in renal impairement. Yearly LFT's (can cause liver problems, rare). weight gain (average 3 kg) takes 3-6 months to see the benefit. Linked to heart failure, bladder cancer and increased fracture risk. 
• GLP1 agonists: glucagon like peptide 1( gut derived incretin hormone: stimulates insulin release, suppresses glucagon secretion, inhibits gastric emptying, reduces apetite). daily: liraglutide, weekly: dulaglutide. rarely cause hypos and pancreatitis. weight loss. suitable in renal impairement. Patient must demonstrate weight loss and improved HbA1c to continue because it has severe GI SE.  
• INSULIN: basal insulin only (always prescribed by the brand). start with OD/BD NPH insulin. If HbA1c is >70 mmol/l: basal bolus + short acting, biphasic, analogues. 

• cBG: stands for capillary blood glucose. It shows the blood glucose at time of testing. linked to symptoms of hyperglycaemia and hypoglycaemia. One result= poor indicator of long term control. 
• HbA1c: shows the amount of glucose attached to haemoglobin in RBC. requires a blood test. carried out every 3-6 months. good measure of average blood glucose over the last 3-6 months. poor predictor of early death, other heart diseases, stroke, foot ulcer. good predictor of heart attack, amputation, microcomplications. 

NORMAL: <42 mmol/ml

PREDIABETIC: 42-47 mmol/ml

GOOD CONTROL: <58 mmol/ml

MODERATE CONTROL: 58-70 mmol/ml

POOR CONTROL: >70 mmol/ml

Aim for 48: if on lifestyle changes or 1 drug.

Aim for 53: if on lifestyle changes and 1 drug associated with hypos or 2 drugs. 

• Hypothalamus: means below the thalamus and above the brain stem. 
• Hypothalamus and the pituitary gland are the master regulators of the endocrine system. Endocrine system is a ductless system, where the hypothalamus releases regulatory hormones which target other endocrine glands.
• Anterior pituitary: independent. Produces GH aka somatotropin and prolactin. Parvicellular neurones ( hypothalamus secretes regulatory hormones known as releasing and inhibitory hormones).
• Posterior pituitary: linked via the posterior stalk. Produces ADH (aka vasopressin) and oxytocin. Magnocellular neurones (long axons which extend into the posterior lobe i.e. direct endocrine link). 
• The pituitary gland is aka hypophysis and is connected to the hypothalamus via the infundibilum. 

FLAT PiG acronym:

• F: follicle stimulating hormone is a gonadotropin, produced by gonadotropes. Hypothalamus stimulates the anterior pituitary gland by releasing the gonadotropin releasing hormone. 
• L: leutinizing hormone: is also a gonadotropin.
• A: adenocorticotropic hormone is a corticotropin hormone, produced by corticotropes. It stimulates the adrenal gland cortex. as a result of corticotropin releasing hormone. 
• P: prolactin is produced by lactotropes. It is a 198aa single chain polypeptide. dopamine inhibits prolactin, hypothalamus is thought to release the prolactin stimulating hormone. 
• G: growth hormone is aka somatotropin, is produced by somatotropes. It is a 191aa single chain polypeptide. Children hypersecretion: gigantism. Adult hypersecretion: acromegaly. growth hormone releasing hormone. 

NB growth hormone inhibiting hormones are somatostatin (14 aa) and sandostatin (8 aa). Sandostatin has a much longer half life i.e. 90 vs 3 minutes. 

GH defficiency: pituitary defficiency. GH resistance: laron dwarfism. Give somatotropin drug known as somatropin. 

FLAT: tropic hormones: these stimulate other endocrine glands. Unlike, non-tropic hormones which have a dirrect effect on the tissues or cells. Prolactin is for lactation. 

Magnocellular neurones stimulate the synthesis and secretion of oxytocin and ADH. They are then released at the axon terminals, where they diffuse into the capillary network of the posterior lobe. 

• OXYTOCIN: motherhood. Positive feedback regulation i.e. cervic pressure causes the activation of sensory neurones, which release oxytocin, and causes contraction of the uterus.  Contractions, lactation and maternal instincts.
• ADH: bind to receptors on cells in collecting ducts. synthesise and insert aquaporins. This leads to reabsorption of water. Without ADH, the collecting ducts are impermeable to water. Diabetes insipidus (defficiency in ADH secretion). Nephrogenic diabetes insipidus ( kidney is insensitive to ADH). ADH is aka vasopressin. 

The pineal gland is found in the epithalamus between the 2 hemispheres, centre of the brain. 

Pinealocytes secrete melatonin in darkness and are inhibited by light to the retina. Melatonin promotes sleep onset by causing the homeostatic drive to sleep, therefore playing a role in the cicardian rhythm. Melatonin releases the skin pigment melanin. 

Melatonin can be used to treat seasonal affective disorder and insomnia. 

• Adrenal glands are divided into the medulla and cortex. 
• Medula are responsible for catecholamine release i.e. adrenaline and noradrenaline. 
• Cortex are involved in steroid production i.e. steroidogenesis. The cortex has 3 different anatomical and functional structures:
• Zona glomerulosa: Mineralcorticosteroids production such as aldosterone. Involved in water and electrolyte balance. MC have limited tissue distribution, they cause sodium uptake and potassium loss. NB spironolactone is a competitive inhibitor of MC receptors. 
• Zona fasciculata: Glucocorticoids production such as cortisol. They have immunosuppresive, anti-inflammatory and metabolic effects. 
• Zona reticulatis: Adrenal androgens precursors production aka androstenediones, for maturation and development. 

renin converts angiotensin to angiotensin 1. angiotensin 1 is converted to angiotensin 2 by the ACE. angiotensin 2 is converted in the adrenal cortex to aldosterone. This inceases sodium and water retention, which increases BP. 

• Steroids aren't stored in secretory glands. Cholesterol is the precursor molecule of all steroids.  C17 and C=O, H-C=O.
• Rate limiting step in steroidogenesis is the coversion of cholesterol to pregnesolone. 
• They all have the classic 4 ring structure, and c17. The c17 functional group is what differs. 
• Cholesterol to progesterone. Progesterone to cortisol or aldosterone or testosterone. Testosterone to estradiol. 
• Cortisol and aldosterone  are corticosteroids. 
• Transcortin and albumin are carrier proteins. Transcortin binds 90% C and 60% aldosterone. Transcortin is the main carrier protein. 

Synthetic steroids 

• These have varying half lifes:
• SHORT: 8-12 hours: hydrocortisone (GC) and fludrocortisone (MC).
• INTERMEDIATE: 13-36 hours: prednisolone (mixed).
• LONG: 37-72 hours: dexamethasone and betamethasone (GC)

• Addison's disease: hyposecretion of the adrenal glands, due to adrenal failure. Replacement therapy needed with a short acting corticosteroids. 
• Congenital adrenal hyperplasia: fault in the function of the enzyme 21-hydroxylase, which causes an overproduction of androgens. Limited negative feedback, therefore adrenocorticotropic hormone isnt switched off. Need a long acting corticosteroid.
• They can also be used an anti-inflammatory's, immunosupressants in eczema, psoriasis. 
• SE of corticosteroids: drug induced cushing's syndrome, osteoporosis, muscle wasting and an increased infection risk (inhaled drugs). 
• Blocking steroid synthesis: AMINOGLUTETHIMIDE (inhibits the rate limiting step). METYRAPONE (inhibits hydroxylase enzyme). TETRACOSATIDE (diagnoses adrenal corticol insufficiency by stimulating the release of adrenal hormones).
• GC release: Hypothalamus releases the corticotropin releasing hormone. This causes the pituitary to release ACTH hormone, which stimulated the adrenal cortex, and produces cortisol. NEGATIVE FEEDBACK system. 
• MC release: A decrease in BP, causes renin to convert angiotensin to angiotensin1. ACE then converts angiotensin 1 to angiotensin 2. angiotensin 2 stimulates the adrenal cortex to release aldosterone, which increases salt retention. 

• Scrotum: contains testes, nerves and blood vessels. Protective and climatic control function. It needs to be slightly cooler than body temp. for normal sperm development. 
• Testis: sperm production and steroid hormone production (oestrogen, testosterone and progesterone).
• Epididymis: sperm collects and matures here.
• Vas deferens: sperm transport. vasectomy. 

NB epididymis and vas deferens contribute 5% to the ejaculate. 

• Bulbourethral, prostate and seminal vesicles: all accessory glands and contribute to the seminal fluid. seminal vesicle has the highest contribution. 
• Urethra: urine and semen transport. 
• Seminiferous tubules: specific location of meiosis and androgen binding protein production. they have tall columnar sertoli cells. Myoid cells surround the seminiferous tubules. They convert testosterone to dihydrotestosterone via NADPH.  DHT is a more potent androgen. All the cell populations in the penis have the androgen receptor. 
• Androgen receptors have 2 binding sites: one for the steroid and one for  the steroid response element or HRE in DNA: they are transcription factors. When the steroids bind, they form a steroid receptor complex which acts on DNA and alters  gene expression. 

• Semen: ejaculate volume (1.5-5 ml). sperm count (40-250 million). motility after 1 and 3 hours (70% and 60%). leukocyte count (0-2000ml). pH (7.2-7.8). fructose [ ] (150-600 mg/100 ml). 
• Erection: erectile tissue are corpus cavernosa and corpus spongiosum. They get engorged with blood, arterioles dilate due to parasympathetic nervous system activity. 
• Emission and ***********: sympathetic nervous system, release of sperm and semen into the urethra. Emission: production and release of semen from the glands. 
• Erectile dysfunction can be due to psychogenic reasons (stress), neurogenic, vascular, endocrine, drugs (SSRI, beta blockers, calcium antagonists). Management: naturally occuring prostaglandin E1 for vasodilation (ALPROSTADIL) or PDE5 inhibitor which prevents cGMP reduction and thus maintains the erection (SILDENAFIL). 
• Prostatic cancer: all factors can contribute and be a risk such as age, ethnicity, family history etc. Symptoms include: urgent and frequent urination, nocturnal enurisis, difficulty emptying bladder, weak urine flow, back or pelvic pain, prostate specific antigen. Management: both agonists and antagonists of the GRH (GONADORELIN), androgen antagonists (CYPROTERONE), 5 alpha reductase inhibitors ( DUTASTERIDE and FINASTERIDE). 
• Aplastic anaemia: bone marrow cells are damaged: treatment is anabolic steroids. 
• Contraception in men: high exogeneous testosterone source: reduced FSH and LH. or vasalgel injected into the lumen of the vas deferens. 

The hypothalamus releases the gonadotrophin releasing hormone, whicts acts on the anterior pituitary. This causes the anterior pituitary to release FSH and LH. These hormones act on the testes for spermatozoa and sex steroid production. FSH binds on the sertoli cells receptors for sperm production (it produces ABP, which testosterone binds toand stimulates spermatogenesis). LH binds to receptors on the leydig cells- these are also known as interstitial cells which surround the sertoli cells and are responsible for androgen production. Myoid cells convert testosterone to dihydrotestesterone, via NADPH. 

Inhibin and testosterone are responsible for the negative feedback control affecting both the hypothalamus and the anterior pituitary. 

• oocytes are stored quiescent in the ovaries. Menarche at 12 and Menopause at 51. Approximatelly 468 cycles. oocytes meiosis is asysmetric i.e. haploid gametes formation. Follicles in the ovaries have both the oocytes and somatic cells which enclose the oocytes. FSH and LH act on the somatic cells. 
• Puberty: the adipose hormone leptin, triggers the kisspeptin neurones, which cause the release of the GnRh hormone: and gonadotropins are released i.e. FSH and LH. Early puberty is associated with a higher type 2 diabetes and CVD risk. 
• Menopause: permanent cessation of ovarian activity after 12 months of consecutive amenorrhoea. Perimenopause begins before and continue for 1 year after menopause begins. Climacteric is the transitioning from reproductive to non-reproductive. A later menopause means an increased lifespan. Vasomotor symptoms occur i.e. sweating at night, hot flushes etc. the vascular oestrogen receptors become supersensitive, therefore only a low dose of oestrogen is required. Atrophy of genitalia i.e. wasting away of your genitals causing dyspareunia and UTI's- approximately 10 micrograms of oestrogen a day. Depression symptoms, slower wound healing, inflammatory system, bone density decreases,   increased CVD (oestrogen increases HDL, reduced LDL, vasodilates, increasing clotting factors). 

• The hypothalamus releases the gonadotrophin releasing hormone which acts on the anterior pituitary. This causes the release of FSH and LH via pulsation frequencies. A fast pulse results in the release of the LH, and a slow pulse releases the FSH. FSH: is for follicular growth and maturation, from the secondary follicular stage onwards. LH is for the completion of meiosis1 and ovulation, as well as progesterone production by the corpus luteum. NB corpus luteum also releases relaxin, to avoid cervical contractions. 
• In females there is both a positive and negative feedback system. Positive feedback during the late follicular phase. Negative feedback during the late luteal phase, via inhibin. 
• Androgen precursors produced by the adrenal cortex in the zoma reticultis are used for the androgen productions in the ovaries. steroids bind to the androgen receptor and forms a complex. this complex binds to the steroid response element or HRE on DNA, as a transcription factor. It alters gene expression. 

NB anti-oestrogens such as TAMOXIFEN and FASLODEX. 

BUSERELIN is an agonist at the GnRH receptor which results in insensitivity, therefore reducing FSH and LH production. 

• Menstrual cycle: 28 day cycle, but can vary. Ovulation usually on the 14th day, but also varies. Period: 3-7 days where the lining of the womb is shed. 
• follicular phase: before ovulation. FSH stimulates the follicles in the ovaries to produce OESTROGEN. As the follicles grow, oestrogen production increases. Increasing oestrogen makes sure the womb lining is thickening with nutrients and blood, fertile cervical mucus release. 
• Increasing oestrogen,causes a rapid rise in LEUTINIZING hormone. This LH causes the dominant follicle to rupture and release the mature egg. 
• Movement of the egg from the ovary to the fallopian tube is OVULATION. When a woman is ovulating she is fertile. A woman can identify her fertility days via an ovulation test, which monitors the hormones. Ovulation triggers the release of PROGESTERONE. Progesterone further builds up the lining of the womb to prepare it for implantation. 
• Egg then moves along the fallopian tube into the womb: IMPLANTATION. 
• The empty follicle aka CORPUS LUTEUM: is a yellow body which is a temporary endocrine structure and releases oestrogen and progesterone, relaxin too. 
• unfertilised egg: results in a decrease in oestrogen and progesterone. superficial lining of the womb sheds i.e. functionalis. 
• If fertilised: human chorionic gonadotrophin released, keeps empty follicle active until luteal-placental switch. 

• Implantation: pre-implantation development (fertilised egg divides sequentially until a blastocyst is formed i.e. 32 cells). Zona pellucida  is a protein shell which protects the embryo so as to avoid ectopic pregnancy. Interstitial implantation: blastocyst buries benath the endometrium surface after shedding its shell. 
• Menstruation: shedding of the functionalis, due to withdrawal of the sex steroids. vasoconstriction, hypoxia, local clotting factors, fragmentation, connective tissue breakdown. NB a continuous supply of exogeneous steroids prevents menstruation i.e. CONTRACEPTION. 
• human chorionic gonadotophin hormone: placenta produces this hormone, from the hatched blastocyst stage onwards. appears in both blood and urine. hcG rescues the corpus luteum. 
• progesterone: regulates transport rate of the egg through the fallopian tube. prepares the womb for blastocyst implantation. sustains the endometrium throughout the pregnancy. inhibits myometrial contractibility. 
• Fetal placental unit: interaction to develop a hormonal balance e.g. foetus may provide precursors and mother develops them. 

• Ultrasound imaging: viable pregnancy, heart pulsations can be visualised within the gestation sac. transvaginally: 5 weeks since LMP. transabdominally: 6 weeks since LMP.
• Ectopic pregnancy: embryo finds itself attached outside the uterus causing the following: abdominal pain, hcG detected, tubal rupture can be fatal. Management: METHOTREXATE or surgery. 
• Pregnancy termination: medically or surgery. up to 6 months, but usually done before 3 months. Medically: MIFEPRISTONE (progesterone receptor antagonist). 
• Luteoplacental switch occurs at 7-9 weeks.
• Human placental lactogen: changes the level of insulin like growth factor i.e. increasing glucose and aa availability to the foetus. 
• Gestation: 38 weeks, each trimester is 3 months. 
• Pre-embryonic: 2 weeks, embryonic: 2 months ( major organs form), foetal: 2-9 months (growth and development). 
• Preterm labour: < 37 weeks. oxytocin starts to increase around week 36. If induction of labour is planned due to eclampsia, give GC to mature the lungs. Pitocin given if contractions are greater than 90 seconds and less than 2 minutes apart. 
• Avoid all drugs during the first trimester. especially weakly basic, lipolhilic drugs. 

• Ethinylestradiol and progestogen. Ethinylestradiol is an oestrogen. Progestin is a synthetic P. 
• 21 active pills and 7 sugar pills (ED) or pill free period 
• Monophasic pills: same amount of both hormones in each active pill i.e. consistent levels. 
• Biphasic pills: same amount of ethinylestradiol,  progestogen increases i.e. 2 [ ]'s. First 7-10 days are one strength of P, next 11-14 days are another strength.
• Triphasic pills: 3 different [ ] of hormones for both ethinylestradiol and progestogen. 
• Phasic pills: simply means different strengths of hormones.
• COC MOA: primary action is to inhibit ovulation. thickened cervical mucus and thins endometrial lining. Progestogen: opposes proliferation.
• Advantages: menstrual period (lighter, regular, less painful), decrease in acne..ovarian cysts..bening ovarian cancer..ovarian cancer..uterine cancer..colon cancer. 
• Disadvantages: nausea, vomitting, breast tenderness, cyclical weight gain, libido loss, vaginal discharge, breakthrough bleeding, increased risk of BP (ethinylestradiol increases angiotensin and insulin, but increases HDL) ..MI..stroke..venous thromboembolism..breast cancer..cervical cancer. Some breakthrough bleeding common in first few months.

NB unlike E, P increases LDL. With COC monitor BP every 6 months. 99% effective if used efficiently. Suitable for healthy non-smokers up to the age of 50. Not suitable if very overweight and smoke more than 15 cigarettes and are aged over 35. Missing pills, vomitting, diarrhoea, some meds: reduce effectiveness. 

• Also contain both ethinylestradiol and progestogen. 
• Contraceptive patch: 99% effective. same MOA: stops ovulation, thickens cervical mucus, thins endometrial lining. ADV: dont have to think about it every day, improves acne, lighter..regular..less painful periods, isnt affected by vomitting or diarrhoea. DIS: not suitable if very overweight or a smoker aged over 35. SE of blood clots, cervical cancer, breast cancer. headaches, nausea, mood changes and breast tenderness. possible skin irritation too. Weekly patch used 3/4 weeks. some meds can make it less effective. breakthrough bleeding common in first few months. 
• Vaginal ring: same MOA and advantages. It is also a small flexible plastic ring which is easy to insert into the vagina. Other side effects include increased vaginal discharge. Also not suitable if youre really overweight and  a smoker over the age of 35. some meds can also make it less effective, and breakthrough bleeding. Used 3/4 weeks- need to be comfortable inserting and removing it. 

• Contains progestogen only and has no pill free period i.e. 28 days of active pill taking.
• Also over 99% effective if used efficiently. 
• MOA: suppression of ovulation by thickening the cervical mucus, delays ovum transport, renders the endometrium hostile to implantation, reduces cilia activity in the falopian tube. 
• Advantages: Can be used if you cant use oestrogen. Can also be used if you are a smoker aged over 35. May help with premenstrual symptoms and blood loss  in women  (reducing anaemia). reduces endometrial cancer risk..bening breast disease..uterine fibroids. 
• Disadvantages: Periods may stop, be irregular, lighter, or less painful. Sustained weight gain. loss of libido. acne. headaches. vaginal dryness. obesity reduces efficacy i.e. 30-32. increased risk of functional ovarian cysts..ectopic pregnancy..breast cancer. 

NB must be taken at the same time each day. vomitting, diarrhoea and some meds may make it less effective. Not effective if taken over 3 hours late or 12 hours if it contains desogestrel. i.e. this is the definition of a missed pill. 

• Same MOA as oral progestogen. i.e. suppresses ovulation by thickening the cervical mucus, reducing cilia activity in the falloppian tube, delaying ovum transport and rendering the endometrium hostile to implantation. 
• Contraceptive injection: IM or SC. Can last for 13 weeks (Depo provera) or 8 weeks (Noristerat). Dont have to think about the contraception for as long as it lasts. May make periods lighter and less painful. DIS: irregular periods. Periods and fertility may take time to return after stopping the injections. Sustained weight gain. Any SE will continue for as long as the injection is in the body i.e. its non-removable. Not affected by diarrhoea, vomitting or other medication.  99% effective. its a method with no user failure. 
• Contraceptive implant: over 99% effective too. small flexible rod put under the skin in the upper arm. same MOA. Works for 3 years but can be taken out sooner. You dont have to think about contraception. When implant is removed periods and fertility will return to normal. Requires a small procedure to fit it in and remove it, using local anaesthetics but no stitches. Tenderness, bruising, and some swelling may occur. Irregular periods too. Medicines can affect the implant. 

• Intrauterine system: over 99% effective too. small plastic T-shapped device is placed into the uterus. Works 3-5 years depending on the type but can be taken out sooner. With the minerva ius: get lighter periods. When IUS is removed, fertility returns to normal. Irregular bleeding or spotting is common in the first 6 months. Very small chance of getting an infection in the first 20 days after insertion. Some people get ovarian cysts. Insertion may be uncomfortable. Patient is thaught to check if the IUS is in place. A check for any existing infection may be advised before the IUS is put in place. Not affected by any other medication. If fitted after 45, the minerva can stay in place until menopause. 

• COC: more than 24 hours late. If its on day 6 or later: you need additional 7 day coverage. If 2 or more active pills are missed and UPSI occurs : EHC required. 
• POP: more than 3 or 12 hours late. Need an additional 2 day coverage. If 1 or more active pills are missed and UPSI occurs: EHC required. 

• Breastfeeding a <6 weeks old infant. 
• Women aged >35 and are smokers (15 cigarretes)
• Multiple CVS risks
• Hypertensive: because ethinylestradiol increases angiotensin levels.
• Vascular disease, history of stroke, HD, VTE.
• Migraine with aura. 
• Current breast cancer.
• Diabetes with complications. 
• Systemic lupus
• Bening hepatocellular adenoma
• malignant hepatoma 

• Quick starting contraception: this is when contraception isnt started at the begining of the cycle. 
• Moving from a COC to COC: start the new active pill immediately, without the 7 day break.
• Moving from a POP to COC: have a 7 day vs a 9 day (Qlaira) extra coverage. 
• Startin a POP: no coverage is needed
• Moving from COC to POP: ensure previous pill was taken correctly or simply exclude pregnancy i.e. 3 weeks after sex tests. 
• Starting a COC on first day of period is efficient. 
• During the fake period: hormone levels reduce but you are still protected. 

• Intrauterine device: over 99% effective. small plastic and copper device is inserted into the womb. Stops the sperm reaching an egg, and may also stop fertilised egg from reaching the womb. Works as soon as it is put in, for 5-10 years depending on type. can be taken out sooner if needs be, and fertility willl return to normal. Not suitable if at risk of getting a  STI. Heavier, longer, more painful periods. Very small chance of getting an infection in the first 20 days of insertion. Insertion can be uncomfortable. You're thaught to check the IUD is in place. Not affected by any other medication. If fitted after 40 can stay in place till menopause. Checking for any existing infection is advised. Method with no user failure. 
• Sterilisation of fallopian tubes: aka tubal occlusion. Hysteroscopic method or via opperation cuts or seals the fallopian tube, stopping the sperm from meeting the egg. Not easilly reversible. hysteroscopy not reversible at all. periods are unaffected. Other contraception methods will be needed until the sterilisation is effective. There is a small increased risk of ectopic pregnancy if sterilisation fails. Needs a general or local anaesthetic. May experience short discomfort or pain for some time: avoid any strenuous exercises. Method with no user failure. 
• Sterilisation of vas deferens: aka vasectomy. Sealled or cut, therefore sperm isnt carried out of the penis. Cant be reversed. Performed under a local anaesthetic. Contraception must be used until a semen test shows that no sperm are left i.e. can take up to 8 weeks. Some people may have ungoing testical pain which cant be treated, but it is uncommon. 

• These are methods with user failure. 
• Condom: Male and female differ by being either external or internal. Male is 98% effective, and the female is 95% effective. 
• Male condom: made of very thin latex, plastic or synthetic latex. Its placed over the erect penis and stops sperm entering the vagina. can help protect from sexually transmitted infections.No serious SE. additional spermicide is not needed or recommended. May slip off or split, if its the wrong size, shape. Penis needs to be withdrawn straight after *********** from the vagina, before it gets soft and spills content. Oily lubricants damage latex but can be usedwith plastic. 
• Female condom: made of soft thin plastic which loosely lines the vagina. covers the area just outside, preventing sperm from entering the vagina. Can help protect from STI. Oil based products can be used. No serious SE. additional spermicide is not needed or recommended. Need to make sure the penis enters the condom and doesnt go between the vagina and the condom. May get pushed into the vagina. 
• Diaphragm cap /  spermicide: 92-96% effective. flexible latex or silicone device used with spermicide covers the cervix. Can be put in as early as  3 hours before sex or earlier making sure you add more spermicide. Some people are sensitive to spermicide. Sizes change depending on birth, abortion, weight gain etc. Needs to be left in for 6 hours after sex. 
• Family planning: takes 3-6 cycles to learn yours effectivelly. 

• Levonelle: levonogestrel 1.5 mg. Available as levonelle 1500 (POM) and levonelle one step (OTC) for 16+. It is a synthetic progesterone i.e. progestin. It prevents or suppresses ovulation, fertilisation and implantation. Licensed for up to 72 hours after sex. effective for up to 96 hours. SE: headaches, nausea, breast tenderness, irregular bleeding, fatigue. CI in pregnancy, hepatic impairement, bowel disease and with enzyme inducers. 
• Ella one: ulipristal acetate 30 mg is a progesterone receptor modulator i.e. prevents the effect of progesterone. It delays ovulation and alters the endometrium. Licensed OTC for all women of childbearing age, but use your professionalism. licensed for up to 120 hours after sex. efficacy is reduced if progesterone is taken 5 days post or pre ella one. SE: headache, nausea, abdominal pain, dysmenorrhoea, dizziness. CI: pregnancy, severe hepatic impairement, severe asthma not controlled by steroids, breastfeeding (36 hours per week of abstinense), DDI (cyp3a4 inducers such as ritonavir, levonogestrel, progestogen).
• Fraser guidelines and gillick competence. EHC aims to reduce high rates of teenage pregnancy. 
• Indications for EHC: After UPSI, after *********** onto external genitalia, after contraceptive failure.
• If vomitting occurs within 3 hours: take another pill. 
• If UPSI> 120 hours: refer for IUD. 

• Broad spectrum antibiotics are okay: ampicllin and doxyxycline. 
• Enzyme inducing antibiotics arent: rifabutin and rifampicin
• St jhon's wort
• anti-epileptics: carbamazepine, phenytoin, phenobarbital
• patenteral POC and IUD arent affected by the drugs. 
•  COC, and the POP and ius / implant POC.

• Fully breastfeeding
• or you are nearly fully breastfeeding AND baby is under 6 months AND amenorrhoeic
• Risk of pregnancy increases when: breastfeeding reduces, long intervals between feeds, night feeds cease, 6 month+ infant. 

• This is a blanket term which covers different features and mechanisms. 
• Common factor is aquired progressive neuropathy: optic nerve damage, visual field loss and blindness. 
• Risk factors for glaucoma include: normally asymptomatic, IOP >21 mmhg (normal is between 10-22), family history, african carribean origin, systemic high BP, CVD,migraine, previous occular disease, topical / systemic steroidal use.
• primary glaucoma: aka open angle glaucoma: angle where the iris meets the cornea is as wide as possible. slow clogging of the drainage canals, develops slowly, and its symptoms arent usually noticeable. 
• secondary glaucoma: aka closed angle glaucoma: almost closed angle between iris and cornea. blocked drainage which resuls in a sudden increase in IOP. Demands medical attention immediately and the symptoms are very noticeable.
• aqueous humour production: cilliary body has both muscle and epithelial cells, as well as a rich blood supply.  Blood which gets to the capillary bed, filters through the epithelial cells, to produce AH. aka cilliary processes i.e. in the ciliary epithelial folds. 
• aqueous humour drainage: first goes through the posterior chamber, and follows the route to the anterior chamber. It then exits the eye through the trabecular meshwork into the Shlemm's canal, into the collector channels and out via the episcleral vein. Greatest resistance to AH flow is via the trabecular meshwork i.e. trabecular flow. 

• Uveoscleral outflow refers to the drainage of AH other than through the trabecular meshwork. Unlike the trabecular route, it is not a distictive route with clear tubes and channels to follow. Instead, the AH seeps through and around the tissues in the eye including: ciliary muscle, sclera, lymphatic vessels etc. The lack of a structured pathway has labeled this route the rather unconventional pathway. 
• Uveoscleral outflow is thought to be driven by pressure gradients through the uvea, movement of cilliary muscle, and by changes to the extracellular matrix within the drainage tissues. UO slows down every night.

• FIRST LINE 
• These are analogues of prostaglandin aka F2 alpha isopropyl ester which act on FP receptors to open drainage sites. The receptors are G protein coupled receptors.  They increase UO by remodelling the extracellular matrix. They dont have much of an impact on the trabecular meshwork as it is already compromised. 
• Increase UO by: increasing matrix metalloproteinases, degrade collagen, decrease resistance of cilliary muscle and sclera. 
• They are prodrugs converted via esterases. 
• OD very tolerable
• LATANOPROST TRAVOPROST TAFLUPROST 
• SE: red eye, CI in pregnancy, eyelash growth, iris pigmentation, worsen cystoid macular oedema.

NB Prostamide F 2 alpha 1-ethanolamide analogue. Have a slightly different chemical structure. Impact the prostamide receptors which results in a higher impact on the trabecular meshwork. Exist in the acid form already. BIMATOPROST

• Beta blockers block this mechanism:
• Beta 2 activation stimulates cAMP production. cAMP activates Na 2Cl K transporter which results in Cl efflux. Osmosis to balance out the ions, results in aqueous humour inflow. Effective with only 75% of patients, compatible with other drugs. 
• TIMOPTOL: timolol gel 
• BETOXALOL: b1 selective 
• CARTEOLOL: least lipophilic, therefore less CNS side effects
• LEVOBUNOLOL: has polyvinyl alcohol which increases eye contact time. 
• SE: treated and untreated eye is affected, systemic SE: CV (hypotension), vasoconstricts bronchioles, masks hypoglycaemia. 
• EFFICACY: timolol=levobunolol > carteolol

• both systemic and topical use: systemic is reserved for emergency situations such as closed angle glaucoma. 
• MOA: inhibits carbonic anhydrase in cilliary epithelium, which is required for bicarbonate formation. Bicarbonate is then required for the aqueous humour production. 
• ACETAZOLAMIDE: systemic and for short term use where you want to bring down the IOP before starting other medication. NB it is a sulfonylamide derivative, therefore there is an increased risk of allergy and blood disorders, GI problems, diuresis, drowsiness etc Acetazolamide was then developed to be made more lipophilic with fewer SE risks, leading to:
• DORZOLAMIDE: pH 5-6
• BRINZOLAMIDE pH 7.5
• These are used adjunct with prostglandin analogues or betablockers. As well as, in sole therapy when they cant use either or. But not as effective. They cause transient burning or stinging of the eye: so adherence is low. SE include: dry mouth, blurred vision, red eye, transient myopia, blerpharitis. 

NB blerpharitis: eyelids inflammation 

myopia: near sightedness

• They decrease secretion of aqueous humour by decreasing cAMP, which decreases ion transport and aqueous humour secretion. 
• Decreases ultrafiltration to a slight extent too. 
• Increases uveoscleral outflow. 
• Has neuroprotective properties. 
• Advantages: no mydriasis, no vasoconstriction and little effect on the CVS.
• BRIMONIDE : more selective 
• APRACLONIDINE: less selective and short term use due to tachyphylaxis. 
• Local SE: allergy, stinging, blurred vision and photophobia when drops first go in. 
• Systemic SE: hypotension, dry mouth. 

Parasympathomimetics: PILOCARPINE: myotic: decreases pupil size i.e. pulls scleral spur, which opens up the angle and trabecular meshwork. 

mechanism: contracts ciliary muscle, pulls scleral spur, opens trabecular meshwork, increases trabecular outflow, decreases IOP. effects last for 6 hours, therefore need QDS administration. 

• Iris: coloured part of the eye with 2 smooth muscles: dilator and sphincter. control pupil size. When the sphincter contracts: miosis. When the dilator contracts: mydriasis. They are in an antagonistic relationship. 
• Pupil: opening at the centre of the eye which determines the amount of light which enters the eye. pupilliary light reflex: protects photoreceptors in the retina and controls depth of field vision of the eye. 
• Sympathetic: mydriasis (apha1), far vision (beta 2), AH production (beta 2), vasoconstriction (alpha 1). 
• Parasympathetic: miosis (M 1,3,4,5), near vision (M 1,2,3,4), vasodilation, tear production. 
• Muscle contraction i.e. miosis (Ach @m3) or mydriasis (NA @alpha1): G protein coupled receptor activates Plc, which produces inositol triphosphate. This increases [Ca], and forms a calcium calmulodin complex. This complex activates the myosin light chain kinase, which phosphorylates myosin and causes muscle contraction. 
• Parasympathetic for near vision: ciliary muscle contracts, cilliary body pulled forward, relieves tension on suspensory ligament, lens become convex and there is an increase in refractory power. CYCLOPLEGICS: block near vision e.g. tropicamide, atropine, homatropine and cyclopentolate (these are also Mydriatics i.e. M3 antagonists)
• Miotics: PILOCARPINE:  M3 agonists. 

• Pathogenesis: low bone mass density. bone microarchitecture is disrupted. increased skeletal fragility and fracture risk (fractures which doesnt usually occur in healthy patients).
• Cortex: thick outer shell of bone. Trabecular bone: meshwork of bone on the inside. 
• Takes approximatelly 100 days for bone to breakdown and remodel. 
• OP occurs as a result of an imbalance between the osteoblasts and osteoclasts. Resulting in reduced osteoblast acitivity, increased osteoclast activity, low peak bone mass, thinner cortex, holly trabecular bone. Bone turnover is influence by hormones such as oestrogen and testosterone, as well as cytokines and Prostaglandins. 
• Bone remodelling cycle: Resting phase (before activation occurs to trigger resorption), Activation phase (osteoclasts break bone down: erosion), Reversal phase (mononuclear cells prepare the surface for osteoblasts), Formation (osteoblasts form matrix to replace resorbed bone). 
• Bone density: peak bone mass reached at 25-40. After 40 years: 0.5-1% / year bone loss.
• Symptoms of OP: fractures, reduced bone density on the DxA scan, pain, reduced mobility, kyptosis (spine curvation), height reduction (10-20 cm). >75 just assume, dont scan. 
• Risk factors of OP: fracture Hx, fracture Hx in a first degree relative, smoking, low exercise, alcohol consumption, low body weight, oestrogen defficiency, corticosteroid use, white race, increase in age, dementia, poor vision, poor health and low [Ca].  
• DxA scan: high risk / established OP. hip / lower spine. T score of < or equal to 2.5. 

• Calcium: daily intake recommended at 400-700 mg vs 500-1000 mg in high risk groups.
• Vitamin D: 10% obtained from the diet vs 90% obtained from UV rays and cholesterol. 800 units a day. CALCITRIOL: vitamin D analogue given to PM women: 250 ng BD. 
• FIRST LINE: BISPHOSPHONATES: works on osteoclasts. treats PM OP, treats / prevents steroid induced OP, given alongside Ca and Vitamin D. Counselling points: take 30-60 minutes before food as they are poorly absorbed. take whilst sitting or standing with a full glass of water. stay upright for 30-60 minutes after taking the medication, to prevent oesophageal irritation. SE: GI upset, oesophageal irritation,  bone + joint + muscle plain, osteonecrosis of the jaw. ALENDRONATE: weekly. RISENDRONATE: weekly. IBANDRONATE: monthly. 
• SECOND LINE: selective agonist and antagonist acivity on oestrogen receptors. reduce bone resorption. used in PM OP, for women intolerant to bisphosphonates. Compared to traditional HRT: have a reduced cancer risk, but same DVT risk. RALOXIFENE. 
• SECOND LINE: STRONTIUM: works on osteoblasts and osteoclasts. PM OP. one sachet at bedtime: 2 hours after food.  SE: GI, hypersensitivity, CVD. 
• Parenteral bisphosphonates: used if unresponsive / intolerant to oral. ZOLENDRONATE. short infusion evry 12 months. PM OP. flu like symptoms occur at infusion time. or IBANDRONATE (every 3 months) or PAMIDRONATE (men with OP resistant to oral). 

• DENOSUMAB: newer treatment. monoclonal antibody. SC twice a year. given for PM OP resistant / intolerable to oral bisphophonates. 
• HRT: shouldnt be used as first line due to increased risk of blood clots. isnt recommended either. started early in menopause. continue for up to 5 years. bone loss increases soon after stopping. should not be used as long term prevention in those over 50 years.
• Calcitonin: reduces bone resorption. used as an option if other treatments fail. As a nasal spray or injection. 
• PTH: increases osteoblast activity. Restrictions as per NICE: women >65 unresponsive to bisphophonates with either: very low bone density (-4 or lower), or very low bone density + more than 2 fractures + other RF (premature menopause, rheumatoid arthritis, prolongued immobility). Continue for up to 18 months. daily s/c injection. SE: dizzy, leg cramps etc 

• Most common onset at the age of 40-60 years. More common in women and obese patients. Also has a genetic factor to it. It is the most common form of arthritis, where joint pain is worsened on movement. Can be accompanied by swelling. Common in knees, hands, lower spine region and cervical spine. EMS of up to 30 minutes. 
• Pathophysiology: cartillage gradually roughens and thins out. The underlying bone thickens. Osteophytes aka spurs form which rub together and cause pain. Thickened and inflammed synovium. Thickened and contracted ligament. some joints may repair, others dont. 
• Primary intervention include: weight reduction, hot / cold packs, surgery, psychological support, occupational therapy review, physiotherapy. 
  • Secondary intervention:
• Simple analgesics: paracetamol, codeine, combined analgesics or opioid analgesics. nsaids (only if there is swelling and for the shortest time possible, topical nsaids). 
• CORTICOSTEROIDS: only intra-articular. no more than 4 injections in one joint per year. reduce pain and synovitis. 
• HYALURONIC ACID: intra-articular. improves the synovial fluid integrity. may help delay time to surgery. 
• CHONDOPROTECTIVE AGENTS: they protect / build up cartillage, reduce cartillage breakdown rate, delays OA progression. arent sure about long term safety yet. CHONDROITIN and GLUCOSAMINE. 

• Typically at 30-50 years. But juvenille arthritis also occurs. Reduces life expectancy due to conditions likely to develop due to RA. more common in females (3:1 ratio). slow progressive symmetrical polyarthritis i.e. more than 4 joints are affected. Pain and stiffness in hands, feet, wrists, shoulders, elbows, knees. 
• Extra-articular symptoms: can also occur such as sjordens syndrome (dry eyes and mouth), vasculitis, neuropathy, subcut nodules, lymphadenopathy, CVD, depression, respiratory disease. 
• Pathogenesis: lymphocytes infiltrate the synovial membrane and inflame / thicken it. pannus formation over cartillage, leads to bone erosion. eventual bone and joint degeneration.
  • Secondary management:
• Analgesics: paracetamol, codeine, tramadol. adjuvant at night amitriptyline. nsaids: again the lowest possible dose. celecoxib is a Cox 2 nsaid: arent too sure about the safety though.
• Conventional DMARDS: disease modifying anti rheumatic drugs. they suppress the disease activity, reduce the release of inflammatory cytokines, may prevent radiological changes, start within 3 months of confirmed diagnosis to reduce damage. FIRST: METHOTREXATE. SECOND: SULFASALAZINE. THIRD: HYDROXYCHLOROQUINE. 

• Biological DMARDS: are divided into 2 groups the TNF and non anti-TNF. They target specific inflammatory mediators, thus are more effective than conventional DMARDS. They are genetically engineered to mimic proteins within the immmune system. 
• Anti-TNF: they target the pro-inflammatory cytokine TNF, especially TNF alpha. prevent and might repair current joint damage. superior to methotrexate alone. NICE guidelines to use: clincially active RA that hasnt responded to at least 2 dmards. must be monitored and report to national biologics registry. INFLIXIMAB ETANERCEPT ADALIMUMAB GOLIMUMAB CERTOLIZUMAB. Nb they are all sc, except for infliximab. 
• non anti-TNF biologics: RITUXIMAB (depletes B cells), TOCILIZUMAB (blocks IL6 action), ABATACEPT (inhibits T cells). 
• Corticosteroids: Intra-articular (methylprednisolone and triamcinolone: risk of infections, benefits seen in 48 hours). Intra-muscular (methylprednisolone: single dose in acute flare up). Intra-venous (rare: usually for severe extra-articular symptoms). Oral: given as a temporary relief drug before initiation of dmards, prolongues use only if intolerant to dmards. 

• Preventionof falls in >65 year olds in hospital / community or 50-64 year olds in high risk hospitalised patients via: multifactorial falls risk assesment, assess environment, history of falls, cognitive function, visual impairement, medication review, polypharmacy ( 4 or more drugs), compliance (e.g. BP medication), new medication (antihypertensives, sedatives, psycotropics, analgesics, steroids). 
• Prednisolone: major RF in OP: inhibits osteoblast formation. 
• DMARDS counselling points: explain why they are taking the medication, the benefits of the medication, when and at what dose to take the medication, how long will it take for the medication to work, SE, monitoring and interactions, fertility, pregnancy, alcohol and vaccinations. 
• Calcium / vitamin D: choice of preparations depends on the patient's choice: sachets, dispersible, tablets, chewable. 
• Compliance issues: manual dexterity, memory problems, CRC lids, access to blister packs, dosette boxes / medidoses, autodroppers, haleraids. 
• METHOTREXATE: weekly dose, folic acid prescribed for SE, 3 months till effect, chicken pox history, DDI (nsaids, trimethoprim, septrim), Pregnancy..fertility (3 months wash out), alcohol (3-4 units a week), vaccination (avoid live, recommend pneumonia and flu), monitor every 2 weeks for 6 weeks and then every 4 weeks, then every 3 months. SE: GI, hair loss, mouth ulcers, blood disorders like neutropenia, hepatotoxicity, pulmonary fbrosis. 

• SULFASALAZINE : daily medication. need e/c tablets. response time 3 months. SE: GI, dizzy, headache, rash, discolouration of urine, stains lenses. DDI. 6 months wash out for men's fertility. safe in pregnancy for women. okay with alcohol consumption. monitor every 2 weeks for 2 months, then every 1 month for 3 months, then every 3 months. Includes a urinalysis in the monitoring. 
• HYDROXYCHLOROQUINE: daily medication. response time 3 months. milder disease modifying drug, but has a good adjuvant effect. may cause retinopathy (opticians appoitment within 1 year of starting drug). Rash (advise patients to report rashes). 
• Monitoring conventional DMARDS: FBC, differential WCC, LFT's, creatinine, platelet markers, erythrocytes sedimentation rates / CRP, BP. 
• Biologic DMARDS prescreening checks: baseline blood, TB status, travel history, Hep B status, infection and cancer history, pregnancy, CVD screening. Counselling point: training them how to administer injections via a homecare service. Report any signs of infections. dietary advice: avoid uncooked meals, risk of salmonella. avoid in pregnancy and breastfeeding. vaccination flu and pneumonia before treatment. 

• Amenorrhoea: no bleeding
• oligomenorrhoea: infrequent menstrual periods.
• polymenorrhoea: cycles of 21 days or less.
• metrorrhagia: cycle of 35 days or more.
• Menstruation: breakdown of the functionalis i.e. superficial layer of the endometrium. tissue hypoxia, fragmentation, connective tissue breakdown, vasoconstriction, local coagulation factors. occurs when fertiisation doesnt occur and oestrogen and progesterone levels drop, via negative feedback.
• Dysmenorrhoea: pain during menstruation.
• Primary: no underlying cause. 12-20's. GI effects. cramping. thigh pain. headache. Feminax express and ultra i.e. ibuprofen and naproxen. hyosine butylbromide (POM). oral contraceptives. 
• Secondary: underlying cause. e.g. endometriosis, PID, fibroids, uterine polyps, menorrhagia. 30-40's. pain usually starts 3 days or so before. 
• Higher [ ] of PGE and PGF. myometrial contractility. endothelins: vasoactive proteins which locally regulate PG, they constrict blood vessels and increases BP. ADH decreases uterine blood flow. vasoconstriction. 
• Cell wall phospholipids are converted to arachidonic acid by phospholipase. arachidonic acid is then converted to the prostaglandins, prostacyclins and  thromboxanes via cox enzymes. 

• Endometryosis: this is when the endomterial tissue travels outside the uterus and deposits somewhere else: GI tract, urinary tract (cyclical haematuria, dysuria, dyschezia, cyclical tenesus, rectal bleeding), lungs ( cyclical haemaptosis). results in retrograde menstruation. menstrual irregularities, pelvic pain, infertility. surgical treatment: aims to restore pelvic anatomy, divide adhesions and ablate the endometrial tissue. Medical management: gestrinone (synthetic steroid), anastrazole (aromatase inhibitor), COC's, IUS, nsaids, selective androgen receptor modulators (immunomodulators targeting the steroids pathway). 
• Mennorhagia: menstrual blood loss of over 80 ml a month. flooding, large clots, double sanitary pads requried. Cause: dysfunctional uterine bleeding, menopause, fibroids, miscarriage, ectopic pregnancy, IUD, ademyosis, blood thining medication.Diagnosing it: pap smear,cervical smear, biopsy, histeroscopy, ultrasound. Medication: COC's, IUS, tranexamic acid (anti-fibrolytic), mefenamic acid (nsaid), danazol (synthetic steroid), GnRH analogues i.e. antagonists (norethitesterone). 

• butterfly shapped gland. 2 or 3 glands: 2 are connected to each other by the isthmus. lies below the adrenal apple i.e. thyroid cartillage. thyroid follicular cells have a cuboidal epthelial barrier and they contain thyroglobulin. parafollicular cells aka c cells.  these produce calcitonin.
• Low temperatue: hypothalamus releases the thyroid releasing hormone which activates the anterior pituitary to release the thyroid stimulating hormone.this stimulates the thyroid gland to produce t3 and t4 hormones. NB the thyroid follicular cells have tsh receptors, which are G protein coupled receptors, which produce cAMP. 
• Synthesis of T3 and T4:  iodide  moves from the blood into the cells by the sodium iodide symporter, and then into the lumen by the ion exchanger pendrin transporter. in the lumen iodide is oxidised to iodine. thyroglobulin molecules are then iodinated by thyroid peroxidase, forming monoiodotyrosines and diodotryrosines. 2di= T4. 1di and 1 mo= T3. they then move back into the cell via endocytosis, where proteolysis occus to cleave the thyroglobulin molecules. 
• Thyronine hormones: most common one is thyroxine. has a longer half life but is less potent than triiodothyronine. T4 is also hydrophobic and insoluble in serum, therefore it is transported via binding proteins which are synthesised in the liver. 
• Binding proteins: TBG aka thyroxine binding globulin (both T3 and T4, half life is 5 days) TRANSTHYRETIN (T4, half life 3 days), ALBUMIN (T3 more than T4). protein bound t4:t3 is 20:1. they can't enter cells. free t3 and t4 enter via MCT8, MCT10, OATP1. 
• NB: iodide moving from the blood to the lumen is known as basolateral transport.

• ENZYMES: iodothyronine deiodinases: they are selestocysteine containing enzymes. the selenium accepts iodine. T4 to T3 by DIO 1,2. T4 to rT3 by DIO 1,3. 
• DIO 1: predominates in liver, kidney, muscle.
• DIO 2: predominates in CNS, pituitary, thyrotropes. 
• DIO 3: produces inactive rT3: prevents thyroid hormone access to specific tissues. 
• Thyroid hormone action: thyroid hormone receptors: TR alpha and TR beta. they are found in the nucleus. they are heterodimer with retinoid X receptor. it functions as a transcription factor for gene expression: control of metabolic rate, growth, foetal development (neural + skeletal of you get irreversible retardation + dwarfism like endemic cretinism, neonatal goitre, neonatal hypo., congenital abnormalities), CV effects ( increased cardiac contraction and output, HR, O2 supply, C02 removal, increased myocardial calcium uptake, increased expression of alpha myosin and a reduction of beta myosin), muskoskeletal effects (increases both formation and resorption, t3 increases linear bone growth after birth, normal skeletal function requires t3). 

NB thyroid function tests measure free unbound T4. or can meausure the thyroid peroxidase antibody which is usually rare and done by a specialist.

• Primary hypothyroidism: an increase in TSH and a decrease in T4 based on the TFT's. causes include: hashimoto's thyroiditis, treatment for hyperthyroidism, iodine imbalance, congenital hypothyroidism (initially 10-15 microgams per kg, maximum 50 micrograms). Symptoms: lethargy, weakness, fatigue, hate cold, memory loss, weight gain, depression, gruff voice, constipation, hair loss, dry scaly skin. Management: thyroxine and levothyronine. THYROXINE (adults less than 50: 50-100 micrograms initially, adults older than 50 + CVD: 25 micrograms initially).  Measure TSH after 8-12 weeks. maintenance in adults: 100-200 micrograms, in children 50-100 micrograms. monitor TSH yearly. monitor for angina. Entitled to medical exemption certificate. single daily dose. 
• Hyperthyroidism:  a decrease in TSH and an increase in T4. cause: grave's disease. Symptoms: anxious, palpitations, tremor, tachycardia, goitre, like the cold, warm moist skin. Management: thionamides: carbimazole (start with 15-40 mg then reduce to 5-15 mg)(active metabolite methimazole) and propythiouracil ( 200-400 mg intially in divided doses until a maintenance of 50 TDS)(these block thyroperoxidase activity and can both cause agranulocytosis).  block and replace therapy: carbimazole and levothyroxine ( 40-60 mg vs 50-100 micrograms) (carbimazole for approximately 4-8 weeks before starting levothyroxine).  radioactive iodine and surgery.
• Beta blockade:rapid relief of hyperthyroidism symptoms within 4 days. PROPANOLOL NADOLOL. 3-4 times a day. only used when symptomatic. CI in asthma.

• Drug induced thyroid disease:
• IODINE: radiographic contrast media. acute: inhibits release of T3 and T4. prolongued: suppresses release of T3 and T4. iodine deficiency: hypothyroidism: very rare.
•  AMIODARONE: molecule contains organic iodine. hypothyroidism: inhibition of synthesis and release of T3 and T4. mild hyperthyroidism: blocks conversion of T3 to T4, therefore increases TSH, to make T4: usually transient when starting the treatment, then it normalises. Severe hyperthyroidism: need to withdraw treatment. direct thyroiditis: excessive release of T4. 
•  LITHIUM: hypothyroidism: inhibits iodine uptake and T3 / T4 release: usually transient when strating treatment. hyperthyroidism: rare, paradoxycal event. 

NB 

Sodium iodide symporter: secondary active transporter which transports iodide against its chemical gradient coupled to a sodium ion. gradient is maintained by Na+ K+ ATpase.

Thyroglobulin is produced in the thyroid follicular cells at the ER from aa. and exits the follicular cells into the lumen via the GN into vesicles for exocytosis. thyroid peroxidase degrades iodinated thyroglobulin. Highest affinity for T4: TBG. Highest capacity for T4: albumin

• 2 types of cells: chief and oxyphil cells.
• C cells aka parafollicular cells are found in the thyroid gland, in between the follicular cells. They secrete the hormone calcitonin which decreases [Ca]. Calcitonin is a protein hormone, with 32 aa and a half life of 5 minutes. They also secrete parathyroid hormone (chief cells), which increase [Ca]. PTH is a small helical protein hormone, with 84 aa, and a half life of less than 20 minutes.
• Low calcium levels are detected by G protein coupled calcium sensing receptors: they then indirectly stimulate the osteoclasts, increase renal calcium reabsorption and increase vitamin D production. 
• Rickets / osteomalacia: individuals lack calcium and vitamin D: results in softening and deformation of the bones.
• Paget's disease: chronic bone disorder: internal bone structure is distorted. osteoclasts are bigger and more active. Affects the skull, spine and pelvis.