 |
|
|
|
 |
|
||
 |
 |
 |
|
 |
|
||
The Basic Principles of Pharmacology
Introduction
Drugs are small molecules that are introduced into and applied onto the body that induce various effects, amongst which is the desired therapeutic effect.
Most drugs are targeted at our own human cells
Others, for example antibiotics, are targeted at
pathogens such as bacteria that may have
invaded the body.KEY POINT - Drugs bind to Proteins
Generally, drugs act by binding to proteins. The protein targets can be divided into four categories:
ion channels
enzymes
receptors
carrier proteinsA few drugs do not bind to proteins and these include anti-tumour drugs such as cisplatin that bind to DNA and bile sequesterants such as colestyramine that bind to bile acids in the gut. The reason that most of our drugs bind to proteins is that proteins exhibit the greatest heterogeneity of any group of molecules in the body. In other words, there is much variation amongst proteins, there are over 10,000 different types of protein in the body that drugs can recognise and bind to.
Before the action of drugs can be explored further, it may be useful to recap on some basic cell biology, in particular, the structure of the cell membrane.
Cells and cellular components
There are many billions of cells in the body. Cells make up tissues and tissues form organs. Most cells are specialised to a particular task. For example, muscle cells contract, nerve cells conduct nervous impulses and glandular cells secrete hormones. Although these cells may look very different on the outside, inside they generally have the same components and perform the same processes. To understand how drugs work on cells, it is necessary to have a basic understanding of these processes. Figure 01 - Typical cell
Figure 01 - typical cell showing principal organelles
THE COMPONENTS OF CELLS - ORGANELLES.
Several organelles are involved in the production of proteins, these are the nucleus, the endoplasmic reticulum, the Golgi apparatus and the ribosomes. There are tens of thousands of different proteins made by cells (which is why they make such excellent targets for drugs). The code for these proteins is contained within the DNA (deoxyribose nucleic acid) that is found in the nucleus. There are 46 lengths of DNA in most human cells and each length of DNA is called a chromosome. The piece of DNA that codes for one protein* is called a gene. There are tens of thousands genes that code for the tens of thousands of proteins that cells make.
*technically each gene codes for one polypeptide and some proteins are made up of many polypeptides.
Some proteins are used within the cell and others are exported from the cell by a process called exocytosis. Many proteins are lodged in the cell membrane as receptors, ion channels or carrier proteins (see Figure 03). This group forms a major target for drugs. Proteins come in many shapes and sizes and perform many functions. One of the most numerous classes of proteins are the enzymes, complex structures that take part in most of the body’s biochemical reactions. Enzymes are also a major target for drugs (see below)
Mitochondria. These organelles produce most of the energy for the cell. They use the energy from fuel such as glucose and lipid to produce ATP (adenosine triphosphate) a small packet of energy that powers most of the cells' biochemical processes.
Cytoplasm. Not really an organelle, the cytoplasm is a rich mixture of enzymes, nutrients and electrolytes for the myriad of processes that take place continuously in each cell.
Cell membrane. This important structure regulates what goes into and out of the cell. It is composed mainly of a phospholipid bilayer interspersed with cholesterol. The components of the bilayer are arranged as in Fig. 02 (below):
Figure 02 - The phospholipid membrane
The phosphate heads are hydrophilic (attracted to water) and interface with the aqueous environment of the extracellular fluid outside the cell and the intracellular fluid inside the cell. The lipid tails are predominantly long fatty acid chains that form a stable layer in the water-free environment between the outer and inner layer of phosphate heads. Cholesterol molecules give additional stability. Trans-membrane proteins span the membrane and include glycoproteins, receptors and carrier proteins - Figure 03.
Figure 03. Trans-membrane proteins span the cell membrane
THE MOVEMENT OF MATERIALS IN AND OUT OF CELLS
It is important to recognise that the phospholipid bilayer is predominantly lipid in character. This means that lipids such as steroid hormones will pass through easily whilst non-lipid materials such as amino acids and ions have to go through carrier proteins and ion channels in the cell membrane. Sometimes energy in the form of ATP is required to move materials in and out of cells through the carrier proteins - Figure 04.
Figure 04 Carrier proteins and ion channels allow specific materials in and out of cells
THE FOUR PRINCIPLE PROTEIN DRUG TARGETS
1. RECEPTORS
Cells generally communicate with each other by releasing chemicals that are detected by target cells. Some communication operates on a systemic basis e.g. hormones circulate in the blood and are detected by cells distal to the point of release. Other chemicals operate on adjacent cells only and these are generally called mediators or, in the case of nerve cells, neurotransmitters.
Target cells must have the appropriate receptors to detect and respond to hormones, mediators and neurotransmitters. The collective name for a chemical that binds to a receptor is a ligand. A ligand that is produced naturally in the body is called an endogenous ligand. Receptors are proteins that are specific to the shape of the ligand, rather like the way that a lock is specific to a particular key. Only cells that have an appropriate receptor will respond to a particular ligand - Figure 04.
Figure 04. Only ligands with a complementary shape to receptors will bind effectively
Some receptors are found within the cells. These respond to steroid hormones and other mediators that can pass through the cell membrane. As with those on the surface, intracellular receptors respond only to ligands of an appropriate shape.
THE EFFECTS OF A LIGAND BINDING TO A RECEPTOR
Some messenger molecules such as peptide hormones trigger a secondary messenger within the cell which usually initiates a biochemical reaction - Figure 05.
Figure 05. The binding of a ligand to a receptor triggers a secondary messenger
Neurotransmitters and some mediators, bind to receptors and open ion channels, allowing ions to diffuse in or out of a cell - Figure 06.
Figure 06. The binding of a ligand opens an ion channel in the membrane.
There are many important groups of drugs that bind to receptors including bronchodilators used in asthma, antihypertensives such as beta-blockers and anxiolytic drugs such as benzodiazepines.
SPECIFICITY, AGONISTS AND ANTAGONISTS
For a ligand to bind to a receptor, it must be the appropriate shape (lock and key). Drugs also must exhibit specificity to the binding site of their target protein. The lower the specificity, the greater dose will be required and the more likely there are to be side effects. The potency of a drug depends on its affinity to the binding site and its ability on binding to produce effects.
Most of the drugs that bind to proteins do so at sites that would otherwise be occupied by hormones, neurotransmitters or mediators i.e. they mimic the endogenous ligand that would normally bind to the receptor. In the case of enzymes, the drug mimics the enzymic substrate that the active site of the enzyme recognises.
Those drugs that mimic the ligand closely enough may elicit a similar effect to the original ligand and these are termed agonists. Other substances are similar in shape to the original ligand but bind to and block the receptor without producing a response. They also prevent the original ligand from binding and these are called antagonists Figure 07.
Figure 07. Agonists mimic endogenous ligands whereas antagonists block receptors
2. DRUGS THAT ACT ON ION CHANNELS
These can broadly be divided into blockers and modulators. Blocking drugs physically block the channels and prevent the ion specific to that channel from moving in or out of the cell. An example of this type of action is lignocaine, a local anaesthetic. Lignocaine blocks the Na+ channels in pain neurons and so prevents nervous impulses carrying the “pain information” to the CNS - Figure 08.
Modulators do not physically block the ion channel but bind to sites on the channel and either enhance or inhibit its normal operation. Here are two examples…..
Benzodiazepines are anxiolytic and hypnotic drugs bind non-competitively to GABA* receptors which are ligand gated chloride channels, enhance their opening and potentiate the response of the receptor to GABA.
Verapamil a drug used to slow the heart, works by non-competitively binding to Ca2+ channels in the sinoatrial and atrioventricular nodes and inhibiting the carrier’s opening.
*GABA - gamma aminobutyric acid - a neurotransmitter found in the central nervous system
Figure 08 - Example of a drug that work on ion channels - lignocaine
There are many thousands of different enzymes active in the body, intracellular and extracellular, responsible for the catalysis of the myriad biochemical reactions necessary for life. One of the prime targets for those drugs that act on enzymes is the active site where the enzyme interacts with its substrate. Drugs that have a molecular shape similar to the substrate can bind to the active site and inhibit the action of the enzyme Figure 09.
Figure 09 - The action of drugs on enzymes
Non steroidal anti-inflammatory drugs (NSAIDs) are examples of drugs that act on enzymes. NSAIDs inhibits the enzyme cyclo-oxygenase (COX) which catalyses a reaction in the biochemical pathway that results in the production of prostaglandins, important mediators in the inflammatory response.
4. DRUGS THAT ACT ON CARRIER MOLECULESMany substances have to be actively transported across cell membranes and ATPase transporter proteins perform this task.
Frusemide, a loop diuretic inhibits the Na+/K+/Cl- co-transporter in the membrane of the loop of Henle in the nephron of the kidney. This changes the sodium balance in the kidney, so producing large amounts of urine.
Cocaine blocks the dopamine re-uptake transporter in the presynaptic terminal of the dopaminergic neurons in the substantia nigra of the brain. This increases the amount of dopamine in the synaptic cleft and produces the euphoric effects experienced by cocaine users.
THE SYNAPSE
Important targets for drugs are found in the synapse - Figure 10. Synapses are found where neurons meet and are central to information transfer in the body.
Figure 10. Messages are transmitted between neurons via synapses
Information is relayed between a neuron terminal and a post-synaptic cell by the release of neurotransmitters. These chemicals diffuse across the synaptic cleft and bind to receptors on the post-synaptic membrane. This results in ion channels, associated with the receptors, opening and allowing ions to diffuse in or out of the cell. This either stimulates or inhibits the post-synaptic cell. The neurotransmitter in the cleft dissociates from the receptor and is removed either by enzymes or recycled via re-uptake transporters (carrier proteins).
Recalling the protein targets for drugs mentioned earlier, it can be seen from Figure 11 that the synapse contains all four targets; ion channels, enzymes, receptors and carrier proteins. This is why synapses are such an important target for drugs such as atrovent, neostigmine, prozac, propranolol and amitriptyline.
Figure 11. Schematic diagram of a synapse
