Pharmacology.docx

Drugs bind to cells to give an pharmacological effect The drug binds to a ‘target’ protein The types of drug targets are commonly: -Receptors -Enzymes -Transport Proteins -Ion Channels AGONIST When an agonist drug binds, it causes an activation of a receptor Affinity -How likely a drug is to bind to...

Drugs bind to cells to give an pharmacological effect The drug binds to a ‘target’ protein The types of drug targets are commonly: -Receptors -Enzymes -Transport Proteins -Ion Channels AGONIST When an agonist drug binds, it causes an activation of a receptor Affinity -How likely a drug is to bind to a receptor -High affinity would mean a low concentration is needed for an effect Efficacy -How likely the drug is to activate a receptor when bound -High efficacy means a low amount of bound drug gives a physiological effect Antagonist Drugs Drug that binds to the receptor but may or may not cause a physiological effect and also reduces the effect of the agonist at the receptor. Reversible Competitive Antagonism/ Physiological Antagonism -Physiological mediator/drug binds at same receptor as agonist drug -If agonist concentration increased, can overcome blockade -Eg, salbutamol and noradrenaline Salbutamol- β2 adrenoceptor Agonist drug- Acts in airways- Causes vasodilation and relaxation of smooth muscle by hyperpolarization -Noradrenaline- Non-Selective β Agonist- Acts on all β adrenoceptors- Causes vasoconstriction and contraction of smooth muscle by increased Ca flux -If salbutamol concentration high enough, will overcome noradrenaline. Asthmatic patients require this Irreversible Competitive antagonism -Antagonist binds at same receptor as agonist -Drugs form a covalent bond, difficult to break- Produce long lasting effects -Even if agonist concentration increases, still has no effect- Decreases the number of available receptors -Very rarely used in clinical practice- Mostly in receptor classification experiments Irreversible enzyme inhibitors are more common -Eg, MAOIs (phenelzine, tranylcypromine, iproniazid etc) used to treat depression PHARMACOKINETICS - The study of the time course of drugs and their metabolites Administration- Delivery of drug Absorption- Movement of drug across membranes Distribution- Description of the movement of drugs between different body compartments Metabolism- Chemical alteration of the drug Elimination- Transfer of the drug from inside the body to the outside ADMINISTRATION Available Surfaces: ▪Oral- Swallowed ▪Buccal- Oral Mucosa ▪Sub-lingual- “Under the tongue” ▪Skin (topical) ▪Lungs ▪Nose ▪Eye ▪Ear ▪Urethra ▪Vagina ▪Rectal If no surface available, make one: ▪Intramuscular ▪Intravenous ▪Subcutaneous Intradermal Intrathecal (spinal) ▪Intraperitoneal (abdominal cavity) ▪Intra-arterial ROUTES OF ADMINISTRATION Oral + Easy, cheap and convenient + Low infection risk + Painless - Exposed to GI tract - First Pass metabolism - Loss through vomiting Intravenous + Fast delivery to site + Avoids GI exposure + Avoids First Pass, increased bioavailability - Reversibility? - Infection Risk - Pain/Fear Factor - Administration by trained person Lungs + Fast action- Why? -Thin walls between alveoli and capillaries -High surface area + Good point of entry - Effects can be systemic, eg tremor from salbutamol Transdermal + Long term, continuous + Avoids GI Tract and First Pass + Painless, convenient and easily administered - Skin irritation? - Drugs need to be lipophilic to cross tissues BIOAVAILABILITY-Used to define how well a drug is absorbed and reaches its site of action. History of Medicine -The Industrial revolution increased wealth in Britain as well as the prevalence of certain diseases. However, it also helped develop better understanding and treatment of many diseases thus forming the basis of Modern Medicine. -200 years ago, little was known about what diseases were, where they came from or how to treat them. Smallpox (variola virus that produces pus filled blisters / pocks), Typhus (rickettsia bacteria carried by lice) and Tuberculosis (mycobacterium tuberculosis; consumption) were major killers. Increased population density increased disease prevalence but the reasons weren’t known. In the mid-18th century, the life expectancy was only 36 years. Due to the lack of medical knowledge people developed their own methods, such as bloodletting, to treat their disorders. Medical entrepreneurs (at the time were often referred to by the term ‘Quacks’ such as Joshua Ward (1684-1761) made money by developing untested (often dangerous) medicines – some contained arsenic. Dr William Withering (1741-1799) from Shropshire extracted Digitalis from foxglove plants after observing that herbal tea prepared by travellers could cure Dropsy (oedema due to congestive heart failure). He did this by conducted careful drug discovery experiments that took 10 years to complete. Overcrowding in prisons caused high frequencies of Typhus, known as Jailhouse fever, and TB. Hales believed that bad air caused the problem so he developed a ventilation system which reduced prison deaths by 50%. It was discovered later that Typhus was passed on via flees. Lord Anson (1697-1762) observed that about 50% of his crew died of Scurvy during a long voyage. Scurvy (due to vitamin C deficiency) causes loss of teeth, skin soars and death by heart failure. James Lind (1716-1794) conducted a controlled clinical trial (1747) tested if cider, seawater, nutmeg/garlic, vinegar, oranges or lemons could treat scurvy. Oranges and lemons worked within a week. Unfortunately, the navy ignored his work for over 40 years and many lives were lost. Several gasses were discovered in the 18th century. Oxygen was discovered by Joseph Priestly. Nitric oxide was also discovered and became the first form of General anaesthetic. In the 1790’s Edward Jenner (1749-1823) developed a treatment of Smallpox. He noticed that milk maids did not develop smallpox, however, they did get infections from cows that had cow pox. He also learned that groups of Turkish people organised ‘smallpox parties’ in which they inoculated children with small doses of smallpox to prevent the children developing the disease. Jenner inoculated an 8-year-old child called James with cowpox (1796). Two months later he tried to infect the child with smallpox, but the boy was immune (first vaccination) At one stage 10% of all European deaths were due to smallpox. Due to Jenner’s work smallpox has now been eradicated world-wide. Workplace illnesses also become increasingly common due to long hours and poor / dangerous working conditions. Mill workers developed a lung disease Byssinosis caused breathing in the dust from raw cotton and cancer of the lips or groin from oils. In the 16th and 17th centuries there was a shortage of bodies for medical training. The main sources of corpses were from the Gallows or from grave robbing. However, the 1832 Anatomy Act enabled the bodies of people who died in poverty to be used for teaching anatomy. This significantly increased progress in understanding diseases and the effects on the human body. • Pharmacology is the study of how drugs affect the function of the bodies tissues or combat infectious organisms: ~ for drugs to act they must be Absorbed and Distributed ~ drugs are also Metabolised and Excreted • The rate of drug absorption depend on: ~ route of administration & local blood flow ~ solubility & ability to cross membranes ~ most drugs absorbed by passive diffusion • Bioavailability refers to the amount of drug that, once ingested (or administered), is absorbed into the bloodstream: ~ the time course of drug action follows the time course of its concentration in blood plasma / bioavailability ~ the fall in drug activity is due to the rate of a drugs elimination via metabolism and / or excretion) Intramuscular (im) and subcutaneous (sc): ~ im and sc often used as they have faster effects than the oral route and are safer than intravenous (iv) ~ sc implants of oestrogen-progesterone pellets for birth control give prolonged hormone release Intravenous (iv): ~ drugs can be injected rapidly or infused slowly into a vein Speed of iv injection is important: ~ if rapid onset is required (adrenalin) ~ good control of drug levels needed (cytotoxic drugs) Slow iv infusions give better control over plasma levels: ~ requires an implanted catheter to deliver the drug ~ cytotoxic drugs can damage blood vessels • Volatile drugs / gaseous anaesthetics are absorbed by lungs: ~ large surface area and good blood supply give very rapid equilibration between plasma and alveolar air ~ rapid systemic effects are achieved • Drugs intended for direct action may be inhaled by the lungs: ~ bronchodilators for asthma (salbutamol) • Drugs of abuse: ~ smoking (nicotine, cannabis, cocaine) • Used for topical effects, but systemic effects may also occur • Percutaneous absorption and transdermal patches: ~ steroid creams / oestrogen for HRT ~ hyoscine patches for travel / nicotine patches for smokers ~ nitroplasters for angina • Nasal sprays ~ anti-diuretic hormone • Eye drops ~ cyclopentolate