Micrometer

My friend has shown me a very useful link to understand how to use Micrometer and here I am sharing with people who need it :)

http://www.stefanelli.eng.br/webpage/en-aka-micrometer-caliper-outside-millimetre-hundredth.html

Hope it helps :) x

Viral Hepatitis Worksheet

1. 

1. There are 5 types of hepatitis: A, B, C, D and E.
   
2. Acute VH is observed with all types and lasting less than 6 months. But chronic VH is viremia (virus enters the blood steam) and hepatic inflammation lasting longer than 6 months following infection. They are usually associated with Hepatitis B, C and D and it may lead to cirrhosis and end stage of liver disease, which leads to complication such as ascites, oedema, jaundice , hepatic encephalopathy, bleeding oesophageal varices, etc.
   
3. A, B, C, D and E
4. B, C, D
   
5. 
   

Parkinson's Disease

Mechanism of Cell death

- Neurones die undergo nercosis, cell swelling , vuculosis and lysis, which are associated with Ca++ overload of cells and membrane damage.

- they are not replaced in adult CNS

- progenitor (stem) cells may occur in some parts of the brain.

Excitotoxicity
- is the pathological process by which nerve cells are damaged and killed by excessive stimulation of neurotransmitters

Glutamate activates by NMDA, AMPA and metabotropic receptors.
Motor system
Eidemiology
Dopaminergic pathways
Metabolism of dopamine
Symptoms
Other symptoms and problems

Treatment of PD

Dompaminergic drugs ( 5 classes)

1. Dopamine precursors (e.g. Levodopa)
   
2. Dopamine receptor agonists (e.g. Apomorphine)
   
3. Monoamine oxidase B inhibitors
   
4. Catechol- O- methyltransferase inhibitors
5. Amantadine

Dopamine precursors
- Levodopa
- Dopa decarboxylase inhibitors

• Benserazide
  
• Carbidopa

SF:

• Dyskinesia
  
• Motor fluctuation ( develop after 5 years onset of the disease)
  

Dopamine receptor agonists
-Pramipexole
- Apomorphine ( expensive)

Monoamine oxidase B inhibitors
-Selegilence
- Rasagilene


Catechol- O- methyltransferase inhibitors (COMT inhibitor)
- Entacapone
-Tolcapone

Amantadine

Antimuscarinic drugs


Treatment strategies

Live disease

Liver Anatomy

• Hepatocytes - hexagonal units called lobules and each lobule centred around central vein that drains blood into hepatic vein
  
• Hepatic portal vein and artery are branched from the lobules .
• Sinusoids are formed by the vessels branch among the hepatocytes
• 70% of SA of hepatocytes to max exchange between blood and cells
  
• 15% faces the bile canaliculi

Function

• Metabolism ( Vitamine D, fat protein, carbo, hormones, drug and toxins )
  
• Clearance
  
• synthesis
  
• storage
  
• excretion
  
• secretion
  
• homeostasis ( glucose)
  
• Defence ( Kupffer cells- hepatic macrophages)
  

Type of live injury

1. hepatocellular - alcohol,toxins or drugs or viruses
   
2. cholestatic - blockage of bile duct
   
3. Infiltrative - cancer

Liver disease classification

1. acute LD
   
2. Acute LF/ fulminant hepatic F
   
3. Chronic LF
   

Causes - Autoimmune, alcohol, drugs, chronic viral hepatitis Wilson's disease

Autoimmune

• auto-antibodies in the serum
  
• usually presents as chronic progressive disease
  
• affects the biliary tree
  

Wilson's disease

• Inherited metabolic disease
  
• characterised by copper overload
  
• excessive absorption and deposition of dietary
  copper in liver, brain, kidneys and other tissues
  

Gilbert syndrome - Benign condition - no active treatment

• Hyperbilirubinemia- >50umol/L
  
• symptoms: Hyperpyrexia, fatigue, nausea, abdominal discomfort.
  

Sign and symptoms of liver Disease

• spider naevi
  
• finger clubbing
  
• Gynaecomastia
  
• Loss of body hair
  
• jaundice
  
• Enlarged Liver
  
• Alopecia- hair loss
  
• White nails
  
• Ascities - abnormal accumulation of fluid in the abdomen
  
• Portal Hypertension
  
• Pruritis - itch

Chronic complication of liver disease

Jaundice

• can be both an acute and a chronic sign of liver disease.
  
• it occurs when serum bilirubin levels are high. ( Bilirubin is metabolised by the liver) Therefore, it will accumulate if the liver is not functioning to its full capacity.
  
• it is clinically detectable when plasma bilirubin is 35umol/L.
  
• Jaundice presents as yellowing of the skin, mucous membrane and iris

Portal Hypertension (PH)

• Usual portal venous pressure is 2-5mmHg. If this becomes chronically high, collateral veins can form. ( This can form throughout the body) but are found mainly in the GI tract.
  
• The presence of these veins allows portal blood to enter the systemic circulation directly bypassing the liver.
  
• if the portal venous pressure remains high, this may lead to bleeding varices ( bleeding of dilated veins caused by liver disease) and it is potentially life-threatening. The damage can cause disruption of blood flow and liver function- processes that take place in the liver. metabolism, protein synthesis, etc. Raise in Bilirubin levels.
  
• PH also contributes to hepatic encephalopathy and ascites.

Cirrhosis- Progressive replacement of normal hepatic cells by fibrous tissue.
* associated with high level of aldosterone.

Ascites
- is the accumulation of fluid in the abdominal cavity. In liver disease, there are 3 main causes of ascities.

• PH : altering capillary pressure and permeability, leading to the accumulation of fluid in the peritoneal cavity.
  
• low blood albumin following reduced synthesis in the liver leads to fluid seepage from blood vessels.
  
• Aldosterone : the hormone responsible for fluid retention) . Accumulation when the damaged liver cannot metabolise it adequately.
  

Hepatic Encephalopathy

• occurs in profound liver dysfunction.
  
• Neurotoxic substances enter directly into the brain, bypassing the damaged liver.
• Ammonia is one such substance and it alters the permeability of the blood-brain barrier.
  
• the patient presents with an altered mental state, euphoria and confusion.
  
• In severe cases, coma can be the end-result.
  

Gynaecomastia

• The damaged liver is unable to metabolise oestrogen which can lead to feminisation in males.
  
• in Women, it presents as irregular menstrual cycle and reduce fertility.

Investigations

Liver function test (LFTs)

• Bilirubin is raised in hepatocellular damage, cholestasis and haemolysis
  
• Transaminases :aspartate transaminase (AST) and Alanine transaminase ( ALT) released from the liver in hepatocellular damage.
  
• Alkaline phosphatase (ALP) is released in cholestasis ( damage of bile duct)
  
• Albumin is synthesised in the liver. Serum albumin indicates the extent of chronic liver disease as it has a long half life ( approx 20 days)
  
• Prothrombin time: Clotting factors synthesised in the liver. Good indicator of acute liver disease due to short half life ( 6 hours) .

Liver biopsy- diagnostic

Management

Ascites- is the excess fluid in between the tissue lining the abdomen and the abdominal organd ( the peritoneal cavity.

• Sodium intake should be restricted to 60-90mEq per day (hyperkalemia)
  
• Spironolactone( aldosterone antagonist) is the drug of choice. SF: hyperkalemia and gyneacomastia. ( 100mg daily increasing to 400mg daily)
  
• Paracentesis is a procedure involving a needle of drainage of fluid from the peritoneal cavity. It can relieve the abdominal pressure from ascites.
  
• TIPSS- is placed to provide portosystemic shunting to reduce portal pressure.
  
• Liver transplant
  
• Desired weight loss: 0.5-1kg per day. Water in versus Water out should be monitored.
  

Portal Hypertension

• Propranolol : the only beta-blocker licenised for portal hypertension. it is given to reduce portal venous pressure and prevent recurrent variceal bleeds. ( 10mg BD-TDS)
  
• SF: vivid dreams, bradycardia, coldness of extremities, fatigue and bronchospasm.
  
• should not stop taking unless advised by a doctor
  

Hepatic Encephalopathy

• dietary protein intake should be reduced to 20g per day
  
• Lactulous : an osmotic laxative. It can reduce the pH of colonic content thus reducing colonic ammonia absorption. The GI transit time will be decreased, so patient are monitored for 2 to 3 bowel motions a day.
• Metronidazole reduces ammonia production from GI bacteria
  
• Interaction with alcohol: a disulfiram type reaction ( like dizziness and vomiting) occurs if metronidazole is taken with alcohol.
• Alternative: Neomycin - reduces plasma ammonia. Max of 7 days 1g QDS ( ototoxicity & nephrotoxicity)

Pruitis

• Antihistamines are not very effective but if given, non-sedating antihistamines would be preferable ( e.g. Loratidine) , as sedating could mask the effect of hepatic encephalopathy
  
• Anion exchange resins ( Colestyramine) bind to the bile acids that cause itching and it is 1st line treatment. it can redice the absorption of other drugs taken at the same time. - taken 1 hour before or 4 hours after taking a dose of anion exchange resins.
• Topical preparations such as calamine lotion can be used.
  

Oesophageal varices

• Vasopressin: reduce portal blood flow and portal pressure; it is given IV to stop bleeding. ( 20units IV over 15-20mins)
  
• SF: angina, myocardial infarction and arrhythmia
• Should not be given to patients with ishaemic heart disease. GTN ( glyceryl trinitrate) can be given to overcome the cardiac SF ( vasoconstriction)
  
• Terlipressin : given IV, is the drug of choice ; it releases vasopressin over several hours without the cardiac effects ( 2mg then 1 -2mg ever 4-6hours until bleeding is controlled for upto 72 hours)
  
• Octreotide: A somatostatin, given IV, stops variceal bleeding and reduce portal venous pressure. it inhibits release of vasodilating hormones (e.g. glucogon)
  

Haemostasis and Thrombosis

- a dynamic process of maintaining fluidity of the blood, repairing vascular injury and limiting blood loss while avoiding vessel occlusion ( Thrombosis) and inadequate perfusion of vital organs.

• formation of platelets which adhere to injured tissue
  
• Blood clotting factors : the protein circulating in the plasma.
  
• Results in formation of insoluble fibrin clot that reinforces the initial platelet plug.
  
• Fibrinolysis : happens when healing and tissues repair are under way.

3 systems

1. intrinsic pathway
   
2. extrinsic pathway
   
3. common pathway
   

Here's a very good website to explain these 3 pathways.

http://www.hopkinsmedicine.org/hematology/Coagulation.swf

Intrinsic pathway

Basic :

Blood on -ve charged surface
|
XII --- Kininogen + Prekallikrein
_________________________
|
|
Kallikrein
|
|
XIIa + XI
_______
|
|
IX (IXa) + VIIIa (cofactor) -----> convert X to Xa---> ( initiation of common pathway)

• initiated when blood comes into contact with -ve charged surface
  
• Factor XII interacts with high molecular weight - kininogon and prekallikrei. ---> to produce Kallikrein which activates factor XII ( XIIa)
  
• The activated factor XIIa then activates factor XI which activates factor IX
  
• the factor IXa together with activated factor VIIIa ---> as a cofactor which converts factor X to factor Xa.
  

Extrinsic Pathway

basic :

Tissue factor from damaged tissue
|
|
VII bind to it and form VIIa
|
|
Activates X to form Xa

• when tissue factor is exposed to the blood on the damaged tissue, The factor VII binds to it to form factor VIIa
  
• which activates factor X to to form factor Xa, leading to the initiation of common pathway.
  

Common pathway

Xa ( activation) +V
|
|
Prothrombin------- Thrombin
|
|
formation of fibrin ( stablised by XIIIa)

• the activation of Factor Xa is the point that intrinsic and extrinsic pathway converge to form a common pathway of coagulation cascade.
  
• Factor Xa together with activated V as cofactor, converts prothrombin to thrombin with a subsequent formation of fibrin which is stabilised by factor XIIIa and form a stable clot.
  

Fibrinolysis

Plasmin (fibrinolysin)
|
digests fibrin clots and II, V, VII, XII

• Clot dissolution
  
• mediated by plasminogen which circulates in plasma as an inactive form, which converts to its active form plasmin ( fibrinolysin) .
  
• This occurs when plasminogen binds to fibrin in the presence of plasminogen activator.
  
• Fibrinolysin digests fibrin clots and hydrolyses factors II, V, VIII and XII.

Thrombosis

- the development of thrombus in the arterial or venous circulation
- if venous thrombus breaks off and enter:

• Right circulation and lodge in the pulmonary arterial circulation->pulmonary emoblism (PE)
  
• Left circulation and lodge peripheral arterial --> cause stroke

Venous Thromboembolism

1. Deep vein thrombosis (DVT)
   
2. Pulmonary Embolism (PE)
   

Risk factor

• Age
  
• immobility
  
• major surgery in recent weeks
  
• pregnancy
  
• malignancy - cancer
  
• oestrogens
  
• inherited coagulation disorders. Previous venous thrombosis

Diagnosis

DVT

-clinical symptoms
- RF

• D-dimer : is a small protein fragment present in the blood after blood clotting generated by fibrinolysis
• the concention of D-dimer can be determined by a blood test.
  

• Duplux ultrasonography scan :

PE

• Pulmonary arteriography
  
• ventilation perfusion scanning
  

Treatment

Nonpharmacologic prevention - external pneumatic compressio, graduated compression socking or venous foot pumps. ( these devices increase venous outflow and reduce stasis within the leg veins.
pharmacologic prevention - Venous thromboembolism

• unfractionated heparin
• oral anticoagulants - warfain
  
• low molecular weight heparin

Unfractionated heparin (UFH)

Mechanism of action

• the major mechanism by which heparin blocks coagulation is by catalysing the inhibition of thrombin. UFH acts as an anticoagulant by catalysing the inactivation of thrombin (factor IIa) , activated factor X ( factor Xa) , and activated factor IX (IXa) by antithrombin
  

- used to prevent thrombosis ( venous , unstable angina)
- prevent blood clotting

Caution

• HIT
  
• Hyperkalaemia -
  

- short duration of action

Low molecular weight heparin

- longer duration of action compared to UFH

Oral anticoagulant - Warfarin

Mechanism of action

• is a vitamin K antagonist and interferes with the synthesis of coagulation factors.
  
• Because vitamin K is essential for production of prothrombin and factor VII, IX and X ( vitamin K is important for postranslational carboxylation of glutamic acid residues of these proteins)
  
• Warfarin blocks vitamin K reductase, needed for vitamin K to act as a cofactor in the synthesis of coagulation faction.
  

SF

• many drug interactions
  
• may lead to increased bleeding
  

Heparin-induced thrombocytopenia (HIT)
- is the development of a low blood count (thrombocytopenia) due to the administration of various forms of heparin.

- stop treatment and use heparinoid or hirudin

Heparinoid ( e.g. Danaparoid)
- a mixture of low molecular weight sulphated glycosaminoglycuronans

Mechanism of action

• inhibits factor Xa resulting inhibition of thrombus generation and thrombus formation
  

Hirudin ( Lepirudin and Bivaluridin)

- a direct thrombin inhibitor
- action independent of antithrombin.

Lepriudin

- a recomninant hirudin
caution
- risk of bleeding

Bivaluridin
Caution
- an exposure to lepirudin

Fondaparinux - a synthetic pentasaccharide

• bind to antithrombin thus inhiits activated factor X
  

SF : haemorrhage.

Pharmacological prevention - Arterial thromboembolism

- if affecting the cerebral circulation results TIAs ( transient ischaemic attacks or cerebral infarction ( a form of stroke)

Antiplatelets

1. Aspirin
   
2. clipidogrel
   
3. Glycoprotein IIb/IIIa inhibitors
   
4. Dipyridamole
   
5. Clopidogrel
   

Cardiac Arrhythmia

ECG ( electrocardiography)
- consist of 12 conventional electrode systems - 6 limb leads and 6 chest leads
- is a trace showing variations in potential over time arising from the heart


Normal ECG

• P-wave =
  
• PR segment
  
• QRS complex
  
• ST segment
  
• T wave

• TP interval

Arrhythmia

-Refer to any change in the normal rate or rhythm of the heart.

Sinus trachycardia
Sinus bradycardias

The skin

There is 2 types of acne:

1. Acne Vulgaris
   
2. Acne Rosacae

Acne Vulgaris

Symptoms

• Seborrhoea ( too much oil on the skin)
  
• Comedones ( blackheads)
  
• inflammation
  
• papules. ( small inflamed elevation of skin) . pustules or nodules
  
• Tenderness
• scaring
  

Cause

• at puberty: pilsoebaceoous gland increase sebum in response to testosterone ( males and female do produce testosterone but males produce more - so it effects more in men)
  
• flow of shedding.
  

- increased keratin and sebum production during adolescence are thought to be important contributory factors

- the increased amount of keratin leads to blockages of the follicles and the formation of microcomedones.

- the microcomedones can develop into a non-inflammatory lesion (comedone) , which may be open (blackhead) or closed ( whitehead) or into an inflammatory lesion( papule, pustule or nodule) .

- excess sebum encourages the growth of bacteria , particularly propionibacterium acnes, which are involved in the development of inflammatory lesions.

Management

- The general aim of therapy are to remove follicular plugs so that sebum is able to flow freely and to reduce the number of bacteria on the skin.

- therefore reduce comedone formation

- lotions, creams and gels ( gels with an alcoholic base dry quickly but can be irritating. those with aqueous base dry shower but are less likely to irritate the skin.) comedogenic moistuiser.

Benzoyl peroxide (BP)

• has both antibacterial and anticomedogenic actions and is the 1st-line OTC treatment for inflammatory and no inflammatory acne.
  
• Antiflammatory action occurs at all strengths but anticomedogenic action is low and has the greatest effect at higher strengths.
  
• it has a keratolytic action, which increases the turnover of skin cells, helping the skin to peel.
  
• Regular application can result improvement of mild acne.
  

1. BP is very like to produce reddening and soreness of the skin. and patient should be warned of this.
   
2. so, treatment should start with a 2.5 or 5%product. moving gradually to 10% strength if needed.
   
3. Oily skin: Gels
   
4. Dry skin: Creams
5. Washing the skin with a mild soap or cleansing help by reducing the amount of sebum on the skin.
   
6. BP prevents new lesions forming rather than shrinking existing area. Therefore it needs to apply on the whole of affected area. and it is best to apply after washing.
7. first use: the skin is like to redden and sore. Stinging, drying and peeling to occur. - lowest strength preparation to begin and to apply cream, lotion...on the first week of treatment.
   
8. Application once daily or on alternate day could be tried for a week and then frequency of use increased to twice daily. After 2 or 3 weeks, a higher strength preparation may be introduced. if irritant affects do not improve after 1 week or are severe. Discontinued.

Acne rosacae

- over 40s
-broken blood vessels


Fungal skin infection

- caused by Tinea

Types:

1. T.Pedis
   
2. T.cruris
   
3. T. corporis
   
4. T. unguium
   
5. T. capitis
   

- Dermatophytes invade stratum corneum ( not living tissus)
- Intertrigo ( rash in skin fold)

T.Corporis : anywhere on the body. Red edge , satellite spots surrounding and clearance in the middle.

T. pedis : affects toe webs- bits in between the toes.

T. Cruris: Affects the groin.

Treatment

• Benzoic acid ( + salicylic acid= Whitefield's ointment)
• Undecanoates
  
• tolnaftate -less evidence
  
• imidazoles
  
• Allyamines
  
• Canesten HC ( with hydrocortisone 1%)
  
• Griseofulvin (1%) spray
  

Onychomycosis

• Amorolfine (OTC)
  
• use weekly
• take 8-12 weeks
  
• Curanail - 3 months treatment and 2 nails only
  

Dry skin

• use emolients
• Apply 4 times a day + after bathing
  

Eczema

• Irritant contact dematitis
  
• Allergic contact dermatitis
  
• Atopic eczema

Treatment

Hydrocortisone ( 0.1 and 1% OTC and 0.25% with crotamiton)

• mild topical steroid
  
• over 10 years of age only
• contact and allergic dermatitis and mild to moderate eczema
  
• Apply sparingly once or twice a day
  
• Max 7 days
  

Clobetasone

• NB Chobetasone butyrate 0.05%
  
• Moderately potent steroid
  
• over 12 years of age only
  
• contact and allergic dermatitis and mild to moderate eczema
• Apply sparingly twice a day
  
• Max 7 days
  

Warts / verrucae
- Growths of the skin caused by human papilloma virus (HPV)
- Verrucae: warts on the foot. Plantar warts

Refer:

• Eczema or broken skin
  
• facila or anogenital
• Diabetic / poor circulation
  
• large area affected
  

Treatment

• 1st line: Salicylic acid for 12 weeks
  
• 2nd line: Gluteraldehyde. formaldehyde

Corns ( Helomas ) and calluses
- caused by friction and pressure ( hyperkeratoses )
- corns: against bony prominences
- hard corns : top tops
- soft corns: between toes, macerated

Calluses: Flattened yellowed white hardened skin

Treatment

• relieve pressure and friction
• shoes that fit
  
• cushioning
  
• Keratolytics
  

Bunions
- caused by inappriate footwears ( sky-high heels etc)

Cold Sores

- infection caused by herpes simplex virus type 1 ( HSV)
- after primary contact virus lays dormant in root nerve
Triggers:
- sunlight
- cold weather
- infection
- menstruation

• start as burning, pricking, tingling
  
• then a painful blisters develop
  
• scab over in a couple of days
  

Treatment

Aciclovir 2% cream
Penciclovir 1% ( fenistill )

• they inhibit HSV DNA polymerase
  
• if applied at prodromal stage can reduce healing time by day.
  

Aciclovir

• apply 5 times a day for 5 days
  

Penciclovir :

• 2 hourly for 4 days
  

Dementia & Alzheimer's Disease

Dementia- is a state of cognitive impairment resulting from the progressive lose of previously acquired mental abilities

• Cognitive impairment - which prevents the normal accomplishment of tasks of daily living such as cooking, cleaning etc.
  
• A deline in memory- makes independant living impossible
  
• A deline in thinking, planning and organising daily activities
  
• Gradual loss of orietation in space and time
  
• A deline in emotional control or motivation or a change in social behaviour
  

Condition causing Dementia

• Alzheimer's disease (AD)
  
• parkinson's disease (PD)
  

Alzheimer's Disease (AD)

Aetiology

• AD is characterised by both cell structure and biochemical changes

- it is associated with the presence of amyloid plaques and neurofilbrillary tangles in the brain. These cause neuronal death in cortical and subcortical regions.

- Amyloid plaques are formed by the accumulation of beta-amyloid of tau proteins. The reasons why these occur are not understood.

1st explaination
- Amyloid precursor protein (APP) abundantly expressed in the membranes of many nerve & gila cells and they are used as function for cell structure and cell-cell recognition.
- In normal life APP is produced and then secretase enzymes sever the chain and release A-beta peptide into the extrecellular space.
* In AD, too much A-beta is produced or it is not being removed properly - so formed the beta-amyloid plaques.
- as the plagues increase in size, they appear to stimulate an autoimmune inflammatory response.
- they inferfere with synaptic function and the regulation of transmitter reuptake.
- excess extracellular transmitter due to impaired reuptake may generate excitoxicity; so eventually cells adjacent to the plaques die.


2nd explaination

• it is also thought that declining memory and cognitive function results from a lack of acetylcholine and an excess of excitatory amine acids, especially glutamate
• Acetlycholine is normally broken down by 2 cholinesterase enzymes, actylcholinesterase and butyrylcholinesterase. In AD, the deline in activity of acetylcholine in accompanied by a decrease in the production of acetylcholinesterase, further contributing to the deline of acetylcholine levels.
  
• Glutamate is a major excitatory neurotransmitter. Its action on the NMDA ( N-methyl-D-aspartate) receptor can lead to overstimulation of neurones, causing permanant damage.

Hypothese on causes of AD

• Genetic factors : Faulty genes
  
• Environmental Factors : Health and degeneration
  

Risk Factors

• Female ( Because females tend to live longer than males)
  
• Head injury
  
• Parkinson's disease
  
• hypothyroidism
  
• chronic exposure to aluminium
  
• cardiovascular disease
  
• smoking
  
• chronic high alcohol intake
  

* Average survial time from diagnosis is 10 years, although patients and their familiesand carers often experience a significant decrease in quality of life for a large part of this time.

Sign and symptoms

AD is characterised by a gradual decline in cognitive and memory function. Therefore, it can present in many ways. Physical signs are:

1. unable to perform daily activities, such as dressing, washing, feeding
   
2. behaviour problems
   
3. reduced muscular function
   
4. sleeplessness
   
5. aggression
   
6. apathy - the feeling of not being interested in or enthusiastic about anything
   
7. delusion and hallucinations
   
8. loss of autonomic control

Symptoms

1. Amnesia - memory impairment ( impaired ability to learn new information or recall info)
   
2. Aphasia - Language disturbance
   
3. Apraxia - impaired ability to carry out motor activities despite intact motor function
   
4. Agnosia - failure to recognise or identify objects despite intact sensory function
   
5. Disturbance in executive function ( planning, organising, sequencing and abstracting)
   

Faulty Genes

• Chromosome 21: APP gene
  
• Chromosome 19: APO E4, a form of apolipoprotein
  
• Chromonsome 1 & 14: Protein called prosenilin-2 & presenillin-1
  

Role of Apolipoprotein E (APO E)

• it is a plasma lipoprotein that is one of the principal constituents of chylomicrons and a very low density lipoprotein (VLDL)
  
• it plays a vital role in cholesterol transport in the blood.
  
• 3 known isoforms of APO E, coded by APO E2, APO E3 and APO E4 genes.
  
• APO E4 genotype : implicated as a risk factor for AD
  
• Recent studies : APO E4 may influence the CNS 's response to injury

Investigations

• As the condition predominately affects cognitive and memory functions, the investigations focus on these areas rather than physical examinations.
  
• it is also possibke to make a presumed diagnosis of AD, as a definiti diagnosis in only possible through autopsy
  
• A number of assessment methods can be utilised that define both cognitive and memory function. This includes:
  

1. Mini Mental State Examination (MMSE) - 5 x cognitive Domain Tested
   
   • Orientation: ( what day of the week is it? / what building are we in? )
     
   • Memory (1) : Immediate word recall
     
   • Attention & calculation: Counting & spelling backwards
     
   • Memory (2) : Delayed recall
   • Language Writing & drawing: Shown 2 daily item & name them. Following simple instructions, sentence writing & intersecting shape drawing.
     
   Maximum score of 30: AD patients will score <26
2. Alzheimer's disease Assessment Scale
3. The blessed test of information
   

Neuroimaging- using techniques such as :

• MRI ( Magnetic Resonance Imagining) - AD's patients shown enlarged ventricles and sulci
  
• CT
• PET (Position emission Tomography) scans- show the differences in brain activity between a norma brain and a brain affected by AD.
  

Management - the aim of treatment is to relieve symptoms and prevent the progression of the disease.

• Four drugs are currently available in the UK

1. Cholinesterase inhibitors- donepezil
   
2. Galantamine
3. Rivastigmine
   
4. NMDA-receptor antagonist - Memantine

Cholinesterase inhibitors ( e.g. Donepezil) CI

- Approximately 30-50% of patients show a definable decrease in their rate of cognitive decline after 3 months of treatment.
- the same degree of modest improvement in approx. 30-40% of patients with mild to moderate AD.

- The major effect of CI lies in their potential to reduce severity of symptoms & slow the rate of symptom progression , but it does not cure it.
- they do not stop the essential pathological process.

Mode of action:

• they reversibly bind with and inactivate the enzyme cholinesterase which breaks down acetylcholine.
• they potentiate the duration of action of ACh in the cholinergic synapse.
  

Side effect/ Adverse effect:

• The main adverse effects are from their cholinergic activity, such as nausea, vomiting, diarrhoea, anorexia, urinary frequency and depression.
  
• This can be a problemas those with AD often losing weight through the disease

(To decrease the potential side effects, the drugs are introduced gradually with a steady dose tituation )

Dose

• One 5mg tablet daily ( can be increase up to 10mg over 4 weeks)
  

Galanthamine

Mode of action

• it is a reversible non competitive inhibitor of acetylcholinesterase + direct nicotinic agonist. They bind to inactivate the enzymes to breakdown acetylcholine and act as an agonist to acetylochine nicotinic receptors.

Side effect/ AE:

• N/V
• Dizziness
• agitation ( an state of excitment, disturbance or worry)
  

Dose

• one 4 mg tablet twice daily for 4 weeks. ( can be increased up to 8mg twice daily for 4 weeks then maintain 8-12 mg twice daily)
  

Rivastigmine

Mode of action:

• same as Donepezil
  

Side effect/ AE:

• N/V
• confustion
• angina
  
• agitation

Dose

• one 1.5mg table twice daily, increased by 1.5mg gradually.

Memantine

Mode of action

• Glutamate transmits its signal via the NMDA receptor.
  
• NMDA receptor activation and Ga2+ influx are important for learning processes
  
• Glutamate is recycled in glial cells
  
• Beta Amyloid inhibits glutamate recycling
  
• excessive glutamate masks the neuronal singal transmission.
  
• so... Memantine blocks effects of excess glutamate and restoration of physiological transmission occurs.
  
• in result to improvement of the symptoms of AD.
  

Side effect/ AE:

• Dizziness
• confusion
• anxiety
• cystitis
  

( so do not use in cases of renal impairment)

Dose

• One 5mg tablet daily ( can be increased up to 10mg twice daily gradually)
  

* Atypical antipsychotic drugs such as SSRI or Lithium and Haloperidol are sometimes used to manage the behavioural problems that can occur in AD.

Particle size Analysis

Primary Characteristics - relating to basic material properties, particulate size shape and SA

Secondary Characteristics - Bahavioural properties such as flow, bulk and tapped density, compactibility, lubricity

particle shape terminology

• Acicular: needle-shaped
• anglular: sharped edged ; having a roughly polyhedral shape
• fibrous: thread-like
• Flaky: plate-like
• Granular : irregular but approximately spherical overall form
• irregular: lacking of symmetry
• Modular : rounded, irregularl shape.

Thickness: the height of the particle ---> when it is resting in its position of max stability

Breath ( width) : minimum distance b/w the two tangential plane- perpendicular to defining the thickness and breadth.

length : the distance b/w 2 planes which are perpendricular to those defining the thickness and the breadth.

Shape factors

circularity

dissolution

range of particle size and units

individual particle characteristics

measures of particle size

- volume equivalent sphere

-volume equivalent diameter

ESD?

- Arithmetic mean

- Geometric mean

- surface mean diameter (SMD)

-VMD

- volume-number mean diameter (VSMD)

particle sizing of powder

Particle size distribution

Particle size Reduction

Particle size

Basic principle

1. The study of particle sizes are important in achieving optimum production of efficacious medicine.
   
2. Virtually all of the solid materials which are in common use--> in a powder/ granular form.
   

Examples

1. Pharmaceuticals ( drugs a+ excipients could be powder handling)
   
2. foods ( grain, flour, sugar)
   
3. Materials technology ( Ceramics , abrasive)
   
4. building materials (sane + cement)
   

* Uses of powders in pharmacy

Example 1

• The bioavailability of poorly soluble drugs exhibiting dissolution rate-limited absorption can be influenced by the state of subdivision of the drug ( like Griseofulvin)
• • Particle size reduction leads to increased surface are per unit weight and faster dissolution rate.
  • Specific surface area --> is when a solid is meassured the total surface area per unit of mass 1. Surface area divided by the volume or 2, Surface area divided by the mass.
    
  --> the reduction in particle size to improve rate of dissolution and bioavailability is not always benefical because, for example, the toxicity effect of nitrofurantoin

Exampe 2

• In inhalation aerosole, particle size is critical to achieve maximum penetration and deposition into the deeper airway of the drug.
  
• it has been estimated that 85% of particles >5 um are retained in the upper respiratory tract ; 90% of particle in the 1-5um range are retained in the alveolae . Particles <0.5um>

Example 3

• Drug particle size influences the content uniformity of low dose drugs in solid dosage forms --> tablets and capsules
  
• Partiicle size reduction increase the number of particles per gram. --> the greater the number of particles per dose, the lower the variability between dosage units
  

Example 4

• Both the physical stability and bioavailability of suspension can be related to the particle size achieved in the product.
  
• Sedimentation rate is proportional to the particle size ( Stoke's law) --> is a law describing that when a resisiting force on a particle movthing through a viscous fluid and shown a maximum is reached in such case.
  
• The large surface area (SA) of finely divided suspended insoluble or poorly soluble drug ensures a high availability for dissolution --> hence absorption
  

Example 5

• The mechanical irritation of topical ( cream or ointment) applied to diseased or traumatized tissues is a function of particle size.
  --> a common '' rule of thumb '' is that particles should pass through 325 mesh sieve ( 44um) to minimise mechanical irritation.
  

Example 6

• Good flowability is essential to ensuring uniform feeding of formulations to high speed tablet machines and capsule filling machines.--> determines uniformity of tablet and capsule weights ( and uniformity of doses, assuming uniformity mixing of drug and excipients had been achieved )
  --> smaller particles with high SA do not flow as well as larger particles. * the greater the SA, the more dominant are surface interactions * ( friction, cohesion/adhesion) that interact with flow.
  
• Irregular shapes do not flow as well as very smooth shapes ( soft particles)
  

Significant effect of particle shape.

1. effect on product quality
   
2. more angular materials had a greater weight variations
3. tablets made with more angular materials had highter strength --> increase in particle interlocking
   
4. better flow will occur with spherical particles
   

Particle Size
Micromeritics : The science and technology of small particles

• Colloidal dispersions particles : are too small to be seen in the ordinary microscope
• unit of particle size used most frequently in um = 10-6 m = 10-4 cm = 10-3 mm
  
• 
  

Comminution : Is an alternatve name for particle size reduction

• derived from the latin minuere meaning less, but size rediction is to be preferred as a more straightforward title
• Crushing, disintegration, dispersio, grinding and pulverization have been used synonymously with comminution depending on the product, the equipment and the process
  

Why is important?
Because it helps to improve the existing active ingredients to be delieved. Particle size influences the performance if the medicine and the pharmacological performance of the drug. For example, powder with different sizes have different flow and packing properties, which alter the volumes of powder during each encapsulation or tablet compression event. Therefore, to avoid this problem, the particle size of drug may be defined during formulation. Because, if there are any interferences with the uniformityof a fill volumes may alter the mass of drug that incorporated into the tablet or capsule and hence reduce the content uniformity of the medicine.

The following factors are infuencing size reduction

• Brittle ( How easy that a particle cracks) - Crack propagation and Toughness
  
• Plasticity - stickiness
  
• surface hardness - Slipperiness
  
• melting point
  
• Glass transition temperature
• environmental factor- moisture ( To be continued)
  

Crack propagation & toughness

• Comminution is carried out by a process of crack propagation, whereby localised stresses produce strains in the particles, which are larger enoug to cause bond rupture and propagate the crack - Cracks are generally propagated through regions of a materials that possess flaws or discontinuities and are related to the strain energy in specific regions according to Griffith's theropy of crack propagation
  
• Following crack initiation, crack tip propagate so rapidly- velocity ~ 40% of the speed of sound in the solid --> This crack propagation is so rapid that excess energy from strain relaxation is dissipated through the material and concentrates at other discontinuties, where new cracks are propagated.
  
• Thus, a cascade effect occur and almost instantaneous brittle fracture occurs
  

Are all materials exhibit brittle behaviour? - Not all materials exhibit this type of brittle behaviour and some can resist fracture at much larger stresses.

why some materials can resist fracture at much larger stress? - because these tougher materials can undergo plastic flow, which allow strain energy relaxation without crack propagation. When plastic flow occurs, atoms or molecules slip over one another and this process of deformation requires energy.

* Thus, the ease of comminution depends on the brittleness or placticity of the material because of their relationship with crack initiation and crack propagation.

Surface hardness

- Size reduction may be influenced by surface hardness. The hardness of a material can be described by its position in a scale devised by a German mineralogist called Mohs.
- Mohs's scale is a table of materials :

1. at the top of the table is diamond, which Mohs hardness > 7 , and this has a surface that is so hard that it can scratch anything below it.
   
2. At the bottom of the table is tale, with Mohs hardness <3,>
3. Materials such as Rubber which are soft under ambient condition.
   
4. Waxy substances such as stearic acid which soften when heated
5. Stick substances such as gums are capable of absorbing large amounts of energy through elactic and plastic deformation without crack initiation and propagation- This type of material, which resist comminution at ambient or elevated temperature can be more easily size reduced by lowering the temperature below the glass transition point of the material. When it is done, brittle behaviour and crack propagation is facilitated. Toughness - it is often more important than hardness
   

• problems in size reduction: it relates to moisture content in the material. ( compare green twig with dry one)
  
• toughness can be reduced by treating the material with liguid nitrogen
• Freezing the material below its glass transition temperature - be aware: the material may melt into waxy substance. ( the mill can be cooled with water jacket or by passing a stream of air through the mill.
  

Stickiness : because of heat - complete dryness and addition of inert substances like kaolin may help
Slipperiness : the reverse of stickiness property like the lubricant effect of materials, magnesium stearate.

Environmental factor

• Moisture content of the feed material , which are material is dry or wet but not damp.
  - Moisture content <>
• - Moisture content >5 % is suitable for wet milling.
  

Energy requirement of size reduction process

- only a very small amount of energy affects size reduction (~2%) . the remainder is lost in many ways.

• Elastic and plastic deformation without fracture
  
• Deformation to initiate cracks that cause fracture
  
• Deformation of metal machine parts
  
• inter particle friction and particle -machine wall friction
  
• Heat
  
• Sound
  
• vibration
  

Criteria for size reduction


An ideal crusher :

• a large capacity
  
• require a small power input per unit of product
  
• Yield a product of the single size distribution desired
  

* The cost of power is a major expense in comminution, so the factors that control this cost are important - To be continued

Milling Equipments

Cutting Methods

• Cutter mill ( C mill)
  

Compression Methods

• Morter and pestle
  (M & P )
  
• End-runner mill (End Mill)
• Edge-runner mill ( Edge Mill)

Impact methods

• Hammer Mill (H mill)
  
• Vibration Mill (V mill)
  

Attrition Methods

• Roller Mill (R Mill)
  

Combined impact and attrition methods

• Ball Mills (B mill)
  
• Fluid energy mill ( FE mill)
  

C mill consists of a series of knives

1. - Size reduction occurs by fracturing particles between stationary and rotating knives
   
2. - a screen is fitted to retain the material in the mill until a sufficient degree of size reduction is reached.

M & P - End/ Edge mill

• End-runner - the pestle is turned by the friction of material passing beneath it as the mortar rotates under power
  
• Edge-runner- the pestle mounted horizontally and rotate against the powder bed.
  

H mill - different shapes are available : Square-faced. tapered to a cutting edge, stepped form.
Priniciple :

• During milling - the hammer swing out radiallly from rotating shaft. The higher velocity of the hammers cause brittle fracture to the particles. Small particles are less prone to fracture than larger particles

• it produces powder with narrow size distributions. Particles are retained within a mill by a screen which allows only adequately comminuted particles to pass through.

V mill - Filled to appro. with 80% total porcelain or steel balls

• During milling: the whole body of the mill is vibrated and size reduction occurs by repeated impaction
  
• milled particles fall through a screen at the base of the mill. the efficiency of vibratory milling is greater than for conventional ball miling.
  

R mill- use of the principle of attrition to produce size reduction of solid in suspensions, pastes or ointment.

• 2 or 3 rolls ( porcelain or metal) are mounted horizontally with an adjustable gap (~20um)
  
• the roller rotates at different speeds , the materia is sheared as it passes through the gap, the material is transferred from the shower to the faster roll, from which is removed by means of a scraper.
  

B mill -Milling efficiency depends on:

1. Feed : too much material - producing a cushioning effect ; too little - causes loss of efficiency and abrasive wear of the mill part
   
2. Size of the balls : - large balls break down the coarse feed material , the smaller helps to form the fine product by reducing the void space between balls.
3. Speed of rotation : -
   

• Low angular velocities : little movement of the balls , so that the size reduction is minimal
  
• high angular velocities: the ball are thrown out of the mill wall by contrifugal force and no size reduction occurs
  
• at about 2/3 of critical angular velocities: centrifuging occurs, a cascading action is produed . Maximum size reduction occurs by impact of the particles with the balls and by attrition.
  

Jet / fiuld energy mill ( FE mill)



P mill

• Lower cylinder rotates at high speeds against the upper fixed cylinder
• particle size reduction occurs by impaction with the pins and by attrition between pins as the particles travel outwards under the influence of centrifugal force.