Categories of Medicines and their actions. Natalie Craythorne 1st February 2013
Aims for today • To know what a drug is and how they are classified • To understand where drugs come from • Be able to explain the “lock and key” and induced fit hypotheses • To define pharmacodynamics and pharmacokinetics
What is a drug? In simple terms a drug is; A substance that has a physiological effect when administered into the body. However, some drugs are actually found occurring naturally within the body. Inside the body they are known as endogenous substances and when introduced to the body they are known as drugs. Example?
Where do they come from? • Drugs are either naturally derived and come from • Animals • Fungi • Bacteria • Plants • Or they are synthetically made in the laboratory
Animals • Insulins and Incretin hormones from pigs, cows and reptiles or in fact humans • Anti-venom – derived from the venom of snakes and scorpion • Heparin – an anti-coagulant derived from pig intestines • Premarin – derived from mare urine to treat menopause • Snake and Scorpion venom – use to treat cancerous tumours
Plants Can you identify the drug from the plant? • Sallixspp - Aspirin • Coca – Cocaine • AtropaBelladona - Atropine • Digitalis purpurea - Digitoxin • Cinchona succiruba – Quinine • Papaversomniferum - Heroin and morphine • Heveabrasiliensis - Latex
Fungi, Bacteria and viruses • Some of the most famous drugs are derived from Fungi, bacteria and viruses including • Penicillins- used as antibiotics • Statins – used to treat high cholesterol • MMR vaccine • Live attenuated influenza vaccine • Some hormones are made from transgenic bacteria • Botox – derived from Clostridium botulinum
Minerals • A mineral is a naturally occurring substance that is solid and stable at room temperature. • Some examples are; • Iron (Fe) – used to treat anaemia • Gold (Au) – used for rheumatic disease and as an anti- malarial • Bismuth (Bi) – to treat gastric ulceration • Lithium (Li) – prophylactic treatment of mania • Silver (Ag) – commonly used antibacterial (more of a therapeutic agent)
Drug classification There are many ways in which to classify drugs. Some of the more common are by; • Chemical name or properties • Route of administration • Therapeutic effects • The biological system affected. • For example, N-acetyl-p-aminophenol is paracetamol of brand name calpol which is an analgesic.
WHO ATC classification system • The World Health Organisation’s Collaborating Centre for Drug Statistics methodology controls the Anatomical Therapeutic Chemical (ATC) Classification System • It divides drugs into different groups according to the organ system on which they act and/or their therapeutic and chemical characteristics.
How the system works • Pick a common drug, one of the penicillins for example, Co-Amoxiclav. • J – General Anti-infectives for systemic use • 01 – Antibacterials for systemic use • C – Beta-lactamantibacterials • R – combination of penicillins • 02 – Amoxicillin and enzyme inhibitor clavulanic acid. • So, the code for co-acmoxiclav is J01CR02.
Further Classificaiton and labelling • POM - prescription only medicine can only be obtained with a paper prescription from a registered prescriber eg, antidepressants • CD – Controlled Drugs are kept in the safe and are only dispensed with a hand written paper prescription eg, Ritalin or Morphine • P – Pharmacy medicines can only be purchased with the consent of a pharmacist eg, 32 paracetamol tablets. • OTC – Over the Counter medicines eg 16 paracetamol tablets.
How do drugs work? • Pharmacokinetics is the study of what the body does to medicinal substances • Pharmacodynamics is the study of what the medicinal substance does to the body. • Pharmacokinetic properties of medicinal properties include things like drug half-life, absorption rate and elimination rate. • Pharmacodynamic effects would be either side effects or simply expected effects.
Antagonist or Agonist • An antagonist is a substance that does not illicit a response in the body when administered. • An agonist is a substance that illicits a response when administered.
Opioids • There are three opioid receptors mu, kappa and delta. • When activated by an agonist a response takes place such as euphoria, pain relief or constipation eg, immodium, co-codamol or morphine. • If occupied but no response takes place it is antagonistic eg, naloxone.
Induced fit explained • The induced fit hypothesis proposes that the interaction between enzyme and substrate is weak but the induction of conformational change in the enzyme makes it stronger. • It can be seen from the diagram that the active site is not a perfect fit for the substrate but it does change over time before releasing the products.
Lock and Key hypothesis explained • The lock and key hypothesis is more of a tight fit than the induced fir model. • The substrate fits into the active site perfectly like a key into a lock. • Sometimes substrates will use co-factors. • A cofactor is an organic or inorganic substance used to help the substrate fit. • They are often called helper molecules.
Inhibition EI complex and EIS complex are non-productive. The possible outcomes are EI, ES and EIS.
Inhibition explained • Inhibitors are either reversible or non-reversible such as cyanide. • Competitive inhibitors - there is competition for the active site where an increase in drug may out compete the inhibitor eg, penicillin • Non-competitive - there is no competition for the active site but enzymatic function is affected. The inhibitor binds to a site other than the active site (allosteric site) and changes the conformation of the enzyme eg, heavy metals • Uncompetitive - where there is no competition for the active site because the substrate is bound.
Routes of Administration Can you identify theses routes of Administration??? • The route of administration is very important when considering pharmacokinetics as it can affect absorption rates, elimination and bioavailability. • There are many routes of delivery including; But, why so many routes?
First Pass • Some drugs have poor oral bioavailability ie, not a lot of the drug is utilised. • This is due to the first pass metabolism • When ingested the drug is taken from the gastrointestinal tract via the hepatic portal vein to the liver where it is metabolised. • The drug is then distributed through the systemic circulation but at a reduced concentration.
Routes of Administration explained • Looking back to our slide about routes of administration and the previous slide on first pass metabolism it gives a clue as to why there are so many routes. • Some routes are not acceptable for certain drugs • This may be down to their properties or structure, bioavailability or side effects.
So, what happens then? • We must think of the following four letters A for absorption D for distribution M for metabolism E for elimination or excretion • There are a few other words we should learn • Dose and Dosing interval – very important!! • Bioavailability • Volume of distribution • Elimination rate and half-life • Clearance
Absorption • Absorption is the movement of a substance or drug into the bloodstream • It follows all routes of administration other than intravenous as it is being introduced to the bloodstream • The fastest route of absorption is by inhalation. • Food, other drugs, rate of gastric emptying and pH can affect absorption.
Distribution • Distribution is the reversible transfer of drug from one location to another within the body. • The distribution of a drug is dependent on blood flow, pH partition and the ability of the drug to bind to plasma proteins and tissue • In highly perfused organs such as the liver drugs are easily distributed. • The volume of distribution of a drug is a way of quantifying the extend of distribution.
Metabolism • Is the biochemical modification of substances by living organisms such as enzymes. • It often converts lipid soluble substances to more easily excreted water soluble products. • Metabolism is mostly carried out by enzymes called cytochromes. • Metabolism is important when figuring out dosage regimes and therapeutic index. • The substances are modified in order to be excreted. However some are metabolised into more active species.
Therapeutic index ED50 is the dose that is effective in 50% of the population and TD50 is the toxic dose in 50% of the population. The therapeutic index is the ratio of lethal dose/therapeutic dose.
Dosing Intervals for antibiotics The dosing interval is the time between administration. For example three times daily would indicate that there should be 8 hours between doses. MIC stands for minimum inhibitory concentration, ie the minimum concentration of antibiotic that can be used but still maintain its therapeutic inhibitory effect.
Cytochrome P450 • CYPs are the major enzymes involved in drug metabolism and bioactivation, accounting for about 75% of the total number of different metabolic reactions. • Over 11,500 of the cytochrome proteins are known to exist. • They are numbered and lettered and responsible for the metabolism of many drugs
Things that can effect drug metabolism • Alcohol – Induces the action of CYP2A1 which metabolises paracetamol. • Tobacco – is an inducer of CYP1A2 meaning it makes CYP1A2 more active. • Grapefruit juice – Inhibits the CYP3A4 cytochrome. • St John’s Wort – Inhibits and induces several CYPs including CYP3A4 meaning that many drugs will linger in the system or be metabolised too quickly. This includes oral contraceptives. • Peppermint Tea – a strong inhibitor of CYP1A2 responsible for paracetamol metabolism...who knew!!!
Differences between individuals • Age • Sex (hormonal) • Weight • Kidney function • Liver function • Pregnancy • Dependencies ie, nicotine or alcohol.
Differences in individual metabolism • Metabolism can be affected by genetics • There are liver enzymes called cytochromes which are used in metabolism. • Differences in CYP2E1 are the reason why some races do not process alcohol as well as others. • CYP2E1 metabolises alcohol. • In asian, korean and chinese populations 80-100% of people have a polymorphism associated with alcohol metabolism • 50% of those people have another gene variant on top of this. This means they are more effective at alcohol metabolism than Caucasian and African populations.
Excretion • Drugs are excreted or cleared through the kidneys and liver via urine. The urine may contain the metabolites and or original unchanged drug. • The three main sites of excretion are urine, feaces and breath • Drug can also be excreted through sweat, milk, saliva and hair. • If excretion is incomplete drugs can accumulate and become toxic.
What should we look out for? • We must refer back to our letters, remove the M and think about our bodies. ADE stands for Adverse Drug Events • ADEs can be anything from gastrointestinal upset and headaches to death and blood disorders. • A classic example where serious adverse effects were observed is Thalidomide. This is now being used to treat cancer!!!
Adverse drug events • These can be very serious, as seen with Thalidomide. • Even something as simple as an increase in bruises can be very serious. • Pharmacies carry yellow forms that we can report these events on. They are taken very seriously. • However, most ADEs are picked up on during clinical trials.
But...we don’t always need drugs!! Headache Remedies • If it is bearable or you simply take for prophylactic reasons please do not!! • It is a little known fact that the more you take the more headaches you can get....scary? • It is called medication-induced headache and is the third most common type of headache. Antibiotics • We need dirt! • Overuse and misuse of antibiotics has led to widespread antibiotic resistance. • Bugs decide they no longer want to respond and so diseases like MRSA become more prevalent. • This is why we culture bacteria.
To Conclude. • Drugs undergo very thorough and lengthy testing before coming on the market • Without them the world would not be the same and we would suffer for it. • Always think about how it works and how is doesn’t, ie lock and key/induced fit, agonist or antagonist and inhibitors. • Remember your lettering systems. ADME and ADE • Abuse of prescription medicines is just as serious as illegal drugs and is increasingly more common.