Medicinal chemistry Option D Part 1

What are drugs and medicines? What is the difference between a drug and a medicine? What is a pharmaceutical? List different types of medicines. What is a therapeutic effect? What is a physiological effect? How are new drugs developed?

Pharmaceutical products A medicine or drug (pharmaceuticals) is any chemical that does one or more of the following to the human body: Alters the physiological state (=how it functions) of the body, including consciousness, activity level or coordination alters incoming sensory sensations alters mood or emotions There is a variety of different effects of medicines and drugs. These effects are often also used to classify the medicines (good) and drugs (good or bad) .

Pharmaceuticals products Physiological = to do with the functions in living organisms; physiological effects = effect on the functioning of the living organism

Physiological effect: drug-receptor interaction A drug achieves its therapeutic effect as its molecular structure allows it to bind (through ionic bonding, hydrogen bonding or Van Der Waal’s forces) with a receptor e.g. a protein molecule such an enzyme or a cellular receptor such as a cell membrane. The binding prevents or inhibits the biological activity (e.g. enzyme activity) that allows the disease to develop. The receptor part in the molecule or cellular structure is referred to as the site of activity.

Drug receptor interaction

Stages in development of a drug Identify disease, could be new disease. Identify target e.g. gene or enzyme which is necessary for disease to progress. Identify ‘lead’ molecule which can act on gene/enzyme in the disease organism or host and isolate or manufacture it. May need to be modified. Preclinical trials: testing of ‘lead molecule’ in laboratory, ‘in vitro’: the lead molecule is tested on animal/human cells and tissues which have been removed from the body and are kept in an artificial environment. ‘in vivo’: testing in live animals (usually 3 different species) to establish LD50 which is the amount which kills 50 % of animal population.

Stages in development of drug Clinical trials: on humans!! Testing of its effectiveness and dose range on humans using the placebo effect. This is a ‘blind trial’ in which half of the people/patients involved are given the drug whilst the other half are given a similar substance which is not the drug but none of the patients or even administrators know which half they are in. All patients should/could experience placebo. Structural modifications likely to be made to, for instance, improve effectiveness or reduce side-effects. Submission of reports on drug and its trials to regulatory bodies. Monitoring of the drug after it has been launched; molecule might need further structural changes; new side-effects e.g. thalidomide.

Name different ways in which drugs are administered? Why are drugs administered in a particular way? Give advantages and disadvantages of some of the methods you have answered.

Administering drugs (1) Oral: taken in by the mouth e.g. tablets, syrups, capsules - advantages and disadvantages? Parenteral - by injection: for fast delivery !!! intravenous: into a vein of the blood stream – used for immediate impacts as its fastest method; drug is immediately pumped around the body by the blood, e.g. anaesthetic. intramuscular i.e. into the muscles, e.g. many vaccines, antibiotics, usually used when a large dose needs to be administered. To act locally. subcutaneous: in the layer of the skin directly below the cutis (dermis and epidermis) e.g. dental injections, morphine, insulin. Slow absorption and effect.

Oral Advantages Disadvantages Easily taken No specialist equipment needed Can be destroyed by stomach acid Slow to have an effect Can cause stomach bleeding or vomiting Only small amount of drug is absorbed Patient needs to be conscious Kids????

Parenteral administration

Parenteral administration

Administering drugs (2) Inhalation: e.g. medication for respiratory conditions such as asthma. Rectal: inserted into the rectum e.g. treatment for digestive illnesses, drug absorbed into the blood stream. Transdermal: Skin patches: e.g. hormone treatments. Topical, on the skin and in eyes/ears e.g. creams, eye drops, ear drops, …

Factors to consider when administering drugs Discuss the following terms: dosing regime addiction tolerance therapeutic effect side-effects therapeutic window

Terms Dosing regime = the amount of drug used for each dose i.e. how much drug should be taken at one time and how often (amount + frequency e.g. 1 tablet a day) to obtain desired therapeutic effect. Target is to achieve safe, constant and most effective level in blood. Tolerance Tolerance refers to the body’s reduced response to a drug i.e. its therapeutic effect is less than what it is intended, usually as a result of taking the drug over a long period of time. As a result more of the drug needs to be taken to achieve the same initial physiological effect with the danger of exceeding the lethal dose. Can lead to addiction.

Addiction Physical dependence. A condition that occurs when a person needs the drug just to live normally and shows withdrawal symptoms when not taking the drug.

Therapeutic window and index The therapeutic window is the range in the amount or concentration of the drug in the blood over which a drug can be safely administered to a typical population. It is the range of dosage between the minimum amount that produces the therapeutic effect (=effective dose) and the maximum amount that produces a medically adverse effect.

Therapeutic index The therapeutic window can be expressed quantitatively as a ratio called the therapeutic index. This index can have a different definition depending on whether the it is obtained in an animal study or in humans trials. A measure of the safety of a drug – how?

Therapeutic index In animal studies, the therapeutic index is the dose of a drug that is lethal for 50% of the animal population (LD50) divided by the minimum effective dose for 50% of the population (ED50). TIanimals = LD50/ED50. In humans, the therapeutic index is the dose of a drug that is toxic (undesirable effect) for 50% of the human population (TD50) divided by the minimum dose that has the therapeutic effect (=effective dose) for 50% of the population (ED50). TIhumans = TD50/ED50.

Large therapeutic index Wide therapeutic window Low effective dose (ED50) and larger toxic dose (TD50) as a result there is a big difference between effective and toxic dose. For more common and minor diseases. Can be bought without doctor prescription. Safe to take in high doses Example: if TI is 60 then the patient can take 60 times more then the prescribed amount.

Low therapeutic index Small therapeutic window Small difference between effective (ED50) and toxic dose (TD50). Usually because toxic dose is low. Correct dosage is important. Only used for serious conditions. Administered by qualified personnel. Overdose is a high risk/low margin of safety

Therapeutic window (3) – dosing regime Depends on: Type of drug Age Sex Weight of patient Diet Environment Activity of patient Bioavailability of drug

Bioavailability What is it? What effects it?

Bioavailability Bioavailability of a drug is the fraction of the administered dosage that reaches the target cells in the human body (sometimes also just the blood). 
 Bioavailability depends on how much drug is broken down by chemical reactions (e.g. in stomach) or how well it dissolves and is therefore affected by: Functional groups: e.g. acid or basic groups affect the pH of the environment and that can affect reactivity and solubility of the drug. Polarity of the drug molecule: polar molecules dissolve well in aqueous environments whilst more non-polar drug molecules dissolve better in lipids. Method of drug administration: e.g. intravenous is 100 % bioavailability whilst orally taken drugs could have a bioavailability of 40%.

Side effects beneficial e.g. protect against heart disease. Side-effects = physiological effects which are not intended and therefore undesired (intended = therapeutic effects); these could be: beneficial e.g. protect against heart disease. benign e.g. causing drowsiness, nausea constipation. adverse i.e. causing damage to other organs – should only be administered by qualified staff  

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