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Pharmacology; Read my study notes!
Topic Started: Sep 12 2011, 02:18 AM (3,490 Views)
Tim
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So yea, got a pharmacology test tonight so thought i'd share some notes for your perusal :3

After some thought here are my introduction and ADME notes :3


Pharmacodynamics: The study of molecular, biochemical and physiological effects of drugs on cellular/body systems and their mechanism of action.
Pharmacokinetics: The study of the fate (absorption, distribution and elimination) of drugs.
Pharmacogenomics: The study of genetic influences on the effectiveness and fate of drugs.
Toxicology: The study of the adverse or toxic effects of drugs and other chemical agents.
Therapeutics, Pharmacoeconomics and Pharmacoepidemiology.

Drug: A chemical/substance usually used to treat a disease/condition. Must have regulatory approval e.g. FDA and have gone through extensive valuation procedures e.g. food supplements can't make claims about therapeutic properties, only approved drugs can. Manu drugs come from natural sources, many of which were discovered by investigation of folklore claims e.g. paclitaxel (Taxol) from Yew trees.

Drugs can come from:

Plants: Opium poppy: dried juice from seeds yield morphine, only effective drug of choice early 1900s, powerful painkiller and inducer of euphoria (sideeffect of constipation)
Foxglove: leaves contain digitalis (digoxin), a reversible inhibitor Na/K ATPase, widely used to treat congestive heart failure.

Microorganisms: Antibiotics e.g. Penicillin, a prototypic b-lactam antibiotic discovered as a product of a mold growing in Alexander Fleming's lab in 1928. Interferes with bacterial cell wall synthesis.

From the body itself (endogenous): Hormones e.g. insulin (treats diabetes), thyroxine (treatment of thyroid insufficiency), growth hormone (treatment of short stature). Most hormonal drugs are now produced by recombinant DNA technology.

Chemical modification of the body's own hormones/chemical regulators: Hormonal drugs e.g. ethinyl estradiol (readily absorbed form of oestrogen), prednisolone (synthetic steroid with gluccocorticoid-like actions. Anti-cancer drugs e.g. 6-mercaptopurine and 6-thioguanine - modified base components of DNA/RNA which interfere with DNA/RNA synthesis.

Chemical synthesis of novel compounds with desirable properties: Indomethacin, celecoxib (COX inhibitors or NSAIDS), Cimetidin (histamine receptor modulator), Simvastatin (HMG-CoA reductase inhibitor).

Drugs discovered by chance: Antidepressants (some monoamine oxidase inhibitors and tricyclic antidepressants discovered during failed attempts to develop treatments for tuberculosis and pre-anaesthetic agents respectively). Cisplatin, a platinum containing drug used to treat a number of cancers, discovered while investigating the effects of electrical fields on bacterial cell growth. Viagra, originally tested in a study of hypertension.

Drugs have a generic name related to the structure/composition/source of the drug, which is the preferred name for general use. They also have a capitilised brand name. Brand names, but generic names also can differ between countries.

Drug action: usually bind to a target (normally a protein). Common targets are receptors, enzymes, ion channels and transporter molecules. MABs are a new class of drug targeting ligands. Non-protein targets include DNA/RNA and lipids.


ADME = Absorption, Distribution, Metabolism and Excretion.

Important drug physicochemical properties are their solubility in lipids and water (non-polar or ionized), determined by their chemical structure.

The ADME processes of each drug affects the onset of drug action and the duration and intensity of the effect.

Gastro-intestinal tract - absorption. Liver - metabolism. Kidney - excretion. Lungs - absorption and excretion of volatile anaesthetic gases.

Transport across biological membranes:
Small, uncharged and lipid soluble drugs will distribute faster and more widely due to their ability to easily pass through lipid membranes. Transport across biological membranes can occur via Transcellular diffusion, facilitated diffusion, active transport or endocytosis.

Four primary methods of membrane transport, dependent on physicochemical properties:
Passive diffusion - most important, applies to non-polar drugs. A concentration gradient is required. No energy required.
Facilitated diffusion - may depend on an oscillating carrier protein. Depends on concentration gradients, not energy. Sugars and amino acids are usual substrates. For a few drugs, movement occurs faster than predicted.
Active transport - proceeds against a concentration gradient. Requires energy, can become saturated. Organ specific. Allows cell to accumulate compounds essential for growth, remove waste products, protect against toxins.
Endocytosis - internalization of large molecules (mainly MW > 1000). Involves ligand binding to receptor, invagination of receptor-substrate complex, budding off and delivery of vesicle into cell.\

Filtration - most drugs pass through cells to cross biological barriers, except blood capillaries and glomerular capillaries.

Absorption:

Passage of drug from site of administration to general circulation (into bloodstream).
Absorption rate - affects onset of action - mainly dependent on how lipid soluble drug is.
Absorption extent - expressed as % bioavailability (F). Affects how long drug acts for.
Drug absorption extent needs to be above the minimum therapeutic level and rate fast enough that concentrations of the drug can build up above the minimum level (if too slow, elimination prevents this from occurring).

Routes of administration:
Enteral - By the GI tract. Can be oral (sometimes written as po), sublingual (beneath tongue as a pill or spray, dissolves and is absorbed into capillaries beneath tongue), rectal (useful for nil by mouth patients).
Parenteral - Outside of the GI tract. Can be intravenous (IV), subcutaneous (SC), intradermal, intramuscular (usually the shoulder or bottom), lungs (by inhalation).

Most popular routes of drug administration:

Intravenous - rate of absorption is immediate and extent is 100%.
Advantages: Is very rapid and 100% absorption allows precise control of dosage. Is a good administration route for drugs that are too irritating to be taken orally or by tissue injection.
Disadvantages: requires skill to administer (must avoid air embolism), careful preparation of injected material and is the most hazardous route (there is no way to recall the drug).

Oral (po) - absorption rate is gradual and extent of absorption is incomplete.
Advantages: Safest, most convenient and economic route.
Disadvantages: Slow (30min-3hrs for effect), unpredictable rate, extent and reproducibility (depends on what patient has eaten etc.)

Taken orally, a tablet disintegrates in the stomach, dissolves in gut fluids and is absorbed in the intestines. It is taken via the portal vein to the liver where a variable fraction is metabolised and destroyed by enzymes (depends largely on the physicochemical properties of the drug). The remainder (bioavailability) is then distributed to tissues via the circulation.

Bioavailability - affected by acidic gastric juices, hydrolytic gut enzymes, gut microorganisms, food (can act as a chelator), metabolism by gut wall enzymes, metabolism by liver enzymes before reaching systemic circulation.

Patient factors influencing absorption - stomach emptying rate (the rate limiting step of absorption), intestinal motility (increased due to gastroenteritis and diarrhoea and increased or decreased by various drugs), interactions with food. Al(OH)3 (found in antacids) and milk often reduce bioavailability. Fast passage into the intestine occurs 1 hour after a meal, but taken with a meal delivery to the intestine is slow (this is exploited to control administration rate).

Distribution:

Drugs usually leave the bloodstream via capillaries (relatively porous). However brain capillaries have no pores and have a layer of glial cells making up the blood brain barrier so drugs to be administered to the brain need to be lipid soluble.
H2O soluble drugs are restricted to the plasma and extracellular fluid (about 14L), whereas lipid soluble drugs can move into the intracellular fluid as well (+28L for a total of 42L).
Tissues that receive greater bloodflow receive more drug. The heart, brain, liver and kidney receive drugs rapidly, while skin and fat receive drugs more slowly. Rate of delivery to muscles is generally slow but depends on the activity of the muscle.
As a result of distribution, drugs are excreted from the kidneys and also from the gut lumen (enter lumen in biliary secretions)

Metabolism:

Main site is the liver. Also in the GI tract (gut bacteria and proteases), intestinal wall (CYPs), plasma (enterases) and specialised tissues (monoamine oxidase, MAO, in nerve endings).
The fate of drugs for further metabolism or excretion depends largely on their lipid solubility. Lipid soluble drugs are readily reabsorbed into the bloodstream from the nephrons and need to be metabolised to water soluble molecules before they can be excreted.
As a result of metabolism into more water soluble molecules, metabolites are less likely to diffuse into cells and reach receptors, favour increased excretion in urine or bile and usually have their activity abolished. However, sometime metabolism can promote activity (prodrug e.g. acetylsalicylate → salicylate), no change in activity (diazepam → nordiazepam – a intermediate metabolite which is further metabolised into an excretory metabolite) or produce toxic metabolites (paracetamol). Normally, toxic metabolites are bound to something to detoxify, but during overdose detoxification methods are saturated and the body is harmed, usually the liver.

Reactions: Phase 1 (creates a reactive group), usually by oxidation, reduction or hydrolysis, making the molecule more susceptible to phase 2. May slightly increase water solubility.
Phase 2 (conjugation), addition of glucuronide, sulphate, amino acids, GSH, acetylation/methylation (these increase polarity making metabolite more water soluble).

Oxidation is the most important phase 1 reaction, with the most important class of enzymes being the cytochrome P450 dependent mixed function oxidase system (CYPs). They are family of related isozymes. CYP1, CYP2 and CYP3 are the 3 key families.
Drug + O2 + H+ + NADPH → Oxidised drug + H2O + NADP+ (requires O2, NADPH and cytochrome P450 reductase).
Example enzyme is CYP3A4, with 3 specifying the family, A the subfamily and 4 the isoforms.

Phenytoin - a highly lipophilic molecule undergoes hydroxylation by CYP in phase 1 to a slightly water soluble molecule that is inactive. It is then conjugated by UDP glucuronosyl transferase. The added glucuronyl unit makes the metabolite very water soluble.

Sometimes drugs can undergo phase 2 reactions without phase 1 and sometimes drugs can be excreted after phase 1 without phase 2. Metabolised drugs end up in urine or fecal excretions.

Drug metabolism varies between people due to various factors:
Age (metabolism peaks at 20-30 and then declines). Sex (males have higher metabolism than females). Pregnancy (changes levels of CYPs).
Diet. Cigarettes (increase metabolism, can increase likelihood of toxic metabolites, or impair drug therapies). Alcohol (short term inhibition of metabolism).
Diseases and other drugs (can increase or decrease metabolism).
Organ function – liver, kidney, heart (cardiac deficiencies reduce distribution, less blood to liver reduces metabolism), gut (CYP3A4 is abundant in the intestines and plays a major role in the metabolism of quite a few compounds).

Theophylline - neonates have reduced capacity to metabolise theophylline (a drug to treat asthma). Then, their capacity to metabolise the drug quickly rises (coupled with a fall of the half life of the drug). From about 20 onwards, the plasma half life of drugs then increases again. Smokers metabolise theophylline more quickly than adult non smokers, reducing the effect of the drug. Children have the greatest capacity to metabolise the drug.

Induction of CYP enzymes:
Caused by environmental factors e.g. cigarette smoking, eating BBQ meats, cruciferous vegetables, ethanol and drugs e.g. Barbiturates, phenytoin, carbemazepine. Increased enzyme synthesis initiated within 24 hours, reaches a maximum at 3-5 days (slow), due to the complex pathways of inducing transcription. Effect decreases over 1-3 weeks as inducing agent is discontinued.
For example, BBQ meats contain PAHs which induce CYP1A1 and CYP1A2. These enzymes are good at metabolizing compounds to produce mutagenic (sometimes carcinogenic) metabolites.
Induction means higher doses of drugs are required, but isn't dangerous.
Smokers have an increased body clearance for some drugs and chemicals e.g. caffeine.

Inhibition of drug metabolism:
Onset is rapid (within 1 day) as the mechanism is not complex; the inhibitor only needs to bind with the enzyme. This results in an exaggerated response to the drug with increased risk of toxicity. Reversible inhibitors (mainly competitive) bind to the catalytic site e.g. cimetidine, HIV protease inhibitors, grapefruit juice. Heavy metals e.g. lead, cadmium and mercury complex with CYP450 in a non-competitive way. Grapefruit juice can triple the levels of Felodipine (a Ca2+ antagonist for treating high blood pressure) in the plasma -dangerous.

If enzymes in both the gut and liver are induced or inhibited, the bioavailability of orally taken drugs can be greatly affected.
When comparing induction and inhibition graphically, inhibition is rapid and increased levels of a drug fall quickly after the inhibitor is gone. Induction is slow to begin and it takes a long time for plasma levels of a drug to increase again after the inducer is gone.

A standard dose of a drug generally only has therapeutic benefits on 50-60% of a population. About 20% show no response and about 20% have adverse side effects. This is due to the many factors which influence metabolism e.g. genetics, gender, age and environmental factors.


Excretion:

Process where compounds are removed from the body to the external environment.
Kidney (most important), biliary excretion (important for some drugs, usualy MW>400 and ionised e.g. glucuronides (M.W. > 177), lungs (e.g. anaesthetic gases).

Kidney - removes H2O soluble drugs and metabolites (depends on physic-chemical properties). 3 main mechanisms are involved in renal excretion:

1. Glomerulus - Glomerular filtration - of unbound drug, GFR is 130mL/min in healthy adult, about 10% of renal blood flow.
2. Proximal convoluted tubule - Active secretion - of both free and protein-bond drug by transporters. Includes anions (urate, penicillin, glucuronides and sulphate conjugates) and cations (choline, histamine, basic drugs e.g. amines).
3. Loop of Henle - Filtrate 100-fold concentrated in tubules for favourable concentration gradient for reabsorption by passive diffusion.

E.g. renal excretion of Benzylpenicillin (BP). Is a weak acid (pKa of 2), 65% bound to plasma proteins. 35% is free and available for filtration, 20% of plasma is filtered therefore 7% of BP is filtered. Active secretion by acid pump of free and bound BP in proximal tubule. No passive reabsorption as BP is ionised in urine. Results in little or no drug in blood stream, with clearance of about 600mL/min which is similar to renal plasma flow.

Factors influencing - gender (female have 80% the renal function of males), age (renal function decreases 50% with age between 25 and 75), pregnancy (renal function increases 50% and disease (renal disease/heart failure).
Factors altering - competitive inhibition of tubularsecretion (probenecid decreased renal clearance of penicillin by 90%). Influence of pH (sodium bicarbonate in urine - alkaline diuresis - increases excretion of salicylate), (ammonium chloride acidifies urine, enhanced excretion of basic drugs such as amphetamines). Influence of urinary flow rate (increase in rate decreases concentration for passive reabsorption of drug).
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Mc Esse
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Lucky guy, one day you'll become rich with your profession.
Edited by Mc Esse, Sep 12 2011, 02:24 AM.
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Frankie
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Holy Moly.

No wonder your so busy.

Take me half a semester just to read your post, if I even understood any of it.
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Tim
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Parmacokinetics:

The study of ADME on a quantitative basis - drug concentrations in blood (plasma), saliva, urine, faeces etc. and how these concentrations change with time. Studied through concentration-time profiles of a drug in the body.

Time-course of plasma drug concentration - steep rise due to absorption, distribution shows lessened slope as drugs are taken up by peripheral tissues out of the blood. Elimination begins with the decrease in the curve. Exposure = area under curve (AUC). Typical units are mg.h/L.

Absorption - relevant for extravascular drug administration. Bioavailabilty (F) = AUCpo/AUCIV x doseIV/dosepo. First pass effect = loss of drug occurring before the drug has reached the systemic circulation. Oral administration shows a much slower (less steep gradient) absorption curve and lower peak than IV administration.

Distribution - defined by the parameter known as volume of distribution (V or Vd). V = amount of drug in body/plasma drug concentration. Determined by body mass (larger body mass, typically higher Vds), tissue binding (increases V), drug binding to plasma elements (decreases V). Bathtub model is oversimplistic - body is not a uniform container through which a drug can evenly pass. Vd is indicative of a drugs movement from the bloodstream. Vd of 5 indicates all the drug is in the bloodstream. Vd of 1000 indicates the drug is bound to tissue and not evenly distributed between the tissues and blood. Vds below 5 or above 1700 are probably miscalculations.
Loading dose is the first dose of drug treatment, intended to achieve target concentration rapidly. LD (mg) = V (L) x target concentration (mg/L) or LD (mg/kg) = V (L/kg) x target concentration (mg/L) to account for different body masses.

Drug elimination - irreversible removal of a drug from the body (could be physical excretion or chemical metabolism to another compound). Defined by the parameter clearance (CL) = volume of plasma cleared of drug per unit time (L/h). CLbody = CLrenal + CLhepatic + CLother = dose/AUC. Drug is immediately redistributed to blood which has been cleared of it, so CL cannot be used in conjunction with the total volume of body fluids to estimate the time taken to remove all drug from the body. CL is not changed by concentration of a drug. It can be affected by induction of metabolism and disease states.
Elimination rate = Clearance x Concentration. Clearance can’t be changed, but concentration varies and effects the speed of elimination.
Maintenance Dose Rate = CL x target concentration. This is the dose required to achieve and maintain a target concentration and is equal to the rate of elimination at steady state.
Half-Life (T1/2) = 0.7Vd/CL. Time taken for drug concentration to fall by half. Usually constant irrespective of drug concentration. Useful for determining when the effect of a therapeutic or toxic drug effect is likely to cease.
Accumulation occurs until input rate = elimination rate. After 4 half lifes, accumulation is over 90% complete, but this is not a suitable estimate for the time at which steady-state concentration is reached. Graphically, is the mirror image of the % dose in body v. half life graph. The idea is that the patient is dosed faster than the elimination rate to begin with, but as concentrations increase, so does elimination rate until the elimination rate = dose rate at the steady state concentration. A loading dose reduces the time it takes to reach this steady state.
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Tim
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Drug Targets:

Drugs mimic or prevent physiological, biochemical or pathological processes. Pharmacodynamics follows what drugs do to the body, including where these drugs bind. Most common binding sites are proteins (enzymes, carrier proteins, ion channels, receptors). Other binding sites are DNA, lipids and ligands (e.g. anti-inflammatory molecules). Receptors are the most common target and the most thoroughly understood.

Receptors - recognition sites for endogenous ligands for neurotransmitters e.g. noradrenaline, hormones e.g. adrenaline and local hormones/autacoids e.g. prostaglandins. They have at least one binding site. Endogenous ligands (and some exogenous ones) activate signal transduction - efficacy. Some drugs inhibit signal transduction.

Ligand-receptor binding is determined by the shapes and size of the ligand and binding site of receptor and on the charges of each. A ligand must have some specificity to have its intended effect.
Affinity - attraction of ligand for a receptor. Efficacy - intrinsic activity. Maximum effect = efficacy of 1, no effect = 0. Agonists have affinity and efficacy (mimics) while antagonists have affinity but not efficacy (prevent).

Receptors are often membrane bound (steroid receptors are an exception). Their structure is important for ligand specificity, verification of receptor family subtypes and characteristics of their signal transduction. No drug is totally specific to one receptor, often leading to unwanted side effects. H = receptor family, H2 = receptor subtype. Families are usually characterised by having an endogenous molecule bind to them while subtypes, while generally similar, have different characteristics, structure, location, targeting drugs.

Drug action depends on drug properties (receptor subtype selectivity) and the distribution of subtypes e.g. H1 is in the skin, allergic reactions. H2 is in the stomach, acid secretion. H3¬ is in the CNS, ileum and cardiac tissue, often presynaptic and autoregulatory. Selectivity means preferential binding to a certain subtype, leading to a greater effect at that subtype than others e.g. salbutamol is an agonist of β2 (lungs) rather than β1 (heart) in asthma treatment, while fenoterol bound to β1 as well, resulting in the deaths of some users. Antihistamines (antagonists) are now H1 selective, so no longer cause drowsiness. H2 antagonists inhibit gastric acid secretion and H3 antagonists are used primarily as experimental tools, but can treat pain and inflammation. NSAIDS universally inhibited cyclo-oxygenase (of which there is an inducible and a constitutive subtype), had the unwanted side effect of uncontrolled bleeding and ulcers. COX II inhibitors are selective to the inducible form. Chemotherapy is selective for cells/organisms it targets.

Receptor occupancy theory - drug effect ∝ number of receptors occupied. And equilibrium of D + R ←k2 k1→ D-R exists. Similar to Michaelis-Menten kinetics.
Rate theory - drug effect ∝ rate of occupancy. Occupancy tails off as fewer binding sites are available and the occupancy rate decreases.
Two State Model - receptors exist in active or inactive form. With no ligands, equilibrium favours the inactive form. With full agonist, there is a strong preference for the active form. With partial agonist, there is a weak preference for the active form, equilibrium partially shifted. Antagonists result in no preference for the active form and equilibrium is not shifted. Antagonists will however prevent agonist from binding to receptors and thus reduce the agonist’s effect.
Floating Receptor Model - the D-R complex may interact with a variety of effectors in the membrane to produce its effect.

Plasticity - receptor states and populations can alter due to physiological, pharmacological or pathological states. This is largely responsible for changes in the effectiveness of chronic drugs (or endogenous compounds) e.g. tolerance, insulin resistance.


Receptor families:

Ionotropic (linked to ion channels) - extracellular binding domain near N terminus, four transmembrane domains. 4-5 proteins making up channel. Very fast, msec (receptor is part of channel, one step mechanism). Binding of agonist causes conformational change in receptor, ion channel opens.
E.g. nACh (nicotinic), GABAA. Depending on which receptor involved, agonists can cause an increase in channel-opening time (duration or frequency – nAChR) or an increase in channel conductance (glutamate).
The GABAA receptor allows flow of Cl- into cells - hyperpolarizes neurons and makes them less excitable. Bezodiazepine (e.g. valium) or barbiturate (e.g. pentobarbitone) binding sites enhance binding of GABA and increases the rate (benzodiazepine) or duration (barbiturates) of channel opening. This is the basis for these drugs use as sedatives.

Metabotropic (G-protein coupled) - extracellular (near N terminus) and intermembrane binding domains. Intracellular G-protein coupling domain near C terminus. Fast (seconds - multiple steps involved). Binding of the agonist causes G-protein activation → opening or closing of an ion channel or generation of second messengers (e.g. CAMP, IP3) resulting in a biological effect.
E.g. mAChR (muscarinic), adrenoreceptors. G-protein (guanine nucleotide binding regulatory proteins) families - GS, GI and Gq
Binding of ligand to receptor results in α subunit of G-protein dissociating from βγ complex and being bound with GTP. The α subunit then binds with and activates a target protein while the βγ subunit also binds with and activates another target protein. GTP is hydrolysed to GDP and the α and βγ subunits dissociate from their target proteins and complex with each other again.
Different receptor-G-protein complexes can control a single target enzyme (bi-directional control), allowing different receptors to exert opposing effects (gS stimulatory, gI inhibitory).
2nd messenger systems can occur via G-proteins e.g. adenylate cyclase which converts ATP into cAMP; activating protein kinases and a cascade of kinase reactions. The main protein kinase types are PKA and PKC. Sometimes thirds messengers are operated by protein kinase activation, leading to regulation of genes (would be a very slow response for the G-protein coupled receptor).
G-proteins also target phospholipase C, which produces DAG and IP3. IP3 is important in the contraction of smooth muscle. It binds to an IP3-gated Ca2+ channel in the endoplasmic reticulum. DAG activates PKC.

Catalytic (linked to kinases) - Extracellular binding domain near N terminus, intracellular catalytic domain near C terminus. Tyrosine-kinase and guanylate cyclase-linked receptors (actions take minutes-days). Examples include growth factors, hormones (insulin) and cytokines. A protein kinase cascade is triggered. Some have their own kinase activity (insulin and growth factor receptors) while others associate with kinases upon an agonist binding (cytokines and Jaks). Transduction involves dimerization of receptors → autophosphorylation of tyrosine residues → phosphotyrosine residue act as acceptors for the SH2 domain proteins → cascade event → control of cell function. Mainly controls cell differentiation and growth by transcriptional control.
Ras/Raf/MAP kinase pathway (differentiation): growth factor binds, tyrosines dimerize, autophosphorylate, SH2 domain binds to phosphates on tyrosine and is itself phosphorylated – activates Ras GDP/GTP exchange, beginning kinase cascade and gene transcription.
Jak/Stat - cytokine binds to receptor, receptors dimerize and Jak binds, phosphorylating complex. SH2 domain (Stat) binds to phosphate and is itself phosphorylated - Stat dimerizes and leads to gene transcription.

Nuclear/Intracellular (linked to gene transcription) - binding domain near C terminus and DNA-binding domain (zinc fingers) near middle of protein. Slow-acting (hours-days).
E.g. steroid hormone receptors e.g. oestrogen, cortisol, vitamin A (ligands often need to be lipid soluble to easily penetrate cell membrane). Bind to highly conserved regions of DNA attached to highly variable ligand-binding and transcriptional control domains. Results in changes in gene transcription and protein synthesis.

Agonists:
Have affinity and efficacy
Curve is S-shape and shows increased response for increased concentration (note decrease of –log concentration along x axis = increase in concentration along axis). Concentration is not to be interpreted as dose, as dose refers to an entire organism whilst many of these curves are from organs/tissues bathed in solution of drug.
Organ bath - removes ADME process, tissue is suspended in bath of solution.

EC50 (effective concentration at which response is 50% of maximum) or pD2 (-log EC50) is a measure of potency. The lower the EC50 or the higher the pD2¬, the more potent a drug is.

Antagonists:
Concentration-response curves show agonist at varying concentrations in the presence of fixed concentrations to antagonist. Antagonism can be competitive (reversible or irreversible) and non-competitive.

Competitive reversible - antagonist competes directly with the agonist for the receptor. Shows a parallel rightwards shift of concentration-response curve. No depression in maximal response, but maximum response requires a larger agonist concentration than with agonist alone.
pA2 - measure of antagonist potency. The –log concentration of antagonist which causes a two-fold shift in concentration response curve (visually not great as x axis in log scale). When EC50 of a given concentration of antagonist is known, pA2 can be calculated
pA2 = pAx + log (x-1) where x = EC50 with antagonist/EC50 without antagonist, and pAx is the –log concentration of the antagonist.

Competitive irreversible (sometimes referred to as orthosteric, irreversible or non-competitive) - antagonist competes directly with agonist for binding site, but binds with greater affinity (often covalent). Because of their strong binding, competitive irreversible antagonists are not favourable as drug therapies (effect is only reversed when patient produces new receptors). They cause a non-parallel rightwards shift in the concentration response curve. Often, the maximal response can nearly be reached with high enough concentration of agonist (theoretically it can sometimes reach 100%). The spare receptor theory suggests that not all receptors need to be occupied for 100% response to occur.
pD2’ (note use of ‘) is the measure of potency and is the concentration of antagonist required to decrease the maximum achievable response to 50% of the maximum response without antagonist. The higher pD2’ is, the more potent the antagonist.

Non-competitive antagonism - the antagonist does not bind to the agonist-binding site. Interferes instead with the cascade of events resulting from agonist binding. Causes a non-parallel rightwards shift in concentration-response curve, with a lower maximum response. Potency is measured as pD2’. Calcium channel blockers, such as verapamil are an example. These bind to the channels and stop signals from other receptors (for noradrenaline, histamine, angiotensin etc) from opening the channels.

Physiological antagonism - two agonists working at different receptor types have opposing actions e.g. Histamine at H1 receptors cause bronchorestriction and adrenaline at β1 receptors cause bronchodilation.
Partial agonists - have affinity but have an efficacy < 1. Can act as antagonists to full agonists (with an efficacy of 1).
Note in graph that at higher concentrations of agonist, the partial agonist limits the response by occupying receptors.

Inverse agonists - some receptors have constitutive activity and ligands which show a preference for binding to the resting state can shift the equilibrium of receptor states towards resting. The concentration-response curve is the same as that of a competitive reversible antagonist.

Receptor regulation:

Receptor state changes (desensitization) – rapid, pronounced desensitization of metabotropic receptors.
Can be homologous e.g. of β1 adrenoreceptors. The binding of agonist remains the same, but it is unable to activate adenylate cyclase. This is due to beta adrenoreceptor kinase (BARK) which phosphorylates a serine residue, stopping normal binding with the G protein.
Can be heterologous e.g. PKA and PKC, where activation of one receptor desensitizes another.

Receptor population changes (occur over a time period of at least days as involves slow changes in transcriptional control).
Chronic agonist administration can lead to down regulation of receptors. Receptors are internalised by the cell and possibly destroyed. Receptor production is decreased too. Chronic salbutamol causes this, resulting in a decreased bronchodilation effect.
Chronic antagonist administration can lead to up regulation of receptors. Chronic propranolol can cause increased synthesis of β1 receptors in the heart and the antagonist has a reduced effect (heart rate and blood pressure increase again).
This is the reason behind tolerance. Drug dose needs to be increased to produce the same effect. In the case of morphine, increasing dose increases the dangers of respiratory system depression and addiction. Adverse effects are increased – chronic haloperidol (antipsychotic) is a D2 antagonist. Striatal D2 receptor levels are increased and over months-years tardive dyskinesia (uncontrolled movements) develops.
Some drugs take time to show therapeutic effects e.g. tricyclic antidepressants which take 2-4 weeks due to the down-regulation of β and α2 adrenoreceptors and 5HT2 receptors.


Non-receptor mediated drug action - not all drugs act directly at receptors e.g. drugs which modify the synthesis, storage or release of neurotransmitters (amphetamine), drugs which act at non-receptor targets such as enzymes, carrier proteins and ion channels.

Enzyme targets - NSAIDS target cyclooxygenase (COX) and are used to treat pain and inflammation. ACE inhibitors target angiontensin converting enzyme and are used to treat hypertension.
COX has two forms, COX 1 and COX 2. Its action is important in the release of various prostaglandins and a thrombotic. NSAIDS inhibit both COX 1 and COX 2 decreasing inflammation, pain and fever, but also reduce homeostativ pathways involved in kidney function and maintenance of the stomach wall. Use of aspirin and voltaren can lead to ruin of the stomach lining, ulcers and bleeding. COX 2 selective inhibitors such as rofecoxib and celecoxib are much safer with the stomach, but have other adverse effects such as renal COX inhibition. They also upset the balance between PGI2 and PGD2, resulting in platelet aggregation and increased risk of heart attack.
Carrier protein targets – good examples are drugs which act on monoamine neurotransmitter uptake proteins. Fluoxetine (Prozac) blocks the reuptake of 5HT from the synapse. Levels of 5HT in the synapse increase and post-synaptic receptors have increased occupation by 5HT. Depression is thought to result from decreased 5HT, so increasing synaptic 5HT has an antidepressant effect.

Ion channel targets - local anaesthetics block Na+ channels as these are important in nerve impulse conduction. This prevents pain signals from reaching the brain. Antiepileptic drugs dull overactivity of the brain in the same way. Some toxins are Na+ channel blockers e.g. that of the puffer fish.
Ca2+ channel blockers (verapamil, niphedipine) are important in muscle cells (predominately cardiac and smooth, not skeletal).

Drugs which modify neurotransmitter synthesis, storage or release – mostly affects monoamine NTs which are synthesised, stored in vesicle and taken up by uptake proteins back into the nerve terminal.
Synthesis is affected by L-Dopa which increases precursor and thus increases dopamine synthesis (alleviates symptoms of Parkinsons).
Storage is affected by reserpine which prevents storage of NTs, decreasing levels of NT able to be released.
Release is affected by guanethidine and amphetamine which push NTs out of storage vesicles so that vesicles are empty when they are released.
Drugs which are agonists at noradrenergic receptors (NA receptors) are said to be direct-acting sympathomimetics (mimic noradrenaline and activate the sympathetic nervous system). Drugs such as amphetamine which result in the endogenous release of noradrenaline are said to be indirect-acting sympathomimetics. Reserpine treatment can be used to distinguish the two - if the drug has indirect action, there won’t be noradrenaline in vesicles and no action will result. If the drug has direct action, the drug will act on receptors and continue to have an effect in the presence of reserpine.
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Noir
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Tim...wikipedia isnt a valid source lol
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Tim
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Huh? O.o Where on wikipedia did you get this? :o
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Noir
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It twas a joke..it just looked like a wikipedia article..
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Doggo Champion 2k17
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Holy crap. One of my friends wants to be a pharmacist, but I've never understood why.

... I still don't understand. :p
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Tim
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Autonomic Nervous System

An involuntary part of the nervous system which relays information to internal organs. It links to the parasympathetic nervous system (controls organs in times when body is at rest) and the sympathetic nervous system (controls organs in times of stress).

Anatomy

Parasympathetic - pre-ganglionic fibres leave the CNS in cranial nerves and sacral spinal roots. Post-ganglionic neurons usually lie close to or within the target organ.

Sympathetic - pre-ganglionic fibres leave the CNS in thoracic and lumbar spinal roots. Post-ganglionic neurons form two paravertebral chains on either side of the spinal cord, plus midline ganglia.

Function

Parasympathetic - accumulation, storage and preservation of resources; rest and digest. v heart rate, ^ GIT activity, pupils constrict, glands secrete.

Sympathetic - prepares the body for strenuous activity, stress emergencies; fight or flight. ^ heart rate, v GIT activity, ^ blood flow to skeletal muscle, v blood flow to skin and visceral organs, ^ glycogen and lipid breakdown, pupils dilate.

Neural Transmission:
- The junction of an axonal ending with another nerve cell (neuron), a muscle cell or a glandular cell is called a synapse.
- Neurotransmitters are synthesized and stored in vesicles in the nerve terminal and then released into the synapse.
- Transmitter action must then be terminated by either metabolism or transport of the transmitter back into the nerve terminal for recycling.

General mechanism of a synapse:
- A precursor is transported into nerve terminal where specialised enzymes convert it into the transmitter.
- The transmitter is transported into synaptic vesicles where it is stored until release.
- When an action potential reaches the terminal, the nerve ending becomes depolarised by an influx of calcium.
- This causes the vesicles to fuse transiently with the cell membrane and discharge their contents.
- The transmitter diffuses into the synapse where it acts at both post synaptic recepters and pre-synaptic receptors. Most commonly the presynaptic receptors act as an autoinhibitory feedback loop, leading to the hyperpolarisation of the terminal that inhibits further transmitter release.
- Transmitter action must be termination. Two common mechanisms: either enzymatic degradation to give a degradation product that can be recycled or the transmitter is transported back into the nerve terminal.

There are 10 potential places for a drug to act to change the normal events of synaptic neurotransmission.

Chemistry

Parasympathetic - Acetylcholine is the neurotransmitter in both the pre and post ganglionic neurons. Pre-ganglionic has nicotinic receptors. Post ganglionic has Muscarinic receptors.

Sympathetic - Pre-ganglionic uses acetylcholine with nicotinic receptors. Postganglionic it uses noradrenaline, exception being sweat glands which uses aAch. Receptors are alpha 1 and 2 and beta 1 and 2.

Neuromodulation:
- describes the effects of other chemical mediators on synaptic transmission.
- mediators act to increase or decrease the efficacy of synaptic transmission without participating directly as a transmitter.
- generally involves slower processes (sec to days) than neurotransmission (msec).
- occurs pre-synaptically and post-synaptically.

Pre-synaptic modulation:
- Homotropic presynaptic inhibition: the transmitter acts on a presynaptic receptor to inhibit its own release - autoinhibition.
- Heterotropic presynaptic inhibition: another transmitter acts on a presynaptic receptor to inhibit the release of a second neurotransmitter.

- Paresynaptic and postsynaptic receptors are pharmacologically distinct in the NA and cholinergic systems.
- Specific agonists and antagonists can distinguish between pre and post-synaptic receptors.
- Many other chemical mediators influence noradrenergic or cholinergic signaling

Postsynaptic modulation:
- Chemical mediators influence postsynaptic receptos to alter excitability or cell firing.

Non-adrenergic, non-cholinergic (NANC) tranmission:
- Drugs that abolish the responses to ACh and NA do not completely block autonomic neurotransmission.
- Suggests existance of other transmitters - NANC
- Non-peptides, eg ATP, nitic oxide (NO)
- Peptides, eg Neiropeptide T (NPY, vasoactive intestinal peptide (VIP)

Cotransmittion:
- nerve terminals may store and release more than one neurotransmitter, eg ATP & NA
- functional advantages - can elicit differences in response time and duration of effect.

I think i'll leave it there. Only 30 minutes until my test and still got 3-4 lectures to summarise into this so im better off just reading it over :)

Hope you guys enjoyed a brief read into pharmacology :D

~Tim
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Sam
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It takes a mere second for treasure to turn to trash.

...wut.

Tim, what the hell?

Also, please edit your posts instead of double posting. :p

And ... oh yeah! I can do that too! Except with carnivorous plants! And World of Warcraft: Wrath of the Lich King tanking styles! So uh... yeah.
WoW Legion Ending - Thank you Darker for making this into one, big incredible gif! <3
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Tim
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I thought the posts were too long to be in one? I may have been mistaken :p
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Spirit
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Hmmm! This is good stuff and I know ownage when I see it.


I just really hope you didn't copy and past any of lol
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Tim
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Spirit
Sep 12 2011, 06:47 AM
Hmmm! This is good stuff and I know ownage when I see it.


I just really hope you didn't copy and past any of lol
I copied and pasted from my notes? :p

Except for the last one, that one I typed directly into the thread :3
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+ Rebel X
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Those look like my notes, stop showing off

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