Pharmacodynamics by Cayte Hoppner

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  Introduction:

Pharmacodynamics is the mechanism where drugs exert their effects on the body. To produce therapeutic or toxic effects drugs interact with receptors in the body – the pharmacodynamic phase of drug action.  Pharmacodynamics is often referred to as “what the drug does to the body”. In order to exert their effects, drugs usually interact in a structurally specific way with a protein receptor or act on physiological processes within the body. This activates a secondary messenger system that produces a physiological effect. The aim of drug therapy is to reverse any changes so the body can return to its homeostatic state. All bodily functions are a result of interactions of various chemicals and drugs act by interfering with these processes. Drugs usually combine with particular chemicals to modify its effect on the body.

 

The most common receptors are trans-membrane receptors linked to guanosine triphosphate binding proteins (G proteins)

How do drugs produce their effects?

Drugs acting by chemical reactions:

A few commonly used drugs have a direct chemical action on the body. Simple chemistry is all the drug is required to do to have a physiological effect.

Example: Acetylcysteine used in paracetamol poisoning

Drugs acting on enzymes:

Enzymes are catalysts and carry out numerous reactions in the body. A catalyst is involved in a reaction but remains unchanged at the end of the reaction. Enzymes react with substrates in a reversible way (enzyme reactions are equilibrium reactions) to create a product. If the product is removed, more enzymes will combine with a substrate to form more products. Enzymes are relatively or sometimes completely specific for a certain substrate. There are two types of actions known as competitive inhibition and non-competitive inhibition.

Competitive inhibition - the drug competes with the natural substrate for the active centre of the enzyme. The more drug that is present with the enzyme the slower the enzymic reaction will take place. Drugs that act this way can be counteracted by increasing the concentration of the substrate, and this is how many antidotes work. Competitive inhibition occurs when the enzyme combines with a substance that has a very similar structure to the normal substrate but because it is not normal, discards it and begins to look for another substrate.

Non-competitive inhibition – The inhibitor binds on to a site distinct and remote from the active centre of the enzyme. This causes a change in the structure of the enzyme rendering it inactive. Non-competitive inhibitors combine with the enzyme in a permanent and usually irreversible fashion.

Example: Aspirin, garden insecticides and some Monoamine antioxidase inhibitors

Drugs acting on receptors:

A drug which binds to a receptor and produces a maximum effect is called a full agonist. A drug which binds and produces less than a maximal effect is called a partial agonist. Partial agonists produce an effect if no agonist is present but act as antagonists in the presence of a full agonist.

Drugs which bind but do not activate a secondary messenger system are called antagonists. Antagonists can only produce effects by blocking access of the natural transmitter (agonist) to the receptor. Ion channel blockers act on the ion channel receptors associated with transporting ions (sodium, potassium, calcium) to and from cells. Drugs react with the receptors in channels to prevent the transport of ions. For drugs that are receptor agonists -when a drug is administered the response usually increases in proportion to the dose until the receptors are saturated.

Example: Olanzapine and Nifedipine

Drugs acting by physical action:

There are not many drugs which act in this fashion. One common physical process occurring in the body is osmosis. Osmosis is important in ensuring fluid balance between body compartments. Osmosis results when two different concentrations of molecules are separated by a semi-permeable membrane. Molecules can move from areas of high concentration to low concentration. Some drugs can also be largely adsorbent and bind to many materials in the body. This is another type of physical action.

Example: Normal Saline 0.9% and Activated Charcoal

Drugs acting by a physicochemical reaction:

This mode of action usually acts by altering the lipid part of cell membranes, particularly in brain tissue.

Example: Anaesthesia

Enzymes as drugs:

Many enzymes are also used as drugs and they have a biochemical action. Enzymes can be replaced, used to increase the speed of absorption and be used to destroy unwanted materials in the body.

Example: Pancreatin and Hyaluronidase

Table 1: Affinity, specificity, potency and efficacy

Potency – the relative amount of the drug that has to be present to produce the desired effect

Efficacy- the ability of a drug to produce an effect at a receptor

Affinity- the extent to which a drug binds to a receptor. The greater the binding the greater the action

Specificity- the ability of the drug to produce an action at a specific site

Pharmacokinetics

Introduction:

Pharmacokinetics describes the relationship between the dose of a drug and the drug receptor and the time course of drug concentration in the body. Pharmacokinetics is also known as ‘what the body does to the drug’. The concentration that a drug reaches at its site of action is influenced by the rate and extent to which a drug is:

1. Absorbed – into the body fluids
2. Distributed – to the sites of action
3. Metabolised – into active or inactive metabolites
4. Excreted – from the body by various routes

The study of the kinetics of a drug during the processes of absorption, distribution, metabolism and excretion is collectively described as pharmacokinetics.

Table 2        Key Pharmacokinetic Definitions

• Absorption- the process by which the unchanged drug moves from the administration site into the blood
• Bioavailability- the proportion of the dose of the drug that reaches the systemic circulation intact
• Bioequivalence- where two formulations of the same drug reach similar concentrations in the blood and tissues at similar times with no differences in therapeutic or adverse effects
• Distribution- the reversible transfer of a drug between one location and another in the body
• Elimination- the irreversible loss of the drug from the body by metabolism and excretion
• Excretion- the loss of chemically unchanged metabolites or drug from the body in urine, sweat, expired air, faeces or gut content
• Metabolism- the chemical modification of a drug
• Volume of distribution- the relationship between the drug concentration in the blood and the drug in the tissues of the body at the site of action
• Clearance- the efficiency of irreversible elimination of a drug from the body
• Half-life- the time taken for the amount of the drug in the body or the plasma concentration to fall by half
• First Pass Clearance- the extent to which a drug is removed by the liver during its first passage in the portal blood through the liver to the systemic circulation

Key Point:

Half-Life:  The elimination of a drug is usually an exponential process so a constant proportion of the drug is eliminated per unit of time. The half life is increased by an increase in the volume of distribution or a decrease in clearance and vice versa. Half life is a major determinant of the duration of action of a drug after a single dose, the time required to reach steady state with constant dosing and the frequency with which does can be given.

Absorption:

This is an important factor for all routes of administration except for intravenous drugs. In intravenous drugs the drug is administered directly into the circulation and does not require absorption from the administration site.

For absorption to occur the drug must cross the membranes and enter the blood vessels. Some drugs can be transported through membrane openings or pores however most drugs cross the membrane by diffusion. Amino aids, glucose, some vitamins and neurotransmitters are transported by carrier mediated transport. Carriers form complexes with the drug molecules on the membrane surface to carry drugs through the membrane and then dissociate.

Drugs can enter the circulation via oral, parenteral, inhalation or topical routes.

Drug absorption is determined by the properties of the drug, dosage forms, pH, food, other drugs, antacids, intestinal motility and enzyme metabolism.

Distribution:

After the drug reaches the systemic circulation it can be distributed to various sites within the body such as body water, blood, plasma, bone and fat. Most of the drug is distributed to organs that have a good blood supply such as the heart, liver and kidneys. Cardiovascular function affects the rate and extent of distribution of a drug. On entry to the body a proportion of the free drug binds with proteins to form drug-protein complexes.

The major drug binding sites are albumin, alpha-acid glycoprotein and lipoproteins. Drug protein binding is the reversible interaction of drugs with proteins in plasma. Some drugs are highly bound, others less so and this depends on the affinity or attraction of the drug for the protein. Protein binding decreases the concentration of free drug in the circulation and limits its distribution. As the free drug is removed from the circulation, the drug-protein complex dissociates so that more free drug is released. It is only the free or unbound drug that exerts pharmacological effects.

Plasma protein binding is commonly expressed as a percentage and there is a ratio between the free and bound drug.  For example, Propanolol is 93% protein bound so only 7% of the free drug is available for distribution to have any significant clinical effect. Some drugs have a high affinity for adipose tissue and bone crystals. The distribution of drugs can also be affected by the blood-brain and the placental barrier. Only lipid soluble drugs can be distributed through the blood-brain barrier and into the brain and cerebrospinal fluid, such as anaesthesia. Tissue enzymes in the placenta can metabolise certain drugs. The placental barrier is permeable to a great number of drugs. Many drugs intended to provide therapeutic benefits can cross the barrier and cause serious and harmful effects on the foetus, such as steroids, narcotics and some antibiotics.

Metabolism:

Drug metabolism is a process of chemical modification of a drug and is carried out mostly by enzymes. About 70% of drugs undergo metabolism to some extent. In some cases, the products of metabolism have less biological activity than the parent drug. Metabolism results in the formation of more water-soluble compounds which are then excreted by the body. The primary site for drug metabolism is the liver by conjugation or functionalisation reactions, but with some drugs the kidneys and lungs can be involved. Functionalisation and conjugation are chemical reactions that produce more water soluble metabolites. The major enzyme associated with drug metabolism in the liver is the Cytochrome P450 family. This family of enzymes is numerous and has many different isoforms. Drug metabolism and the impact of drug-drug interactions are associated with this enzyme family. The rates of metabolism of drugs are impacted by genetics, environmental factors, age and disease states, and metabolism is very important in determining the therapeutic and toxic effects of drugs.

Excretion:

Drugs continue to have effects on the body until they are eliminated. Drugs can be eliminated by a number of routes. Drugs can be excreted unchanged or after having been extensively metabolised, in urine via the kidneys. Post metabolism by the liver drugs can be transported into bile and excreted in faeces. Other drugs are excreted via expired air and this is affected by respiration rates and cardiac output. Drugs can also be excreted in saliva and sweat, as well as breast milk.

Pharmacogenetics

The effects of genetics on the action and elimination of drugs is called pharmacogenetics. The greatest causes of variability in the activity of enzymes are genetic factors. This is particularly relevant when a single enzyme is responsible for the metabolism of a drug. If one gene controls the metabolism of a drug then a mutation in the gene may give rise to genetic polymorphism (the occurrence of two or more distinct types in a population) which is recognised in a population as individuals described as poor or extensive metabolisers.

The incidence of genetic polymorphism varies: Pseudocholinesterase deficiency which affects the metabolism of suxamethonium occurs at a rate of 1 in 2500 and is considered very uncommon.

However, a deficiency in CYP2D6, which metabolises many clinically used drugs occurs at a rate of 7-10% in the Caucasian population but at only around 1% in the Asian population. CYP2D6 metabolises many drugs that have a narrow therapeutic index so this action is of considerable clinical significance.

Examples: Fluoxetine, Haloperidol, Risperidone, Codeine

In 50% of Caucasians, there is a deficiency in N-acetyltransferase. Polymorphism in this system leads the population into two significant groups – rapid and slow acetylators. Rapid acetylators metabolise a greater proportion of the drug dose abd therefore do not achieve therapeutic plasma concentration of the drug. Slow acetylators can be more sensitive to the drug and often experience serious adverse effects.

References:

Galbraith, A, Bullock, S and Manias, e. (1994) Fundamentals of Pharmacology for Health Professionals – a text for nurses and allied health professionals, Addison-Wesley Publishing Company, Sydney.

Birkett, D. (2002) Pharmacokinetics made easy: revised, The McGraw-Hill Companies, Inc, Sydney.

Bryant, B and Knights, K (2007), Pharmacology for health professionals: 2^nd ED, Mosby Elsevier, Sydney.