Pharmacology Sem2

Respiratory disorders

Pulmonary dysfunction, can be obstructive or restrictive

Restrictive Pulmonary Dysfunction

Difficulty getting air into lungs, an issue with lung capacity. Non-compliant lung tissue (ability to expand/deflate). Has neuromuscular weakness, interstitial lung disease like fibrosis (scarring)

Obstructive Pulmonary Dysfunction

Difficulty getting air out of lungs, and increased contractility of lumen wall. An example is COPD and Asthma.

COPD

Chronic obstructive pulmonary disease, serious as it limits air flow and not fully reversible. It include chronic bronchitis and emphysema, which means that the airway produces far more mucus and more coughing, as well as the destruction of lung tissue. COPD is associated with asthma, diabetes, smokers, respiratory cancer, and that 15% of patients with COPD are diagnosed with asthma.

Asthma

Chronic inflammation of airway, reversible airway obstruction. Airways are hyperactive and remodel over time. Risk factors include heredity, gender, poverty, environmental exposures, obesity, prematuriety. It is said that developed countries have higher levels of asthma as they don’t expose themselves to the same amount of bacteria as underdeveloped countires when younger, so they are more susepctible.

Intrinsic Asthma

Non immune, parasympahtetic stimulation leading to bronchoconstriction, and develops later in life. Triggers include smoking, bush fire smoke, chemicals, some medicines (Beta blockers), stress and anxiety.

Intrinsic asthma - exercise enduced asthma

exercise increases respiration, faster movement of air into mouth which can’t filter so the air is not worm or moist and can irriate the throat. in winter this occurs more often

Extrinsic Asthma

IgE driven through a type 1 hypersensitivity. There is a trigger, with a rapid onset. trigger include rye grass pollen, thunderstorm related asthma, dust mites, animals.

Asthma - Type 1 Hypersensitivity

similar to specific immune responses, need a couple of exposure to the allergens. First inital exposure to allergen → allergen presented by macrophages to T helper cells, decide which response is needed → T helper cells induce B cells to make IgE (in a normal reaction T helper would use B cells to make IgG cells). _> IgE bind to ast cells and basophiles to make → IgE mast cell complex.

Then

Second exposure to allergen → allergen binds to IgE mast cell complex → mast cells degranulate and release inflammatory mediators like histamine, prostaglandins and leuktrienes → occurs within minutes → Causes vasodilations and inflammation, parasympathetic NS stimulation leads to bronchoconstriction and mucus secretion occurs. airway diameter decreases. This is called the early phase. After 3-5 hours, T helper cells release cytokines that attract eosinophils, take time → esophils defranulate over a long period of time (12-24hrs). Corticosteroids cant do much at stopping early phase but they are good at preventing the late phase. The late phase can lead to long term remodelling of the airway.

Long term effects of asthma

Airway remodelling due to eosinophil infiltration. Hypertrophy of smooth muscle in airways, hyperplasia of goblet cells (increases mucus). increases sensitivity to attack and bronchochonstrict, even without atopic trigger.

3 categories of drugs for asthma treatment

preventer, relievers and controller

preventors

corticosteroid, leukotrienes antagonist and Mast cell stabilisers

corticosteroids

bind to glucocorticoid receptors and reduce gene transcitpion to reduce inflammation and obstruction of airway. treatment of severe acute asthma, reduce late phase response. Can be inhaled or in a tablet form, adverse effects is oral flush as droplets of the corticosteroid can be left in the mouth, which is why a spacer is used.

Reliver

Salbutamol. sympathetic NS, when beta 2 receptors are activated and causes bronchodilation. Sympathetic = Dilation. Parasympathetic NS, acetylcholine binding to muscarinic receptors at airways and cayse bronchoconstriction so Parasympathetic = bronchoconstriction. So a drug that stimulates sympathetic output can be used to broncho dilate. This is why a patient having an asthma attack can use an epipen as adrenaline will cause bronchodilation

Salbutamol

(short acting B2 adrenoreceptor antagonist), binds to B2 receptors and acts like noradrenaline, causes bronchodilation. Used to elevate symptoms of acute asthma, can be used before exercise. Key rule is worry about negative side effects later, manage severe asthma attack first

xanthire derivatives

used for asthma and COPD, inhibits enzime breaking down cAMD which leads to smooth muscle relaxation and bronchodilation, used if one has a tolerence to salbutamol.

Controllers

similar to salbutamol but last longer (12hrs), used for nocturnal asthma and to minimise SABA use and steroid doses.

Diabetes

type 1, lack of insulin secretion, Type 2, insulin can be made and released but it is unable to work on target cells (insulin resistance).

Insulin

hormone produced by beta cells in the pancreas. Secreted when BGL is too high, some cells that rely on insulin to bring glucose to the cell (like the liver). GLUTS1-3 dont require insulin to enter cell, but GLUT4 (skeletal/caridal/adipose tissue) does require insulin to bind to the receptor. Liver is GLUT2, allows it to store glycose as glycogen.

Major effects of insulin on carbohydrate metabolism

Liver - stimulates glycogen synthesis, Muscle - increases glucose uptake via increase GLUTs, and stimulates glycogen synthesis. Adipose tissue - increased glucose uptake via GLUTS, stimulates formation of glucose → fat → fatty acid → tryglycerides

Glucagon

released when BGL is low, promotes glycogenolysis (breakdown of glycogen), glucogenesis and lipolysis (breakdown of fat). increases BGL and lipids to be used as energy ATP

1st insulin phase release

within minutes of consuming ameal, rapid and significant release of insulin from beta cells in repsonse to the initial rise of blood glucose levels. Responsible for quickly lowering blood glucose levels after a meal.

2nd insulin phase release

extended period, helps maintain stable BGL over time and facilitaies the storage of glucose in tissues for energy of glycogen formation.

Type 1 diabetes

autoimmune disease, spontaneous or triggered by environmental insult. T cells recognise beta cells as forgein and kill them. Genetic susceptibility. patients immune cells mistakenly attack its own b cells, the few left produce insufficent insulin and damages tissue dye to high BGL.

Type 2 diabetes

not autoimmune disease, not linked to HLAs or a genetic predesposition. life styles factors like diet and activity levels. Two metabolic deficts, insulin resistance and insulin deficiency. glucose cannot enter cells that require insulin for glucose uptake.

insulin resistance

Tissue cannot respond to insulin, which brings glucose in. hyperinsulinaemia, pancrease release more insulin as the cells arent getting them and cause excessive b cell stress. leads to beta cell dysfunction and exhausion.

Obesity and insulin resistance

large amounts of free fatty acid in obese people inhibit target cells from responding to insulin. fat cells produce cytokines which inhibit target cells to repsonding to insulin

Insulin deficiency

B cells exhaused, cause dysfunction

Acute complicaitons of type 1 and 2 diabetes

hypoglycaemia - low blood glucose level due to overmedication, alcohol use (decreases glycongeogenesis), not eating enough, missing meal, increasing exercise. Low blood glucose imparis brain function, poor concentration, irritability, headache and can even cause coma or sezuires.

hyperglycaemia - high blood glucose level due to undermedication (insulin or oral hypoglycaemic drug), illness infection or stress and high intake of carbohydrate food.

Acute complications of just type 2 diabetes

non-ketotic hypersomolar coma - insufficient insulin, illness and infection/ BGL is very high.

acute complication of type 1 diabetes

ketoacidosis - insufficient insulin, ketones in blood and urine causes illness and infection.

Chronic complications of diabetes

Accelerates glycosylation and osmotic injury as cells which arent insulin dependent can just uptake glycose, they become heavily concentrated with glucose and draws water into the cells. increased water = damage and can burst. main cells are kidney, retna and nerve. Macrovascular complication is it affects large blood vessels, and altherosclerosis can form. Renal disease due to renal impairment, microvascular complication as normal function is interupted, protein leaks into the nephron and appears in the urine. losing the ptroein will decrease fluid bein gpulled out of tissue =edema. Neuropathy due to peropheral nerve damage and retinopathy which can cause blindness. this all occurs becayse these cells are not dependent on insulin, and uptake too much glucose.

Management of diabetes

Exogenous insulin - (type 1) subcutaneous administration, binds to receptors on target cells (muscle, fat, liver) and increases storage of glucose after meal.

Oral hyperglycaemic medication (Both) will raise BGL when low, sugar source followed by a complex carbohydrate like bread or dried fruit, servere hypglycaemia requires glucagon injection.

Metformin - Hight BGL, increases glycose uptake in skeletal muscle (reducing insulin resistance, reduce glucose production in the liver.

Neoplasam

new cell growth in an area where there are other type of cells/tissue

metaplasia

change in cell from one type to another

anaplasia

loss of cell differentiation

dysplasia

abnormal arrangement of cells

Cancer - benign

slow growing, capsulated (walled off), differentiation, local, not often lethal, surgery to remove, no chemo needed.

Cancer - malignant

fast frowing, not capsualted (can invade tissue), undifferentiated cells, can be lethal, is invasive, lost ability to respond to apoptosis, can be metastatic (breaks off and grows somewhere else), abnormal cell shape and size.

cancer deveopment

adult cell division goal is to maintain organs, need balance between mitosis and apoptosis. in cancer, this balance is distrupted, favours mitosis and cells divide without end and differentiation. In mitosis, to form two identical daughter cells, they go through 3 check points (G1, G2 and M) to ensure that there are no mistakes

Mutations

Germline (inherited) or somatic (cant be inherited). Two types of genes: Proto-oncogene and Tumour suprpressor gene

Proto-oncogene

control and enhance cell division, nromally have adequate control but when mutated onto oncogene, increases cell dvision. cause the cancer cells to divide at a quicker rate

Tumor suppressor Gene

acts as a break on cell division, also serves as a check on cell division and intiates apoptosis if there are any errors found. if mutated, increasese rate of division and causes faliure to initiate apoptosis when mistakes are made. an example is BRCA 1 and 2 genes, normally they repair mistakes in cell division but if theyre mutated, they have a higher chance of causing cancer

stages of cancer

Initiation - Irreversible genetic mutation (changes in DNA)

Promotion - Help promote the growth of the mutated cell. enhance and favour division of mutated cells

Malignancy - prolonged exposure to promotor, causes cells to loose differentiation (anaplasia), organisation (dysplasia) loose anchoring and ability to respond to communication with other cells.

Metastasis - tumour cells can then invade, spread and relodge elsewhere in the body. typically via bloodstream or lympathic system. secondary tumours can occur, and treatment assymes presence of metastatic tumours (surgery and chemo) .

Anaemia

from chronic bleeding, red bone marrow suppresion leads to poor replacement of RBC. cytockines production by cancer, invasion into bone marrow. RBC division effected due to chemo radiation

Cachexia

progressive weight loss, loss of body fat and muscle. Driven by decreased intake due to treatments and decreased appetite, as well as increased output due to systemic inflammation from cancer and increased energy use. once this starts it is difficult to correct and is one of the signs they are deteriorating.

Grading for cancer

Grade 1 - Best, well differentiated and normal tissue

Grade 4 - worst, poor differentiation, anaplastic, poor prognosis

Staging for cancer

T1-4 = size of primary tumour (4 is bad)

N1-3 = lymph node involvement (3 means spread)

M0-1 = detection of metastases (1 is yes)

Treatment for cancer

Surgery (Local), Radiation (Regional) used to shrink tumours down to size more suitable for surgery, chemotherapy (regional) targets rapidly dividng cells, stops DNA synthesis, but has high adverse effects.

Noradrenaline

Concentration transmitter, involved in controlling wakefull ness and alertness, has important roles in the regulation of blood pressure and its funcitonal deficiency, is thought to contribute to the pathogenesis of depression

GABA (gamma amino butyric acid)

CALMING transmitter, common inhibitory neurotransmitter in the cerebral cortex, ethanol stimulates one of its receptors

Serotonin

MOOD transmitter, assists in regulating feeding behaviour and body temp. controls sleep, waking and emotions, also assocaited with behavioural changes.

Acetylcholine

LEARNING transmitter - important for the function of neuron, in the hippocampus and frontal cortex, involved in memory formation and learning, and therefore contributes to pathogenesis of alzheimers.

Dopamine

PLEASURE transmitter - feeling of pleasure or feeling or reward, pathogenesis of parkinsons, schitzophrenia and major contributor of drug addiction.

Glutamate

MEMORY transmitter - learning and memory, major contributor to neuronal cell loss that occurs in the penumbra region of ischaemic stroke.

enzymic degradation in the synaptic cleft

reupate by the presynaptic terminal (e.g. serotonin) uptake by glial cells (e.g. glutamate), diffusion out of the synaptic cleft.

Dementia

decline in intelecctual functioning resulting in a loss of social independence. impairment of memory and at least one other area of cortical funciton like language, judegement, orientation. symptoms progress over moths to years, and alterness is preseved until very late stage. major causes is alzheimers disease and cerebrovasular diesase and trokes.

Alzheimers disease

disorientation, unable to recall names, basic calcuations become difficult, then personality change, paranoia, delusions. Areas of the brain effected is frontal, temporal and parietal lobe. as well as prefrontal cortex, hippocampus and amygdala. hippocampus required for converitng short term mem into long term, amygdala perceve other emotions and controls aggression.

pathogenesis of alzheimers: Amyloid b peptide

• Abnormal Cleavage: Amyloid precursor protein (APP) is a normal transmembrane protein. In AD, APP is sequentially cleaved by β-secretase (BACE) and γ-secretase (rather than the non-amyloidogenic α-secretase pathway).

• Monomers and Oligomers: This cleavage produces Aβ monomers (such as Aβ40 and Aβ42). Aβ42 is particularly sticky and prone to forming soluble Aβ oligomers (AβOs), which are considered the primary neurotoxic species.

• Senile Plaques: These oligomers further aggregate into insoluble fibrils and extracellular senile plaques deposited between neurons, disrupting synaptic communication.

Tau pathology

healthy tau protein stabilises microtubules that are essential for axonal transport along the neuron → alzheimers, tau is dysfuntional and accumulate sin the cytoplasm (where it is not supposed to be) → Tau will aggreagte and stick together to form neurofibrillary tangles in teh cell → cause neuronal destruction. abnormal tau proteins acculuate intracellular and appear as neurfibirllous.

management of alzheimers

in alzheimers, there is a decrease in acetylcholine, the loss of this in the hippocampuus and frontal cotext is thought to be the reason for loss of short term memory. Acetylcholinesterase (AChE) cuts acetylcholine in 2 in the synaptic celft and stops its transmission. if we inhibit AChE, we can boost aceytlcholine elvels and prolong its effects in the synapse. Inhibition of acetylcholinesterase do improve cognitive impairment but can have some adverse effects

depression - reactive and endogenous

reactive depression is unipolar and common, assocaited with stressful life events, accomponaised by symptoms of anxiety and agitation. Endogenous depression has a familial pattern, unrelated to obvious external stresses.

Disturbances of HPA axis

Disturbances of HPA axis - neuroendocrine mechanism. hypothalamus → anteriror pituitary → adrenal cortext which produced cortison → negaitve feedback loop. Production of cortisol increases during stress, however in depression the corstiol is higher and unregulated.

Monoamine theory

depression is caused by a chemical imbalance of neurotransmitters characterised by a function deficit of serotonin and noradrenaline at certain sites of the brain. serotonin and noradrenaline gets released from presynapse, bind to post receptors and get tarsnported back to pre synapse for reuptake. depression has a decreased amount of serotonin released from pre synpase and causes this depressed mood.

Antidepressant medication

inhibit serotonin transporter, so serotonin won tbe removed as quickly and we can prolong it. inhibition of noradrenaline reuptake are equally as effective but individual patients may respond better to one or the other.

selective serotonin uptake inhibitors (SSRI’s)

Monoamine inihibitors

inhibits enzyme responsible for degradtion of monocrine neurotransmitters. monomines taken back into the presunaptic neuron are either recycled or degraded by monoamine oxidase MAO. so MAO inhibitors stop them from destroying serotonin.

TCA’s (tricyclic antidepressents)

inhibits monamine tranposrt and reuptake. inhibit uptake of serotonin and noradremaline. ssris only inhibit serotonin.

Mixing SSRI’s and MAOs

Can’t mix and match these drugs. Can’t take MAO inhibitors + SSRIs, you will end up boosting serotonin so much that you develop serotonin syndrome which is toxic and dangerous. this is called serotonin sydnrome, a toxic state caused by an increase in brain serotonin activity.

post partum depression

HPA releasing hormones inccrease during pregnacny and remain elevated up to 12 weeks after childbirth. rapid change in reproductive hormones following delivery (estrogen and progesterone) following delvier. Levels of estrogen and progesterone during pregnacny increase rapidly, before a sudden and signficant drop after birth which has been asumed to be a reason.

drug misuse

the use of a substance for a purpose not consistant with legal or medical guidelines, like if a person took two sleeping pills instead of the dose of 1 that is stated on the packaging

drug abuse

excessive, maladaptive or addictive use of drugs for a non medical purpose despite socal, psychologica and physical problems that may arise. like if a person took sleeping pills to get high

drug addiction

a disease that affects a persons brain behaviour and leads to an inability to control the use a legal or illegal drug or medicine. a drug abuser still has control over their life, a drug addict does not.

drug dependence

the want becomes so insistent that it dominates the lifestyle of the individual and damages their life. can cause harm to self and the community.

physical dependence on drugs

withdrawl when drug use stops, physical dependence is less important in sustaining drug seeking behaviour than psychological dependence.

effects of alcohol

effects the central nervous system as it is a depressant, so it decreases activity. however it can increase some pathways like feeling pleasure and reward. at a cellular level, it enhances inhibitor of GABA, decreases Ca2+ energy channels, decreasing neurotransmitter release, activates some K+ channels which decreases activity of neurosn and inhibits glutamate receptor function

arthritis

progressive loss pf articular cartilage, remodelling and scleorisis of subchondrai bone. Joints have a synovial membrane that lubricates cartilage, on the end of the bone for smooth muslce. Arthritis affects joints. osteoarthritis is the most common, hands, kneeds and hips., the cause is unknown but a risk factor includes fmaily, strain, problems with the line up of a bone. there is no cure, only some treatments like acetaminophens, NSAIDS (inflammation), rest, losing weight, physical therapy.

rheumatoid arthritis

chronic, systemic, inflammatory autoimmune disease. joints affected are wrists, hands, kneesm ankles and it is identical on both sides, so both wrists would be affected for example. can effect eyes, skin, heart, lungs and kidenys. autoimmune means body attacks itself by mistake. WBC go into joint, release cytokines that attack the synovial membrane, who release substances in response. inflammation occurs. cannot be used but NSAIDs and steroids can be used.

risk factors for osteoarthritis

ageing (wear and tear over the years), obestiy (stress on weight bearing joints), joint dysplasia, trauma and family history

risk factors for rheumatoid arthritis

female, age, smoking, genetics.

extracellular matrix of a joint and articular cartilage

collagen meshwork, proteoglycans attracts water and nutrients to naurish chondrocytes and allows for energy. cartilage cells (chondrocytes) maintain extraceullular metrix. rates of syntehsis and breakdown of extra cellular molecules are in equalibrim

osteoarthritis pathogenesis

over years of use, more mechanical loading which distrubs cartilage cell metabolism. more catabolic then anabolic (more breakdown then building). breakding down agrocan and collagen = tissue dysfunction, attracks nutrients. cartilage erosin occurs, bone tries to repair itsel fand deformity occurs. overtime you get more destruction and structrual change.

rheumatoid arthritis

autoimmune response, antibodies developed and attack synovium (join lining). inflammatory response and pro inflammatory agents cause cartilalge and bone erosion. growth of pannus = t cell macrophages, tendons and ligaments weaken.

diagnosis of osteoarthritis

asymetrical, limited to one or two sets of joints, .radiology, blood analysis

diagnosis of rheumatoid arthritis

both sides of the body, 3 or more joints, blood analysis, radiology, MRi and ultrasound

osteoarthritis management

lifetstyle: occupational cahnges (avoid further damage) low impact aerobic exercise, power and stregnth training, heat and cold therapy, weight reduction. Pharacological, NSAID’s, corticosteroids to reduce pain at rest and improve movement

rheumatoid arthritis management

life style: balance between rest and moderate exercise. alternative therapies, psychological emotional support.

osteoporosis

metabolic bone disease wehre the rate of bone reabsorption exceeds bone formation resulting in decreased bone density (osteoclasts > osteoblasts) bone is conntective tissue made up of collagen, glycoproteins and proteoglucons, osteoblasts and osteoclasts. bone is continously remodelling. as we age, the number of obsteoblasts decrease.

kyphosis

complication of osteoporosis, abnormal curvature of the upper spine resulting in a rounded or hunched back.

types of fractures

transverse fractures are perpendicular to the axis of the bone, linear parallel to the long axis. non displaced is when the bone remains in its normal postion, displaced is if its out of the normal alginment. if the bone penetrates the skin, its an open fracture. close facture is no bone piece breaches the skin. incomplete means its damaged but in one piece. stress fracture means its complete or partial break of the bone.

bone repair

fracture hematoma, fibriocartilaginous cells formation, bony callus formation, bone remodelling, bone resorption, bone deposition.

hematoma

localised collection of blood outside the blood vessel, result of a trauma. in the context of fractures, hematoma forms at the side of fracture and serves as a temporary scaffold for the healing process.

grannulation tissue

forms during the healing of a wound, composed of new blood vessels, inflammator cells int his context, granulation tissue fills the gap between the fractured bones to help formation of a soft callus

callus

soft and long, soft is formed by granullation tissue and helps stabilise the fracture, while bony formed by the conversion of soft callus into new bone tissu.e

treatment of a fracture

reduction and immbolisation. reduction - reallignment of the fractured bone ends surgically or physically. immolisation - stabilisation of the bone to allow proper healing. braces, plaster casts and metal screws.

pannus

Cartilage and Bone Destruction: The pannus adheres to the articular cartilage and releases destructive enzymes (like matrix metalloproteinases or MMPs) and osteoclasts that erode cartilage and subchondral bone