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Heroin
- Heroin (Diacetylmorphine) overdoses are more frequent when used in conjunction with alcohol, benzodiazepine, cannabis, amphets or when a more pure form is used.- There are many routes of administration.- Typically Heroin produces a narcotic effect because it is converted to morphine (conscious but sedated, euphoric, pinpoint pupils, shallow decreased breathing, unconsciousness).- Heroin is also associated with coma, seizures and delayed encephalopathy in overdose.- Lethal dose is hard to define. Death may be sudden in massive overdose.-Many overdose deaths due to friend allowing sleep; giving milk; giving other stimulants; giving shower (^hypotension). TERM 2
Naloxone Effects on Heroin
DEFINITION 2
Naloxone is an antagonist at the u, k, d receptors- It may be
necessary to administer the drug by IM, SL, endotracheal or
IL route as IV route damaged from heroin administration.-
Naloxone has a shorter half life than heroin and so relapse
may occur.- Naloxone may precipitate heroin withdrawal
also, with risk to healthcare personnel.
TERM 3
Replace Activity: VIT K and
Warfarin
DEFINITION 3
- Warfarin is used in the prophylaxis (prevention of disease) and treatment of venous thrombosis and pulmonary embolism.- It inhibits the synthesis of Vit K dependent coagulation factors which results in activity depression of Factors II, VII, IX, X.- In overdose or warfarin poisoning you see:1) appearance of blood in stool or urine,heamatouria,excessive menstrual bleeding,excessive bruising ,persistent oozing from superficial injuries2) Necrosis and or gangrene of skin and other tissues requiring amputation.3) Death- Warfarin also used as rat poison so narrow TW. TERM 4
Vit K
Effects
DEFINITION 4
- At high concentrations Vit K is reduced to hydroquinone by another warfarin sensitive liver reductase so there is no cycling of vitamin k due to inhibition of Vit K epoxide reductase which thus leads to depletion of normal body stores with 2-3 hrs.-Vit K therapy may be required for weeks to months until prothrombin time (coagulation) returns to normal. TERM 5
Regenerate Targets: Organophosphates
DEFINITION 5
Used in agriculture, industrialism and
terrorism.Organophosphates have various effects:1) Nicotinic
Effects: muscle weakness, areflexia, paralysis, hypertension,
tachycardia.2) CNS Effects: Confusion, seizures3) Muscarinic
Effects: Increase smooth muscle contraction, Increased
secretion of gland cells, GI upset, Pulmonary edema
Pralidoxime effects on Organophosphates
-People with organophosphate poisoning are initially given Atropine to antagonise Ach effects then Pralidoxime to remove the phosphate group from the cholinesterase enzyme to regenerate its catalytic activity (thus decrease Ach effects in long run).- Effects at Nicotinic receptors > effects at muscarinic receptors.- Effect is at erythrocytic esterase if given soon after toxicity.- Reactivation of plasma cholinesterase activity is minimal- Most effective if given <24 hours after organophosphate exposure as organophosphate effects can become aged and irreversible.Treatment may be required for days depending on the half life of the toxicant. TERM 7
Antimalarials and Malaria
DEFINITION 7
Malaria is caused by protozoan parasites of the genus
Plasmodium of which 5 species infect men:1) P. falciparum 2)
P. vivax 3) P. Malariae 4) P. orale 5) P. knowlesi- The
parasites are transmitted by female Anopheles mosquitoes
whilst taking a blood meal. If she has already fed on
someone with malaria the disease is transmitted.
TERM 8
Malaria Life Cycle
DEFINITION 8
- A mosquito takes blood meal from infected person and then transmits that to another person as it feeds on the second person.2) Sporozoites colonize the liver cells and undergo reproduction and multiplication in the liver until eventually they burst out of your liver cells as Merozoites.3) Merozoites get sucked up into your Red Blood Cells and once within RBC's they undergo massive assexual reproduction and it is at this point the RBC's burst and you get the symptoms of malaria. They also feed on the globin part of heamoglobin in RBC's.4) The parasites realize they have put your body under stress and that your body is going to die thus they start to make gametocytes (in a sexual cycle) and that allows genetic mixing and variety to occur.5) When another mosquito comes along and feeds on your blood it takes the gametocytes into it and they along with their progeny transmit the infection. TERM 9
Malaria Control
DEFINITION 9 Early diagnosis - the earlier you can diagnose and treat someone the faster your breaking the cycle of malaria feeding and decreasing spread.- Treatment is with Antimalarials.- Selective use of preventative measures including vector control where is can be sustained is useful.- Potential targets for antimalarial therapy must constitute essential features of the parasites life cycle.- Must be parasite specific and/or be sufficiently different from analogous structures or processes in the host to make selectivity between the host and parasite possible. - so lots of research has been done to identify targets that are different. TERM 10
Malaria Target
DEFINITION 10 Someone has identified a target from the parasite Plasmodium falciparum and isolated it to identify key structural aspects that are essential for the survival of the parasite and now they want medicinal chemists to synthesize a compound that will take out that target. Since mammilians dont have this target, therapy is very selective towards parasites only.
Amodiaquine
Developed at the same time as Chloroquine with similar structure to it but amodiaquine was shelved and chloroquine went ahead as it was conformationally more restrained.- Effective against the blood stages even in some chloroquine resistant strains of P. falciparum.- However, it has an unacceptable risk of toxicity towards granulocytes and the liver. TERM 17
Primaquine
DEFINITION 17 An 8 amino quinolone rather than 4.- Active against the liver stages of P.vivax- Mechanism of action may involve oxidative stress in the parasite - puts the mitochondria under stress and bursts the RBC's thus making it an unsuitable environment for parasite to flourish.- Effective against other (e.g. blood) stages of the cycle too and also used against P. flaciparum but the toxicity is once again very high as it targets RBC--> toxicity.- Causes heamolysis and methaemoglobinanaemia - a critically low ability to carry oxygen. TERM 18
Mefloquine (Lariam)
DEFINITION 18 Not an aminoquiniline structure- Reccomended for most risk areas.- Causes minor side effects (nausea, dizziness, sleeping trouble) but these dont last long and thus do not require drug termination.- However, did have serious CNS effects leading to suicides- now data sheet has been change to contraindicate mefloquine in patients with psychiatric mental disorders or issues- Not reccomended for use if:1) known allergy to it2) history of epilepsy, severe psychiatric disorders, cardiac conduction abnormalities. TERM 19
Pyronaridine
DEFINITION 19
Potential replacement for chloroquine but too complicated
and expensive to make.Requires new routes for synthesis.
TERM 20
Proguanil
DEFINITION 20
It is a pro drug that requires metabolic action to cycloguanil.-
Kills the gametocytes in mosquitoes.-Effective against
erythrocytic and liver stages of P. falciparum by inhibiting
dihydrofolate synthesis and thus inhibiting DNA synthesis.-
Used as a prophylactic but is too slow for a cure. Take it as
prevention.
Sulphonamides/Sulphones
Sulphones and Sulphonamides inhibit dihydropteroate
synthase involved in folate and hence pyrimidine and DNA
synthesis.They act too slowly on their own but act
synergistically with Proguanil and pyrimethamine because
they act at differents parts of the same pathway.Always used
in combination therapy.
TERM 22
Artemisinin Derivatives
DEFINITION 22
These are highly effective, rapid, have limited toxicity and
are cheap1- Hoewver, it is not particularly drugable.- It is
stable when in plant matter but if you isolate it it becomes
less stable.- However, inappropriate use may led to the
development of resistance and toxicity.
TERM 23
Combination Therapy
DEFINITION 23
The idea is to always use combination therapy to avoid
resistance problems as chance of parasite acquiring
resistance to the synergistic effects of two drugs is very
small.Fakes can cause resistance issues in communities.
TERM 24
Bugs and Drugs
DEFINITION 24
Antiobiotices are derived from microorganisms. Other
antibacteriales are synthetic agents (sulphonamides) or a
hybrid of the two.- However, antibacterial agents are referred
to as antiobiotics and resistance to antibiotics is an
increasing concern.
TERM 25
Selective
Toxicity
DEFINITION 25 Antibacterial drugs exploit the differences in the biochemistry and structure between mammalian cells and bacteria.- A typical bacterium consists of a single cell with a protective wall that is either:Gram + - simple wall, allows stain uptakeGram - - complex wall, no stain uptake- Cells can be either aerobic and more likely to infect surface areas (skin and respiratory tracts)- or anaerobic and more likely to infect bowel or deep puncture wounds.Cells can be cocci (streptococcus) or Bacilli (TB) or Spirochete (syphilis)
Inhibition of DNA Synthesis Part 2
Quinolones (e.g. Fluoroquinolone) inhibit the bacterial
enzyme DNA Gyrase (topoisomerase 2) which changes the
3D structure of DNA, necessary for its replication.- Increased
Fluroquinolone leads to decreased DNA Gyrase which means
less 3D DNA and less DNA replication.
TERM 32
Main Mechanisms of Antibiotic Resistance
DEFINITION 32
1) Change in site where drug acts (methylation of ribosomal
RNA receptor where macrolides act)2) Reduced bacterial
uptake or enanced efflux of drug.3) Bacteria produce
enzyme that inactivates drug (e.g.B-lactamase)
TERM 33
Resistance to B-Lactams
DEFINITION 33
Resistant bacteria usually have the enzyme B-lactamse - this
enzyme breaks the B-lactam ring leading to its inactivation.-
Resistance can be overcome by adding a B-lactamase
inhibitor (e.g. Clavulonic Acid) so that B-lactam ring only
interacts with transpeptidase to inactivate it.Amoxicillin +
Clavulonic Acid --> Augmentin.
TERM 34
MRSA Superbug
DEFINITION 34
This is a resistant bacteria that is a big problem in hospitals
around the world as it multiplies very rapidly and can cause
many different kinds of infections.-The last resort antibiotic
left is Vancomycin against HA MRSA but VRSA is a rising
issue!!
TERM 35
Choice of Antibiotics
DEFINITION 35
1) Bacterial Factors: Type of organism, source of organism,
host details, community info.2) Drug Factors: Efficacy, route
of administration, adverse effects, dosing, frequency,
palatibility, stability, cost.3) Patient Factors: Site of infection,
drug allergies, underlying illnesses, contraindications, age,
pregnancy
Antivirals
Viruses are responsible for lots of morbidity and mortality worldwide.-A virus is much smipler and more smaller than a human cell or even a bacterium.-It consists of an outer-envelope of protein, fat and sugarwrapped around a set of genes (barely alive).-Viruses cannot replicate independently and must therefore enter cells and incorporate their RNA/DNA into the host genome- they then hijack the cells own machinery to produce more viruses. TERM 37
Viruse Structurey
DEFINITION 37
Basic structure consists of:1) Nucleoid Region with RNA or
DNA2) Core proteins3) Lipoprotein membrane = evelope4)
Surface Proteins
TERM 38
Problems and Difficulties associated with
Antiviral Therapy
DEFINITION 38 -Late Diagnosis - most viral infections are not detected util late in course of disease.- Viruses hijack the host cells and therefore it is hard for the immune system to distinguish between friend and foe.- Viral infections may be associated with massive, overwhelming proliferation of viral particles.- Viruses have a very rapid mutation rate, leading to evasion from immune system (vaccinations difficult).- Some viruses are subversion measures to interfere with hosts immune response.- Some viruses can integrate their genetic material into host chromosome therefore clinical infection can arise without exposure (e.g. Herpes lies dormant and gets triggered when stressed).- HIV/AIDS infects T4 cells of Immune system making body more susceptible to opportunistic diseases. TERM 39
4 Main Types of Antiviral Therapies
DEFINITION 39
- Reverse Transcriptase Inhibitors2) Protease Inhibitors3) Absorption and Fusion Inhibitors4) Anti-viral Cytokine therapy (involves interferons boosting bodies ability to fight against viruses).-The goal is to exploit differences in viral replication processes/biochemistry to achieve selective toxicity.- Due to availability of new, cheaper anit-HIV drug, HIV is decreasing since
TERM 40
HIV/AIDS
DEFINITION 40
The HIV virus is an RNA reverse transcriptase virus - its
genetic information is RNA not DNA (therefore retrovirus).-It
mostly infects CD4 T lymphocytes of IS.- It uses cell surface
receptors CD4 and CD5 as ports to gain entry into the cell.
Zidovudine - an nRTI
Zidovudine is a pyrimidine nucleoside analog originally developed as an anti-cancer agent.- It is an effective antiretroviral particularly in combination but it is subject to rapid resistance.- It is selective for viral RT and does not affect mammalian DNA polymerase.- However, it is associated with heamtological toxicity, pancreatitis, liver damage, severe anaemia.- It is a prodrug which enter the cell and is triphosphorylated by various cellular nucleoside kinases before it can react with viral reverse transcriptsaes to halt DNA synthesis. TERM 47
Non-Nucleoside Reverse Transcriptase
Inhibitors (nNRTI's)
DEFINITION 47
Useful as part of anti-HIV combination therapyUsed by
themselves resistance quickly develops.e.g. Nevirapine
(NVP) - but it has serious side effects include life threatening
skin reactions and liver damage.
TERM 48
Protease Inhibitors
DEFINITION 48
PI's block the processing of viral proteins and thus the
assembly of the virion.-They bind to the active site of the
protease, inhibiting its function, leaving proteins untrimmed
and glycosylated and inactive.- Mostly used in combination
therapy to overcome resistance.- Side effects are nausea,
vomitting, diarrhoea,.e.g. SAQUINAVIR
TERM 49
Cytokine Therapy
DEFINITION 49 e.g Interferon alpha (IFN-a) for the treatment of Hepatitis C (HC)- IFN-a is a naturaly occurring glycoprotein (cytokine) that is secreted by cells in response to viral infections.- It augments the host immune system and targets cell killing by lymphocytes and inhibits viral replication in infected cells.- Various recombinant forms of interferons are approved to treat viral heptatitis.- Needs to be administered subcutaneously at least 3/week in treatment of chronic hepatitis C. TERM 50
Major Side Effects of IFN-a in treatment of
Hep C
DEFINITION 50
Fatigue
Depression
Flu like symptomes
Nausea
Diarrhoea
Apeptite loss
Major forms of Cancer Treatment
1) Surgery - focuses on bulk tumour - surgeon cannot remove
metasteses.2) Radiotherapy - Focused again on bulk tumour
as you cannot radiate whole body to kill off metasteses.3)
Chemotherapy - Drugs able to be carried to BOTH
metasteses and tumour and so has essential feature of being
able to reach most cancer cells.
TERM 52
Advantages and Disadvantages of
Chemotherapy
DEFINITION 52
- Main advantage of being able to eliminate micro-
metasteses far removed from site of tumour origin.- Main
disadvantage is that it lacks selective toxicity for cancer
cells.- It is cytotoxic to normal cells also, especially those
undergoing rapid proliferation.Bone Marrow Lymphoid
System* Hair Roots* Oral and GI Epithelium*Skin
TERM 53
General Toxic Side Effects of Anticancer
Drugs
DEFINITION 53
- Most suppress the bone marrow and immune system therefore need to constantly monitor patient blood count.- Many also cause neausea and vomitting - although there are drugs to counteract this.- Oral and GI ulceration- Diarrhoea- Hair may fall out (alopecia)- Germ cells can become sterile- Women can experience teratogenicity in their babies- Carcinogenic potential - found couple of years later can cause leukaemia associated with chelating agents. TERM 54
Principles of Cell Kill
DEFINITION 54
- AC drugs kill cells according to first order kinetics - a certain dose of a drug kills a certain percentage of cells (regardless of other drugs present) - note: percentage not number!!2) For most drugs, a linear type relationship exists between dose and cell kill - the higher the dose the larger the cell kill.-with every dose you' re killing a constant fraction of cells NOT a constant number of cells.*1 Log kills 90% *2 Log kills 99% *3 Log kills 99.9% *4 Log kills 99.99%- The minimum that is useful for Cancer treatment is 3 Log cell kill of 99.9% cells. TERM 55
Tumour Cell Kill
DEFINITION 55
10^3 -- Death10^12 -Advanced Disease10^9 - 1g
Tumour10^6 - 1mg Tumour - Clinical Recovery10^3 - Chemo
still required10^0 - Chemo stil requiredAt this point immune
system mops up extra cancer cells.
Chemotherapy Indications
1) Readily curable2) After surgery and radiotherapy -
micrometastatic disease in other organs may be eradicated
and may enhance local killing by radiotherapy.3) Palliation -
cure may not be possible but may improve survival and
symptom control.
TERM 62
Drug Development Time Line
DEFINITION 62
- Discovery + Basic Research - few years2) Preclinical Studies - 2-3 years3) REGULATORY REVIEW - FDA look at all research results, toxicity, kinetics etc and make decisions as to whether you can test it in humans (doctors, hospitals, facilities, volunteer)4) Clinical Testing - Starts getting very expensivePhase 1; Phase 2; Phase 3; Phase 4 ---> 5-7 years.5) REGULATORY REVIEW - FDA again looks through all data and clinical studies to make decision as to whether or not they will grant you a license for drug to be used for treatment of diseases.6) Prelaunch Activies7) LAUNCH8) Post Marketing Studies (Phase 4) - Looking for adverse effects in wider population.- Usually takes 10-12 yearsz from discovery to getting the drug onto the market place and usually costs greater than US$800M. TERM 63
Recent Examples of Drugs Withdrawn After
Successful Clinical Trials
DEFINITION 63
- Drug-Drug Interaction- Sorivudine - antiviral, inhibition of 5'Fluorouracil metabolism- Terfenidine -antihistamine, when coadministered with grapefruit juice it can cause cardiotoxicity.- Inhibitors of CYP450 metabolism and Terf when taken can lead to increased levels of it and thus cardiotoxicity.2) Unexpected Toxicity- Troglitazone - used for non-insulin dependent diabetes but led to severe hepatotoxicity.-Rofecoxib- Selective COX 2 Inhibitor for chronic pain releif - withdrawn in 2004 due to increased risk of heart attack/stroke-Main reason for failure during drug development is due to failed ADME/Tox properties. Almost 40% of compounds failed because of ADME (March 2003).-Nowadays this has been reduced to about 25%.-Large pharmaceutical companies --> Regulatory Authority --> Regulatory Guidelines ---> Review of Drug Data ---> Chem/PK/Tox/Pharmacology ---> Clinical Trials ---> FDA decision to grant ---> Marketing TERM 64
Drug Discovery
DEFINITION 64
- Development from herbal/traditional remedies e.g. Morphine from Opium poppy or Digoxin from foxglove or Salicylic Acid from willow bark.2) Empirical Approach - Development of models used to be predictive of the pharmacological activity. Screening of a large number compounds to predict an active compound that can be used for treatment.AC Drugs developed this wayCyclosporin (immunosuppressant).3) Rational Drug Design - Understanding the cellular/molecular basis of disease (e.g. receptors) and using computer technology to understand the 3D structure of receptor to design drug.e.g. Propanolol (B1 blocker) or Cimetidine (H2 antagonist).4) Prodrugs/Analogs/Metabolites of existing drugse.g. Aspirin (salicylic acid) or Paracetamol (phenacetin)5) Serendipity - a chance observatione.g. penicillin, slidenafil, valproate6) Genomics - Info on genes to identify the drug targets TERM 65
Preclinical Studies
DEFINITION 65
- In vitro/ In vivo tissue/animal studies.- Secondary properties (e.g. addiction etc)- ADME - you want to know and test for all the parameters.- Toxicology - acute or chronic? Mutagenicity? Carcinogenic? Teratogenicity?1) Choice of candidate drug 2) Toxicity - target organs, reversibility, cummulativeWhat is safe starting dose for humans?Toxic potentials (mutagenicity/carcinogenicity etc)3) PK/PD - relationships for effect and toxicity, therapeutic index (Toxic dose/ Effective dose)4) Basic ADME Parameters - Linearity of PK's, metabolism, renal excretion which CYP? Induction/Inhibition, metaboites (active?), absorption (oral?)
Clinical Studies in Drug Development
Phase 1 - require small number of usualy young, healthy volunteers (except for Cancer drugs) - toxicity; tolerate dose range; PK/PD studies.Phase 2- Several hundred patients with specific disease - therapeutic effectiveness (dose/conc/response). Short term safety, dose strategy etcPhase 3 - Several thousand patients around world - Clinical safety and efficacy (overall risk vs. benefit); further reine dose/conc/response relationship; Qualitative vs. Quantitative assessment of ADR's.Phase 4 - Post marketing surveillance and ADR reporting. TERM 67
What Is the Immune System?
DEFINITION 67
- The Immune system is a highly complex network of lymphoid tissues, glands, ducts and cells that protect the body from invasion.- A variety of specialised immune cells carry out various functions to ensure immunocompetence.- Immune cell proliferation, recruitment, migration, activation and destruction are regulated by a large array of chemical messengers. TERM 68
Examples of Immune Mediators
DEFINITION 68
- Cytokines: Interleukin; Interferons; Tumour Necrosis factors etc2) Chemokines: Retention signals for cell. Signal is sent out by immune cell to draw in other immune cells that'll diffuse through tissues in blood and draw to chemokine cell - IL8, MCP-13) Colony Stimulating Factors - Growth Factors (specific) - GM-CSF4) Adhesion Molecules - Allows tissues and cells to bind together - ICAM-1 ; Integrins5) Eiconasoids - Prostaglandins (PG's) and Leukotrienes (LT's)6) Endocrine - Steroids, CRH, Catecholamines, Histamine TERM 69
Steroidal Anti-Inflammatory Drugs
DEFINITION 69
- Endogenous Steroids include cortisol; progesterone - They act via intracellular receptors to regulate gene transcription .*Adrenal Steroids - Glucocorticoids (cortisol) - Have immunosuppressive effects and aren't expressed by all genes.- Glucocorticoids are highly lipophilic, their receptors (GR) are expressed by most cell types and is activated by cortisol and aldosterone.- Activated receptors move from the cytoplasm to the nucleus and alter gene transcription (pro-inflammatory or anti- inflammatory genes)- The GR also interferes with major inflammation associated with transcription factors, NF-kB. TERM 70
Genomic Effects of Glucocorticoids
DEFINITION 70 -Proinflammatory genes that are down regulated by glucocorticoids include:1) Pro-inflammatory cytokines2) COX 2 3) Phospholipase A24) Cell Adhesion Molcules5)Endothelins6) Inducible Nitric Oxide Synthase (iNOS)- Anti-inflammatory genes are that up regulated by glucocorticoids include:1) IL-10 or IL- (anti-inflammatory cytokines)2) Lipocortins/Annexins (PLA inhibitor)
Other Commons NSAID's
- Ibuprofen- Naproxen- Sulindac- Diclofenac- Indomethacin TERM 77
Adverse Effects of NSAID's
DEFINITION 77
- For long course of NSAID's:1) Gastric Upset2) Ulcers3) GI Bleeding - inhibition of COX 1 derived PGE2 leading to mucosal damage4) Renal Complications/Impairment (v blood flow and GFR)5) Increased Clotting Time (inhibition of TXA2)6) Hepatic Toxicity7) Skin Rashes8) Early Pregnancy --> fertility complicationsALL LARGELY ASSOCAITED WITH COX-1 INHIBITION- Recently FDA released warning not to use after hear surgery- Asthmatics allergy type response to NSAID's may be fatal. TERM 78
COX 2 Selective Inhibitors
DEFINITION 78
- Decreases GI irritation and ulcer rate with similar efficacy to non- selective NSAID's.- Useful for longer term use in treatment of chronic conditions.- Also good short term pain releif profile- They selectively inhibit COX 2 but not COX 1. This is for the treatent of inflammatory diseases where COX 1 side effects are problematic.- But still COX 2 inhibitors have ADR's that are harmful also. TERM 79
Unexpected Adverse Effects of COX-
Selective Inhibitors
DEFINITION 79
- All FDA warning are due to high health risks after long term use.- Celecoxib associated with acute cardiovascular events- Rofecoxib associated with increased risk of thrombotic events.- Hundred of thrombotic/embolytic cases attributed to celecoxib/rofecoxib in USA alone.- May relate to inhibition of COX-2 derived prostacyclin (Cardioprotective)- Both drugs increase BP and some evidence of Renal Impairment.*E.g. VIOXX withdrawal in 2004 due to increased risk of CVD after 18 months of treatment. TERM 80
Pancreatic Islet Hormones
DEFINITION 80
- Islets of Langerhans secrete:1) Insulin from B-cells2)
Glucagon from a-cells3) Somatostatin from d-cells
Insulin
- A fuel storage hormone that decreases blood glucose levels
by:1) Increasing glucose uptake into muscle and fat cells2)
increasing glycogen synthesis3) decreasing
gluconeogenesis4) decreasing glycogen breakdown
TERM 82
Glucagon
DEFINITION 82
- A fuel mobility hormone that increases blood glucose levels
by:1) Increasing gluconeogenesis2) Increasing
glycogenolysis and lipolysis
TERM 83
Two Phase Release of Insulin with Constant
Glucose Infusion
DEFINITION 83
- Insulin secretion is stimulated by blood glucose levels.- B-cells respond to both absolute glucose concentrtions and also to the rate of change of blood glucose.- Steady basal release of Insulin as a response to changes in blood glucose- A response to changes in blood glucose has 2 phases:1) Initial rapid phase - reflecting release of stored hormone2) Slower delayed phase - reflecting both continued release of stored hormone and new synthesis. TERM 84
Insulin Secretion
DEFINITION 84
- ATP-Sensitive K+ (Katp) channels determine the resting membrane potential in B-cells.- Glucose enters B-cells via a membrane transporter "GLUT-2" and is metabolised by glucokinase- This leads to increased Glycolysis-Which increases intracellular ATP.- This acts on Katp channelscausing membrane depolarisation- And opens voltage dependent Ca2+ channels- Which induces insulin secretion. TERM 85
Diabetes
DEFINITION 85
- Affects approximately 3-5% of population- Occurs when
ciruclating insulin levels decline and/or target receptors
become resistant to insulin.- TWO TYPES OF DIABETES:1)
Insulin Dependent Diabetes Mellitus (IDDM) - type 1 -
Juvenile2) Non-Insulin Dependent Diabetes Mellitus (NIDDM) -
type 2 - Adult
Non-Insulin Dependent Diabetes Mellitus
(NIDDM)
- Develops after 35 years of age and is associated with
obesity.- It leads to normal or higher levels of circulating
insulin- Does not lead to ketosis.- Due to insensitivity of
target cells to insulin- Causes Insulin Resistance and thus:1)
Decreased number of Insulin Receptors2) Problem in
pathway of insulin action (2* messenger pathway)
TERM 92
Treatment of NIDDM
DEFINITION 92
- Oral Hypoglyceamic Agents - Sulfonylureas/Tolbutamide - Increases insulin release as high affinity of receptors to Sulfonylureas present on Katp channels. These thus block Katp channels causing depolarisation and increased insulin release.Increased insulin sensitivity stimulates glucose reuptake into muscle and fat cells.2) Meglitinides - Work on the pancreas to promote increase insulin secretion through the same action as sulfonylureas but binds to Katp channels at different site than sulfonylureas.3) Biguanides - Metformin - Reduce hepatic glucose production (gluconeogenesis)- Type 2 diabetic has 2 x normal level of gluconeogenesis- Activates AMP-activated protein kinase that is a liver enzyme that has an important role in insulin signalling.- Increase glucose uptake and utlisation in skeletal muscle reduces insulin resistance.- Used alone of in combination with sulfonylureas drugs. TERM 93
Hypertensions
DEFINITION 93
- High Blood Pressure that persists over weeks = Hypertension- There are two types of Hypertension:1) Essential Hypertension - It has no obvious cause (95% patients)2) Secondary Hypertension - Due to kidney disease, tumours etc-They have very general symptoms of tinnutis (ringing of ears) and light headaches/ dizziness.- Untreated hypertension can severely decrease life expectancy TERM 94
Reasons to Treat Hypertension
DEFINITION 94
- Untreated hypertension increases the risk of1) Coronary Thrombosis - clot/blocked arteries therefore decreased oyxygen and increased heart attack risk.2) Stroke - Clot/rupture of blood vessels in the brain and therefore deficity of blood in front part of brain leading to paralysis and decreased motor functioning/death.3) Renal Failure4) Heart Failure6) Aneurysm - weaking of blood vessels - blurting out of blood leading to dramatic blood loss --> death.7) Retinopathy - damage to retina (blindness) TERM 95
Progression of Heart Disease
DEFINITION 95
- Artherosclerosis --> Stroke --> Death2) Artherosclerosis --> Hypertension --> Stroke --> Death3) Artherosclerosis --> Hypertension --> Aneurysm --> Death4) Artherosclerosis --> Aneurysm --> Death5) Artherosclerosis --> Hypertension --> MI --> Heart Failure --> Death6) Artherosclerosis --> Hypertension --> MI --> Cardiac Dysrhytmias --->Death7) Artherosclerosis --> Coronary Heart Disease --> MI --> Heart Failure --> Death8) Arhterosclerosis ---> Coronary Heart disease --> MI --> Cardian Dsyrhytmias --> Death.
Basic Control of Mean Arterial Pressure (MAP)
- MAP is detemiend by 2 physiological components:1) Cardiac Output - Stroke Volume x Heart Rate - how much blood is ejected from the heart per hear beat.2) Peripheral Resistance - Physical factors affecting this are* Blood Vessel Compliance* Blood Volume Viscosity- ^ Flexibility ^ likelihood to accomodate blood v BP- Often early on in disease CO ^ followed by ^ peripheral resistance and thus normalisation of CO. TERM 97
What can we do to lower Blood Pressure
DEFINITION 97
- Lower Cardiac Ouput and Peripheral Resistance will lead to
lower Blood Pressure.- Main physiological targets for anti-
hypertensive drugs include:1) Symphatetic Nervoous
System2) Endothelium derived autacoids - NO or Endothelin-
13) Renin-Angiotensin-Aldosterone System
TERM 98
Diagram Page
DEFINITION 98
- Reduce Heart rate (v CO) by:1) Giving B1 blockers (B1 antagonists - propanolol)- Interfere at level of Blood vessels (v Peripheral Resistance) by:1) a-blocker (Prazosin a-1 antagonist) - acts on smooth muscle of blood vessels to decrease peripheral resistance etc.2) Vaso-dilators (Ca2+ blockers)3) Endothelial autacoids - (NO and ET-1)- Endothelium- (potent vasoconstriction) Acts on :a-receptors of smooth muscle on arterial wall when activated cause vasoconstrictionb-receptors found on endothelial cells that line blood vessels when activated stimulate release of NO leading to vasodilation.*****These two combined decrease MAP TERM 99
Treatment Goals and Possible Therapies
DEFINITION 99
- Reduce Heart Rate - B1 agonist- Widen Blood Vessels - Vasodilators - a-1blocker or Ca2+ blocker- Increased formation or prolonged activation of vasodilating substances or their 2* messengers (NO donors)- Prevent formation of endogenous vasoconstrictors- Reduce thickness of blood (e.g. anticoagulants)- Prevent further loss of compliance (statins, ACE inhibitors) TERM 100
Renin-Angiotensin-Aldosterone System
DEFINITION 100
Plays an important part in controlling Blood Volume and
systemic Vascular Resistance which together influences CO
and arterial pressure:1) Renin is primary released by the
juxtaglomerular cells of the kidney2) It stimulates the
formation of angiotensin in the blood and tissues3)
Angiotensin stimulates aldosterone from the adrenal cortex.
