13.1 Introduction 13.2 Key Stages of Drug Development 13.3 Discovery and Development of Aspirin 13.4 Discovery and Development of cis-Platin 13.5 Basic Structure and Chemistry of the Nervous System 13.6 Narcotic Drugs and their Adverse Effects 13.7 Stimulants and their Adverse Effects 13.8 Pros and Cons on Using Drugs 13 Drugs
13.1 Introduction Drug: any absorbed chemical substance that affects the body and its processes. • Medicines contain drugs that are used to cure and prevent diseases. • Some drugs are not medicines. • Prescription drugs • Non prescription drugs
13.2 Key Stages of Drug Development • lead compound discovery (Prototype) • molecular modification (Analog) • formulation development • safety tests and human trials, and • approval for marketing. Takes about 10 years 4000 (lab) 5 (human) 1 (approved)
H3+O 13.3 Discovery and Development of Aspirin Salicin from willow tree Salicylic acid the lead compound
Animal and clinical human trials of aspirin were successfully completed in 1899. • The drug was then formally approved for launching into the market. • Patent on acetylsalicylic acid became expired in 1917. • Aspirin then became a generic drug that could be manufactured and formulated by other pharmaceutical companies.
Acetylsalicylic acid formulated with • Caffeine • Mg(OH)2 and Al(OH)3 • Codeine
(a) (b) (c) Extraction of Acetylsalicylic Acid from Commercial Aspirin Tablets. Examples of drugs containing aspirin in the local market. (a) Contains only acetylsalicylic acid whereas (b) and (c) contain both acetylsalicylic acid and caffeine.
3 M NaOH • Extraction with dichloromethane water soluble layer Dichloromethane layer • Dry with anhydrous MgSO4 • Distil away dichloromethane solvent • 3 M HCl to pH ~ 3 • Cool in ice-bath • Filter out solid and wash with iced water Caffeine To be dried and weighed Purified test: TLC with solvent mixture 1-butylethanoate / enthanoic acid 4:1 (V/V)
13.4 Discovery and Development of cis-Platin Serendipity In the early 1960’s, When cis-platin was given to some implanted tumour cells in mice, to the surprise of the researchers, it was found that the tumours in the group of mice vanished entirely
Animal studies confirmed the success of cis-platin in curing tumours in mice, dogs and monkeys. • Human trials more successful for recently diagnosed cancer patients. • cis-platin was approved by the Food and Drug Administration of the United States at the end of 1978 for the treatment of genitourinary tumours. Today it is still one of the most widely used and successful drugs for the treatment of cancers of the neck, ovary and testes.
Action of cis-platin Cisplatin destroys the cancer cells’ ability to reproduce by changing the configuration of their DNA, it binds to two sites on a strand of DNA, causing it to bend about 33o away from the rest of the strand.
Formulation Development of cis-Platin • Combination of cis-platin with 5-fluorouracil to treat terminally ill colon cancer patients. • Synergistic or addition effect
13.5 Basic Structure and Chemistry of the Nervous System • Diagram of a human nerve cell.(12 billion, 1013 connections) • Diagram of a synapse(突觸間梢). When an electrical signal reaches the presynaptic nerve ending, neurotransmitter molecules are released from the vesicles(囊泡). These neurotransmitter(神經傳導物質) molecules migrate across the synapse to the receptor cell(受體細胞) where they fit specific receptor sites.
There are about 100 known neurotransmitters(神經傳導物質)in our body, each having a specific function. Some are aminies and many others are peptides. Some drugs act by mimicking the action of neurotransmitter, others act by blocking the receptor and preventing the neurotransimitter from acting on it.
13.6 Narcotic Drugs and their Adverse Effects • A narcotic(麻醉類藥物) is a drug • produces narcosis (stupor or general anaesthesia) • relief of pain • addictive Their use is regulated by law.
Opium(鴉片) and Morphine(嗎啡) • Morphine is 50 times as potent as aspirin in controlling pain. • Morphine and heroin act by binding to specific receptor sites in the brain that responds to endorphins(內啡太 /安多芬) / enkaphalines produces by our body.
Adverse side effects of morphine • Drowsiness • Constipation(便秘) and retention of urine • Excess morphine leads to slowing of breath and even coma • Development of dependence and tolerance
Heroin and Codeine Structures of morphine, codeine and heroin. The major skeleton is the same and the three structures only differ in the terminal moieties shaded.
The similar physiological and psychological actions of morphine, codeine and heroin can be explained by the possession of a similar T shaped 3-dimensional structure in their molecules. • Like a key fitting into a lock, this similarity in molecular structure enables the three opioid painkillers to bind onto the same receptor sites in the brain, thus exerting similar actions. These actions include alteration in the transmission of nerve impulses, changes in configuration of protein or effecting certain chemical reactions. All three drugs bind onto the receptor site by means of intermolecular attractions. In this case the greater potency of heroin when compared with morphine is explained by the closer fit of its molecular structure with the receptor site.
警方聯同衞生署藥劑師搜查藥房，檢獲千多支咳藥水，遏止青少年濫用藥物。警方聯同衞生署藥劑師搜查藥房，檢獲千多支咳藥水，遏止青少年濫用藥物。 Abusers The problems with the abuse of narcotics are typically related to the neglect of personal health and safety.
physical psychological Tolerance + Dependence Addiction Sharing of needles among abusers: transmission of HIV and hepatitis B and C
13.7 Stimulants(興奮劑) and their Adverse Effects • A stimulant is a drug that increases the activity of various parts of our nervous system. • It produces a temporary sense of alertness and well-being as well as relief from fatique. • It can be used to boost endurance and productivity as well as to suppress appetite. • Some stimulants can produce vivid illusions, fantasies and hallucinations.
Ketamine (氯胺酮, K仔) 一名少女在的士高玩樂「索K」猝死，該名少女與友人於的士高吸服「K仔」(氯胺酮) 約一小時後，突感頭暈並由友人攙扶離開，昏迷街頭，送院後證實不治。 • K, Ket, Kitty or special K. • Depression, nausea, impaired long-term memory and cognitive difficulties, impaired motor function, and respiratory plus heart problems. • Hallucinations of near-death experiences.
Phenylethanamine (苯基乙胺) Basic structure for a wide group of stimulant drugs.
Amphetamine 安非他命(冰) Appetite suppressant for weight control. Release of increased amounts of the neurotransmitter dopamine in the brain mood elevation
Ecstasy 狂喜 • In high energy activities, such as at dance parties. • Increase alertness (reduce fatigue), heighten concentration, decrease appetite, and enhance physical performance. They may also induce a feeling of well-being and euphoria. • Can cause stroke • Can develop tolerance and dependence
Lysergic Acid Diethylamide, LSD (Fing 霸) • The serotonin molecule can have several configurations owing to rotation of its C – C single bond. But only when it is in configuration (iii) that it is in the proper configuration to bind onto its receptor site in our body. • Note the part of LSD molecule shaded in grey. This is already in the proper configuration as (a) (iii) for serotonin without waiting for bond rotation. LSD can thus be considered as a modified form of configuration (iii) for serotonin molecule, that is always in an ideal configuration for proper binding with serotonin receptor sites in our body. • This explains why LSD molecule is active in our body in very, very small amount, i.e., has a high potency.
Hallucinogens (迷幻藥) like LSD distort visual and auditory sensations, bringing a state of happiness. • Produce impaired judgement, which can lead to dangerous decision making or accidents.
Cannabis 大麻 破大麻種植場 警方在新蒲崗破獲一個室內溫室種植大麻場。該溫室以太陽燈提供光線，在泥土中培植幼苗，而大麻則以水種，收成後大麻葉及大麻花以烘乾方式出售。 Illicit growth of cannabis saliva raided by police.
13.8 Pros and Cons on Using Drugs Many use of drugs to relieve pain, to fight infections, to stay awake, to get to sleep, to calm anxiety, to prevent conception, and to prepare the body fittness for various sorts of sports activities. Contributions increased our life expectancies, but have improved our quality of life both emotionally and physically. Cost effective means to treat diseases with a margin of safety. Patients with various psychiatric problems are kept under control by means of drugs. Drugs have, indirectly, contributed significantly to the economy and order in our society. In the US, the drug industry has often ranked as the fourth most profitable in the US economy, following soft drinks, tobacco, and the communications media.
Problems with use of drugs • Different individual response • Resistance, tolerance, side effects • Fault prescriptions • High cost: may be unafforable for those who need them • Illegal / counterfeit drugs
(b) Problems with one of drugs – cont’d Drug abuse • Some problems with the use of drugs. • Examples of propaganda leaflets on drug abuse. • Counterfeit drugs are sometimes found in small dispensaries.