Understanding Drugs and Behaviour phần 2 potx

these molecules can have dual functions as both neurotransmitters and hormones: for example, adrenaline and noradrenaline are not only neurotransmitters but also hormones, released from the adrenal medulla; histamine is a local hormone, a mediator of inflammation; thyroliberin stimulates the release of thyroid-stimulating hormone from the anterior pitui tary gland; and vasopressin is a hormone released from the posterior pituitary gland. In addition, the amino acids aspartate, glutamate and glycine are found in proteins and neuropeptide transmitters (e.g., aspartate in cholecystokinin-8S, glutamate in neurotensin and glycine in methionine-enkephalin). Up until the discovery of the neuropeptides, scientists belie ved that a single neuron could only contain one neurotransmitter – Dale’s law. However, it became apparent that neuropeptides and amines could co-exist as co-transmitters in the same neuron with the neuropeptide modulating the release of the amine. Here, the neuropeptides are referred to as neuromodulators, and in most cells they inhibit the release of an amine: for instance, neurotensin inhibits the release of dopamine from certain forebrain neurons. Unlike many chemicals in the brain, neurotransmitters are not homogeneously distributed, but concentra ted in certain regions. For example, almost two-thirds of the dopamine in the brain is found in the bilateral nigrostriatal (mesostriatal) tract (pathway), where the neuronal cell bodies are located in the substantia nigra and the axons terminate in the corpus striatum. When over 85% of these dopaminergic neurons are lost, the characteristic motor dysfunction of Parkinson’s disease is seen. Neurotransmitters are synthesised at the ‘‘point of use’’, with the biosynthetic enzymes being located in the synaptic bouton. The enzymes can be identified when looking at neurotransmitter pathways by the fact that they usually end in the suffix ‘‘-ase’’: for example, choline-O-acetyltransferase (‘‘choline acetylase’’) is necessary for the synthesis of acetylcholine; and tyrosine-3-hydroxylase, dopa decarboxylase and dopamine-b-oxidase are each required for the synthesis of noradrenaline. In contrast, neuropeptides are synthesised in the neuronal cell body and transported the length of the axon to the synaptic bout on. It is important that a neurotransmitter’s action is brief – allowing a sharp, clean signal. So, as soon as neurotransmitter is released mechanisms are brought into play that inactivate it and/or clear it from the synaptic cleft. In order to terminate the action of a neurotransmitter, enzymatic and/or non- enzymatic mechanisms of inactivation are required. Acetylcholinesterase is an example of a catabolic (‘‘breaking down’’) enzyme (Figure 2.5, catabolic enzyme 2) and rapidly breaks down acetylcholine into acetic acid and choline. Some 50% of the choline produced in this process can be reused to make more acetylcholine; this follows its uptake into the presynaptic neuron via the high-affinity choline uptake system (choline carrier or transporter). The monoamines, dopamine, 5-HT (serotonin) and noradren- aline are inactivated by a combination of presynaptic reuptake and catabolism. Dopamine has the dopamine transporter and serotonin, or 5-HT, also has its own transporters (5-HTT or SERT), as does noradrenaline (NAT or NET). They return their respective neurotransmitters into the synaptic bouton where all three may be broken down into inactive metabolites by monoamine oxidase (MAO; Figure 2.5, catabolic enzyme 1). In the case of the catecholamines, an additional enzyme catechol-O-methyltransferase (COMT) is also involved. The amino acid GABA (g- aminobutyric acid) is inactivated by a combination of reuptake into the presynaptic neuron and uptake into the astrocytes (a type of glial cell) surrounding the synaptic cleft. Neuropeptides are inactivated in the synaptic cleft by plasma membrane-bound 20 Part I Drugs and Their Actions ectopeptidases. As we will see in Chapters 12 and 13, certain types of drugs act by inhibiting the processes of breakdown and reuptake, thus increasing the neurotrans- mitter’s effects. Receptors Neurotransmitters exert their physiological effects through binding to specialised plasma membrane proteins called receptors, so allowing the flow of information from one neuron to another. The binding of neurotr ansmitters to their receptors,is often likened to a key turning a lock. This chemical interaction is high affinity since low concentrations of the neurotransmitter are required and, where the neurotransmitter has isomeric (enantiomeric, or mirror image) forms, it is stereospecific, only one of the forms is active. To illustrate the latter, take the example of noradrenaline, which contains an asymmetric carbon atom (chiral centre) where four different chemical groups or atoms are attached to the b-carbon atom: A single, asymmetric carbon atom in the noradrenaline molecule means it can exist as two enantiomers (stereoisomers), designated L- (laevo) and D- (dextro), which contain the same chemical groups in a slightly different spatial arrangement. Only the L-noradrenaline binds to the receptor with high affinity or potency. Other neurotrans- mitters with chiral centres are aspartate, glutamate and the neuropeptides. In each case it is the L-enantiomer that is physiologically active. Stereospecific binding, giving rise to different pharmacological activities, can also occur if a drug has one or more chiral centres: for instance, D-amph etamine is more potent than L-amphetamine. Neurotransmitter receptors can be divide d into two superfamilies: class 1 comprises the ligand-gated ion channel (LGICR ), or ionotropic, receptors; class 2 comprises the G-protein-coupled (GPCR), or metabotropic, receptors. Both types of receptor are proteins with three distinct regions: (1) extracellular (‘‘outside the cell’’), or synaptic, cleft region to which the neurotransmitter binds; (2) a lipophilic (‘‘lipid loving’’) membrane-spanning region; and (3) the cytoplasmic region (the cytoplasm is the fluid that fills the inside of all cells). Class 1 receptors are complex proteins made up of subunits clustered in a cylindrical formation; the centre comprises an ion channel or pore. One of the most extensively studied of these receptors is a class of cholinergic receptor known as the nicotinic acetylcholine receptor (nAChR). The binding of acetyl- choline results in a conformational change to the protein’s structure, which opens up the ion channels; this allows the passage of Na þ ions into the cell and K þ ions out. This inward current of Na þ causes depolarisation of the muscle membrane and so results in muscular contraction. A broadly similar mechanism occurs in the CNS. Class 1 The brain, neurons and neur otransmission 21 receptors respond rapidly to neurotransmitter binding (<1 ms) and are therefore ideally suited to the demands of rapid phasic activity, such as skeletal muscle contraction. Other examples of class 1 receptors include the GABA A receptor, which in addition to its neurotransmitter binding sites has a number of other sites; these include those for benzodiazepine drugs that regulate the binding of GABA to its site and thus the opening of the Cl À ion channel. The resulting influx hyperpolarises the neuron, making it less likely to fire. Thus, GABA is an inhibi tory neurotransmitter (Chapter 9). Another class 1 receptor is the glutamate NMDA (N-methyl-D-aspartate) receptor, which principally controls the movem ent of Ca 2þ into the neuron. The movement of Na þ and Ca 2þ ions into the cell results in depolarisation and an increase in postsynaptic neuronal excitability. Thus, glutamate acid is an excitatory neurotransmitter. The amine neurotransmitters can be either excitatory or inhibitory, depending on the type of receptor and their neuroanatomical location: for example, with acetylcholine, nicotinic receptors are excitatory in skeletal muscle, whereas muscarinic receptors are inhibitory in cardiac muscle. Similarly with noradrenaline, the b 1 receptors are excitatory in cardiac muscle, whereas b 2 receptors are inhibitory in bronchial smooth muscle. It is clear from the foregoing discussion that there are several different receptors for each neurotransmitter. These multiple receptors are designated receptor subtypes. The nomenclature for these different receptor subtypes has developed piecemeal and is very confusing. Many of the names have historical origins, with muscarinic coming from the fungal alkaloid muscarine and nicotinic coming from the tobacco alkaloid nicotine. With dopamine, Arabic numerals are used to denote receptor subtypes: D 1 -like and D 2 -like. With GABA, Roman letters are used: GABA A and GABA B . While with noradrenaline, Greek letters are used: a and b. Just to make life even more interesting, each receptor subtype has a number of further subclasses: for example, noradrenaline has b 1 , b 2 and b 3 receptors. Serotonin, or 5-HT, currently holds the record, with 14 receptor subtypes. The vast majority of receptor subtypes are class 2, or GPCRs. Class 2 receptors are sometimes referred to as metabotropic. Rather than change the excitability of their cell immediately through the rapid passage of ions, they induce a less immediate and longer lasting metabolic cascade in the cell. Here, when the neurotransmitter binds to its receptor, the conformational change activates a closely coupled G-protein which in turn regulates the activity of an intracellular enzyme; this stimulates (or inhibits) the biosynthesis of a second messenger molecule, so-called because the signal (or message) is passed onto it from the ‘‘first messenger’’ system, the neurotransmitter–receptor complex. There are several different types of G-proteins, G standing for guanine nucleotide, including G s ,G i and G q . Table 2.2 summarises the main features of these systems. Each class 2 receptor follows the general mechanism of receptor binding causing a change in a G-protein which then activates a second messenger system (see Table 2.2). The second mess engers then go on to activate specific protein kinases that phos- phorylate (add phosphate groups to particular amino acids) ion channel proteins in the plasma membrane, opening up a channel in the centre of these proteins, thus allowing the passage of ions into or out of the cell. It is evident from these events that GPCRs are much slower in response time than the LGICRs; however, this 22 Part I Drugs and Their Actions cascade of biochemical reactions does enable amplification of the extracellular (neuro- transmitter) signal. G i -protein-coupled receptors are often located on the presynaptic plasma membrane where they inhibit neurotransmitter release by reducing the opening of Ca 2þ channels; like inactivation and breakdown of the neurotransmitter by enzymes, this contributes to the neuron’s ability to produce a sharpl y timed signal. An  2 receptor located on the presynaptic membrane of a noradrenaline-containing neuron is called an autoreceptor; but, if located on any other type of presynaptic neuronal membrane (e.g., a 5-HT neuron), then it is referred to as a heteroreceptor (Langer, 1997). Autoreceptors are also located on the soma (cell body) and dendrites of the neuron: for example, somatodendritic 5-HT 1A receptors reduce the electrical activity of 5-HT neurons. Finally, perhaps one of the oddest of recen t discoveries is that toxic gases, such as nitric oxide (NO) and carbon monoxide (CO), can act as dual first/second messengers in the nervous system (Hal ey, 1998). Our current ideas of how drugs affect the complex events and regulation of synaptic neurotransmission are very simplistic and the real situation is obviously vastly more complicated. Some of these issues will be addressed in more detail in Chapter 14. Questions 1 Summarise the major divisions of the central and peripheral nervous systems. 2 Describe one neurophysiological or neurobehavioural function for five different brain regions. 3 Describe the components of a multipolar neuron. The brain, neurons and neur otransmission 23 Table 2.2. Class 2 receptor (GPCR) systems. G protein Receptor subtype Second messenger system G s Noradrenaline b 1 and b 2 Stimulates adenylate cyclase increasing the Dopamine D 1 and D 5 concentration of cAMP Histamine H 2 (cyclic-adenosine-3 0 ,5 0 -monophosphate) Serotonin 5-HT 4 G i Noradrenaline a 2 Inhibits adenylate cyclase decreasing the Muscarinic m 2 concentration of cAMP Dopamine D 2 ,D 3 ,D 4 Serotonin 5-HT 1B GABA B Opioid d, k, m Cannabinoid CB 1 and CB 2 G q Noradrenaline a 1 Stimulates phosphoinositidase C, increasing the Muscarinic m 1 and m 3 concentration of the lipophilic 1,2-diacylglycerol Histamine H 1 and 5-HT 2A (DAG) and the water-soluble inositol-1,4,5-trisphosphate (IP 3 ) 4 Using diagrams, explain the different phases of the action potential. 5 Give two examples for each of the following types of neurotransmitter: monoamine, amino acid and neuropeptide. 6 What is the main difference between a first and second mess enger? 7 Explain why the electrophysiological responses to class 1 receptors are much more rapid than to class 2 receptors. Key references and reading Bloom FE, Nelson CA and Lazerson A (2001). Brain, Mind and Behavior. Worth, New York. Carlson NR (1999). Foundations of Physiological Psychology. Allyn & Bacon, Needham Heights, MA. Greenfield S (1998). The Human Brain: A Guided Tour. Phoenix, London. Hindmarch I, Aufdembrinke A and Ott H (1988). Psychopharmacology and Reaction Time. John Wiley & Sons, Chichester, UK. Langer SZ (1997). 25 years since the discovery of presynaptic receptors: Present knowledge and future perspectives. Trends in Pharmacological Sciences, 18, 95–99. Matthews GG (2001) Neurobiology: Molecules, Cells and Systems. Blackwell, Malden, MA. Purves D, Augustine GJ, Fitzpatrick D, Katz LC, LaMantia A-S, McNamara JO and Williams SM (2001). Neuroscience. Sinauer Associates, Sunderland, MA. Rose S (1976). The Conscious Brain. Penguin, London. Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T and Gould E (2001). Neurogenesis in the adult is involved in the formation of trace memories. Nature, 410, 372–376. 24 Part I Drugs and Their Actions Chapter 3 Principles of drug action Overview T he first part of this chapter covers pharmacokinetics, or how the body physiologically processes a drug. In pharmacology textbooks the topic of pharmacokinetics is often treated mathematically. However, the approach adopted here is largely descriptive. The pharmacokinetic process can be remembered by the acronym ADME – absorption, distribution, metabolism and elimination. Each of these key stages will be described using practical drug examples. The various routes of drug administration, although not strictly covered by the term pharmacokinetics, will also be described as a prelude to ADME. Drugs can be administered by injection, tablet, snorted or inhaled, with each route displaying particular characteristics. Following initial drug absorption, drugs are distributed to the different body tissues, where they are metabolised into breakdown products and, finally, they are excreted. These four stages can vary considerably, so that while some drugs remain psychoactive for only a short period (e.g., crack cocaine), others have effects lasting weeks or months (e.g., depot injections of some antipsychotic drugs). The second part of this chapter covers pharmacodynamics, or how drugs modify brain activity. The key topic is how each drug interacts with the neuronal receptors, or modifies neurotransmission. There are many different neurotransmitters, and their actions can be enhanced or blocked in numerous different ways. The diversity of altered transmission patterns helps explain the wide range of behavioural changes produced by different drug types. Thus, a basic understanding of pharmacodynamics is essential to understand how each class of drugs exerts its characteristic effects. Finally, drug tolerance, addiction/dependence and the placebo response will be covered at the close of the chapter. Pharmacokinetics Pharmacokinetics encompasses four stages in the journey of a drug through the body: absorption, distribution, metabolism and elimination (Figure 3.1). Drug administr ation is a prelude to this process; however, in standard textbooks on pharmacology it is not included within the pharmacokinetics section. Thus, the disintegration of a tablet, followed by the release of the drug and its dissolution into the stomach fluids, is referred to as the pharmaceutical phase and is the subject of the branch of pharmacy called pharmaceutics. It is also important to note that not every drug necessarily passes through all four pharmacokinetic stages. The absorption phase may be bypassed and some drugs are eliminated from the body unaltered by metabolism. Drug administration routes Topical routes of drug administration are where the drug is applied directly to the site of action. Many medicines are applied directly: for example, hydrocortisone can be rubbed into the skin to relieve a local area of inflammation. The anticholinesterase neostigmine is dropped directly onto the eye surface to relieve glaucoma, a condition characterised by raised intra-ocular pressure which if untreated can lead to blindness. 26 Part I Drugs and Their Actions Figure 3.1. Pharmacokinetic and pharmacodynamic processes. The skin provides a method for administering several types of psychoactive drugs. Thus, transdermal nicotine patches contain a reservoir of drug, which is slowly absorbed through the skin and provides a useful aid for smoking cessation (Chapter 5). Trans- dermal scopolamine is also used to prevent the development of sea and air sickness, with the antimuscarinic drug scopolamine reducing cholinergic activity in the vomiting centre of the brain stem (Parrott, 1989). However, in both these cases the drug is absorbed from the skin patch into the general circulation and is therefore actually a systemic route. Topical administration is thus not a route for psychoactive drugs; perhaps you might like to consider why this is so? Systemic routes result in the drug entering the body and, then, being distributed to any organ and affecting numerous physiological systems. Many drugs are administered by injection, a route often referred to as parenteral since it avoids the gastrointestinal tract. Often, the complete dose, or ‘‘bolus’’, is given rapidly under pressure using a hypodermic syringe. In other cases it is released as a slow controlled infusion via an osmotic pump or gravity ‘‘drip’’ feed. There are severa l injection routes used in experi- mental and human pharmacology (Table 3.1). For humans the three main routes are under the skin (subcutaneous injection) into a vein (intravenous injection) and into muscles (intramuscular injection). Some practical examples of each route are given in Table 3.1. Another of the main systemic routes is oral (Table 3.2). Sometimes raw plant material is chewed in order to release the psychoactive compound into the mouth cavity. Examples include the chewing of coca leaves to extract cocaine (Chapter 4) and the tobacco leaf to extract nicotine (Chapter 5). The problem with this is that many other plant chemicals remain in the mouth, and many of these are carcinogenic. Tobacco leaf chewing leads to oral cancers of the mouth, lips, jaw and tongue, often Principles of drug actio n 27 Table 3.1. Parenteral routes of drug administration. Intravenous (IV) Into a vein. Because the drug enters directly into the circulation, there is no absorption phase; this means that the peak plasma concentration is reached almost immediately. This route is used when a rapid onset of action is required. Intramuscular (IM) Into skeletal muscle. This route is used to deliver ‘‘depot’’ antipsychotic drugs like fluphenazine and haloperidol decanoate, which are used in the treatment of schizophrenia. Subcutaneous (SC) Into the layer just under the skin; this is most commonly associated with insulin in diabetes mellitus. Intrathecal (IT) Into the subarachnoid space between two of the membranes (meninges) separating the spinal cord from the vertebral column. This route is used for drugs that do not penetrate the blood–brain barrier, but which are required for their central action (e.g., antibiotics). Drugs can also be injected spinally (into the epidural space) for local anaesthesia or analgesia. Intraperitoneal (IP) Into the peritoneal cavity of the abdomen; this provides a large surface area for absorption and is widely used for administering drugs to laboratory animals. It is very rarely used clinically. only 10 years after commencing the tobacco chewing habit/addiction (compared with a 20–30-year induction period for cancers of the lung in cigarette smokers; Chapter 5). Nicotine gum is thus a healthier method for oral nicotine intake. The gum must however be chewed slowly, since nicotine is only absorbed from the mouth cavity; if nicotine-replete saliva is swallowed, it can cause irritation in the stomach resulting in hiccups (Chapter 5). Psychoactive drugs are predominantly taken as oral tablets, especially some of the main illicit recreational drugs: amphetamine, Ecstasy/MDMA (methylenedioxymetham- phetamine) and LSD (lysergic acid diethylamide; Chapters 4 and 6). Many medicines are also typically given as oral tablets, including benzodiazepines, antipsychotics and antidepressants (Chapters 9, 11 and 12). However, it should be noted that many of these drugs can also be given as liquid preparations, as they are then easier to swallow; they can also be injected. One limitation of the oral route is that it can lead to varying concentrations in the syst emic circulation; this is because absorption is influenced by numerous factors: the distance the drug has to travel to the site of absorption, the area of the absorbing surface, its blood supply and various other local factors (see below). A closely related route is nasal, since the mouth and nose form one interlinked cavity. The blood capillaries inside the nose are very close to the surface, which make them a good site for drug absorption. Cocaine is typically administered or ‘‘snorted’’ by the nasal route (Chapter 4). Another systemic route is smoke inhalation; this is a surprisingly efficient route, with inhaled tobacco smoke generating a bolus or ‘‘hit’’ of nicotine which reaches the brain in only 7–10 seconds (Chapter 5). Smoking is thus used to deliver various illicit drugs, including crack cocaine (Chapter 4), cannabis (Chapter 7) and op iates, such as raw opium and heroin, when it is called ‘‘chasing the dragon’’ (Chapter 8). One of the benefits of smoke inhalation is the degree of control it provides to the individual smoker. By controlling the frequency and depth of inhalation, they can self- administer different amounts of drug. In regular tobacco smokers the first inhalation of the day tends to be long and deep, then successive inhalations of the cigarette become 28 Part I Drugs and Their Actions Table 3.2. Non-injection routes of drug administration. Oral (PO ¼ per os) By the mouth. Oral administration is the most common route employed for a variety of dosage forms: tablets, capsules, liquids, suspensions. The major site of absorption is the small intestine. Alcohol is absorbed from the stomach. Sublingual (SL) In the mouth under the tongue; this allows the tablet or gum to slowly dissolve, so that the released drug can be gradually absorbed across the buccal mucosal membrane. Nicotine gum is administered by this route. Nasal (NS) Through the nose. Cocaine is snorted up the nose and then absorbed through blood capillaries in the thin nasal membrane. Inhalation (IH) The administration of volatile gases and vapours, followed by drug absorption in the lungs or nasal mucosa. Examples include general anaesthetics like nitrous oxide, nicotine from the tar droplets in tobacco smoke, cannabinoids from cannabis leaf smoke and various opiates from burning opium resin. lighter and more widely spaced, as the need/desire for further hits of nicotine decreases (Chapter 5). Cannabis smokers often display similar patterns of self-titration, so that when they are replete they stop further smoking and avoid further cannabinoid intake (Chapter 7). Inhalation of burning plant material is always very unhealthy, since tobacco, cannabis and opium smoke contain numerous poisonous chemicals and carci- nogens. The adverse health consequences of smoke inhalation are covered more fully in Chapter 5. Finally, there are two problems common to every systemic route and thus all forms of psychoactive drug administration: first, it is extremely difficult to retrieve the drug and so treat overdose; and second, because the drug may be distributed throughout the body, there is always the potential for unwanted side effects. Absorption Absorption describes the process by which a drug enters the blood circulation. With the exception of some forms of injection, all systemic routes involve an absorption phase. This process can be illustrated with the most common route of administration, oral (PO). Orally administered drugs pass down the oesophagus into the stomach and then the small intestine. The main drug to be absorbed from the stomach is alcohol (Chapter 9). With the majority of other ingestible drugs the major site of absorption is the small intestine. Drugs in the small intestine traverse the mucosa to enter the circulation via the hepatic portal v ein, by the process of passive lipid diffusion. The more lipophilic (fat-loving) the drug the more easily it is absorbed. The presence of food delays absorption, which is why drugs are best absorbed ‘‘on an empty stomach’’. The hepatic portal vein enters the liver where drugs may be broken down into inactive metabolites. This initial metabolism is termed the first-pass effect, and where it is substantially high only a small proportion of the absorbed drug enters the systemic circulation via the hepatic vein; this is why oral tablets result in lower drug concentra- tions than other routes. Drug distribution In theory, once in the systemic circulation drugs may travel to any organ in the body. However, there are two physicochemical barriers that modify this distribution: the blood–brain barrier and the placental barrier. The blood–brain barrier is formed by capillary endothelial cells and astrocytes and ensures that there is no direct contact between blood circulation and brain neurons (Pardridge, 1998). The advantage of the blood–brain barrier is that it excludes many potentially toxic chemicals from the neuron. The disadvantage is that it can block access to some potentially useful thera- peutic drugs. However, it is not completely effective, which is just as well because there would be no drugs for treating ne urological and psychiatric disorders unless they were given by direct intracerebroventricular injection. The placental barrier excludes dru gs from foetal circulation, thereby reducing possible damage to the developing baby. Unfortunately, some drugs can cross this barrier and may have teratogenic effects, giving rise to birth defects. They should not therefore be prescribed during Principles of drug actio n 29 [...]... Press, Oxford, UK Kaplan HJ and Sadock BJ (1996) Pocket Handbook of Psychiatric Drug Treatment Williams and Wilkins, Baltimore Liska K (20 00) Drugs and the Human Body: With Implications for Society Prentice Hall, Englewood Cliffs, NJ Snyder SH (1996) Drugs and the Brain W.H Freeman, New York PART II Non-medical Use of Psychoactive Drugs 4 CNS stimulants: amphetamine, cocaine and caffeine ... metabolism and is only manifested when the individual takes particular drugs Five polymorphisms (variations in the nucleotide or base sequence of DNA coding for a particular protein) in CYP2D6 may account for differences in the metabolism of some 25 % of all drugs, including many psychotropics (Marshall, 1997) Poor/slow and extensive/fast metabolizers may show adverse reactions (Bondy and Zill, 20 01) Several drugs. .. Nootropic 0.03 3 6 20 96–144 5 20 20 10–16 100 6–10 80– 120 3–4 Morphine Desipramine Norfluoxetine Nordiazepam TAD ¼ tricyclic antidepressant SSRI ¼ selective serotonin reuptake inhibitor c SNRI ¼ serotonin–noradrenaline reuptake inhibitor Data from Grahame-Smith and Aronson (19 92) and Kaplan and Sadock (1996) a b Elimination The kidney is the principal organ of elimination, with drugs leaving the body... of over 23 0 structurally and functionally related enzyme proteins (isoenzymes), which are central to the metabolism of thousands of different drugs (Lewis, 1996) The three subfamilies CYP3A (44%), CYP2D (30%) and CYP2C (16%) account for the metabolism of almost 90% of drugs Hepatic drug metabolism usually takes place in two stages: the first phase is oxidation which involves cytochrome P-450 and the... There are numerous other drugs with stimulant properties Indeed, the list of stimulants banned by the IOC covers several pages Details of some of these other drugs may be found in standard drugs and behaviour textbooks (Grilly, 20 01; Julien, 20 01; Maisto et al., 1998) Finally, nicotine is often categorized as a CNS stimulant, although its very different neurochemical actions and unique psychopharmacological... Compare the advantages and disadvantages of the different routes for drug administration 2 What factors influence the bioavailability of a drug following its oral administration? 3 Why is cytochrome P-450 important for an understanding of psychoactive drugs? 4 What are the principal routes for the elimination of drugs from the body? 5 Describe the roles and functions of the blood–brain and placental barriers... physical and psychological is qualitatively similar to that made between hard and soft drugs or between legal and illicit drugs In all three examples the implicit suggestion is that the second of these pairs is safer in terms of individual health and the overall well-being of society This notion is disproved by the massive number of deaths caused by tobacco smoking and alcohol drinking (Chapters 5, 9 and. .. often sleep for short periods and are seen as disruptive at school Several stimulant drugs have been shown to be clinically useful in ADHD, including amphetamine, methylphenidate (Ritalin) and pemoline Placebo-controlled trials have shown that they improve attention span and allow children to undertake their school work more effectively (Brown and Cooke, 1994) Most drugs and behaviour textbooks describe... revealed a beneficial effect of placebo in between one-quarter and one-third of patients and to active drugs in one-half to three-quarters of patients (Bauer et al., 20 02) Placebos are also reported to give adverse drug reactions, or side effects, most frequently headaches, difficulty in concentration, nausea and dry mouth (Grahame-Smith and Aronson, 19 92) There are a number of reasons for the placebo response... Table 4 .2 Dietary sources of caffeine Dietary source Average caffeine content (mg per cup) Coffee: freshly brewed Coffee: instant Coffee: decaffeinated Tea: strong brew Tea: weak brew or green tea Chocolate: hot drink Chocolate: confectionary bar Fizzy beverage (Coca-Cola, others) Over-the-counter medicines 70–180 50–100 2 4 40–90 20 –40 5 20 5 25 20 –50 5–100 51 52 Part II Non-medical Use of Psychoactive Drugs . CB 1 and CB 2 G q Noradrenaline a 1 Stimulates phosphoinositidase C, increasing the Muscarinic m 1 and m 3 concentration of the lipophilic 1 ,2- diacylglycerol Histamine H 1 and 5-HT 2A (DAG) and. 23 Table 2. 2. Class 2 receptor (GPCR) systems. G protein Receptor subtype Second messenger system G s Noradrenaline b 1 and b 2 Stimulates adenylate cyclase increasing the Dopamine D 1 and D 5 concentration. metabolism of some 25 % of all drugs, including many psychotropics (Marshall, 1997). Poor/slow and extensive/fast metabolizers may show adverse reactions (Bondy and Zill, 20 01). Several drugs inhibit