Pharmacodynamics

Question 1

What are some general classification of drug effects?

Answer 1

1. Excitation: an increase or enhancement of mental activity by a drug e.g. stimulation of mental activity by caffeine
2. Inhibition: a decrease of the function produced by a drug e.g. barbiturates induced sedative-hypnotic effect
3. Therapeutic effect: the effect affecting the physiological and biochemical functions of the organisms and pathogenic processes. It is used to prevent and treat diseases
4. After effect: the effect still exists, after withdrawal of the drug, the drug concentration is below the threshold, such as, the patient feels hangover the next morning
5. Adverse effect: any response to drug that is noxious and unintended and that occurs at doses used for prevention, diagnosis, and therapy of a disease, or for the modification of physiological function

Question 2

What is an allergy?

Answer 2

1. Am adverse reaction that results from previous sensitisation to a particular chemical or to one that is structurally similar
2. Such reactions are mediated by the immune system

Question 3

What are toxic effects?

Answer 3

1. Toxic effect: noxious effects induced by over dosage of drugs or accumulation of large amount of drugs
2. Acute toxicity - damage to functions of circulatory system, respiratory system, and nervous system
3. Chronic toxicity - damage to hepatic, renal, bone marrow, and endocrine function

Question 4

What are the different types of treatment?

Answer 4

1. Aetiological treatment: means that the drug may eliminate the primary pathogenic factor and cure disease e.g. antibiotics eliminate pathogenic organisms within the body
2. Symptomatic treatment: means that the drug may improve the symptoms of disease, such as, use aspiring to treat high fever

Question 5

What are the two modes of drug action?

Answer 5

1. Non-specific action - due to their physical and chemical properties
   a) e.g. Mannitol (osmotic diuretic) which is pharmacologically inactive but increases osmotic pressure of tubular fluid and therefore passive water reabsorption is reduced leading to diuresis
   i) Is used to force urine production in people with acute (sudden) kidney failure). Increased urine production helps prevent kidneys from shutting down and also speeds up elimination of certain toxic substances in the body
2. Specific action of drugs
   a) Molecular targets for specific drug action
   i) Act on 4 main types of regulatory proteins including carriers, enzymes, ion channels, and receptors

Question 6

Describe drug action on carriers:

Answer 6

1. Ions and molecules having insufficient lipid solubility are not able to diffuse across the cell membrane - they must be transported by carriers
   a) Carriers are also involved in the uptake of chemicals acting at nerve terminals e.g. noradrenaline, serotonin, glutamate
2. Drugs may block the carrier molecule transport system in the presynaptic membrane
   a) e.g. Tricyclic antidepressants and cocaine inhibit carrier-mediated uptake of noradrenaline
   b) selective serotonin reuptake inhibitors are antidepressant drugs that block the re-uptake of serotonin into presynaptic neuron

Question 7

Describe drug action on enzymes:

Answer 7

1. Enzymes control biochemical reactions in cells
2. A drug can inhibit the action of an enzyme to alter the physiological response
   a) E.g. angiotensin-converting enzyme can be inhibited by Captopril (antihypertensive) - prevents angiotensinogen II production
   b) Neostigmine reacts with acetylcholinesterase to prevent the inactivation of ACh at the neuro-muscular junction
3. Two main mechanisms of drug inhibition
   a) Competitive inhibition
   b) Non-competitive inhibition

Question 8

Describe competitive inhibition:

Answer 8

1. Endogenous substrate and enzyme inhibitor (drug) compete for the same binding sites
2. Generally reversible by increasing the concentration of the substrate
3. Normal is slowed down or in some cases completely inhibited
4. A competitive inhibitor has a chemical structure and molecular geometry similar to the substrate - the inhibitor is able to block the active site of the enzyme making it unavailable to the substrate
5. Examples include:
   a) Monoamine oxidase inhibitors such as moclobemide (antidepressant)
   b) Antibiotics such as sulphonamides

Question 9

Describe non-competitive inhibition:

Answer 9

1. Substrate and enzyme inhibitor (drug) compete for different binding sites
   a) However, binding of an inhibitor to one site changes the shape of the active site on the enzyme to prevent substrate binding/activation at the other site
2. There is no product and this inhibition is irreversible
3. Examples include:
   a) Heavy metal ions
   b) Antimetabolites
   c) Aspirin
   d) Cytotoxic (anticancer) drugs
   e) Mercury

Question 10

Describe drug action on ion channels:

Answer 10

1. Ions are unable to cross the cell membrane without the assistance from proteins
2. Ion channels are small pores that permit water or particular ions to pass through
   a) Ion channels are selective
   b) Ion channels can exist in open or closed form
3. Many drugs target ion channels via two mechanisms of modulation:
   a) Drugs that block open channels (e.g. Lidocaine)
   b) Drugs that act on receptors on ion channels (e.g. Benzodiazepine)

Question 11

Describe drug action on receptors:

Answer 11

1. Most of the drugs act by interacting with a cellular component called a receptor
   a) Receptors are protein molecules present either on cell surface or within the cell e.g. adrenergic receptors, cholinergic receptors, insulin receptors etc
2. Endogenous ligands (e.g. neurotransmitters, hormones) and drugs produce their effects by binding with their specific receptors
   a) Receptors for most water-soluble drugs (e.g. adrenaline or insulin) are located on cell membranes while receptors for lipid-soluble drugs (e.g. steroids) are in the cell cytoplasm or nucleus
3. Drugs act on receptors via specific binding and can be agonists or antagonists

Question 12

What is affinity and specificity?

Answer 12

1. Affinity: extent of binding of a drug to a receptor (measure of fit of a drug to a receptor)
2. Specificity: relates to a degree of selectivity (a drug may interact with one subtype of receptor but not with another subtype - or produce an effect at one site but not another)

Question 13

What is selectivity?

Answer 13

1. Drugs show a preference for a molecular target
2. Selectivity of a drug for any molecular target depends on its chemical structure, molecular size, and electrical charge
3. Changes in drug structure, molecular size, or electrical charge can significantly increase or decrease the binding of a drug to its molecular target, altering its therapeutic effect or toxicity

Question 14

What are the different type of receptors?

Answer 14

1. Type 1: Transmitter-gated ion channels (e.g. ACh receptor)
2. Type 2: G-protein-coupled receptors (associated with 2nd messengers)
3. Type 3: Kinases-linked receptors (catalytic receptors)
   a) Tyrosine-kinases transmit signals from hormones and growth factors
4. Type 4: Intracellular receptors (located in cytoplasm or nucleus)

Question 15

What is a second messenger?

Answer 15

1. An intracellular chemical (e.g. cyclic adenosine monophosphate) that may increase or decrease when an agonist binds to receptor
   a) The 2nd messenger then causes physiological effects through a series of protein kinases that control cell function by phosphorylating proteins

Question 16

What is efficacy and potency?

Answer 16

1. Efficacy: ability of a drug to produce an effect at a receptor (a drug with the higher maximum effect efficacious)
2. Potency: relative amount of drug that has to be present to produce an effect (a more potent drug requires administration of a lower dose to produce the desired clinical effect)

Question 17

What are agonists?

Answer 17

1. Drugs that bind to a receptor and the receptor has an affinity to the drug
   a) If you increase drug you increase product
2. An agonist binds to and activates the receptor to produce the same response (measurable effect e.g. secretion or muscle contraction) as the endogenous ligand (e.g. adrenaline or dopamine)

Question 18

What are antagonists?

Answer 18

1. An antagonist binds to the receptor and blocks access of the endogenous ligand, thus diminishing the normal response
2. For example, propranolol (beta-blocker) can be used in a person with tachycardia to decrease the heart rate (it blocks the action of circulating adrenaline and slows HR)
3. An agonist has both an affinity and efficacy, whereas an antagonist has affinity but not efficacy
4. Drugs may act as reversible or irreversible antagonists

Question 19

What are partial agonists?

Answer 19

1. When a ligand binds to a receptor, bonding occurs between the two to allow a normal action
2. Some drugs do not fit exactly at the receptor site so bond formation occurs to a lesser extent and only a reduced response occurs
   a) Drugs with lower affinity are called partial agonists as their action is less than the natural stimulus

Question 20

What are competitive (reversible) antagonists?

Answer 20

1. Compete with the binding of the endogenous agonist
2. Their action can be overcome by increasing the concentration of the agonist
3. E.g. higher concentrations of adrenaline can overcome

Question 21

What are competitive (irreversible) antagonists?

Answer 21

1. These have limited therapeutic usefulness as they render the target receptor permanently unavailable for binding of the endogenous agonist
2. No clinical value, used experimentally to investigate receptor function
3. An example of a competitive irreversible antagonist is nerve gas

Question 22

What are non-competitive antagonists?

Answer 22

1. These drugs block the response to an agonist at some point during the intracellular events
2. Reduce both the maximal response and the steepness of the gradient of the dose-response curve
   a) Means it reduces the potency and efficacy
3. E.g. calcium channel blockers, which bind to the Ca channel to block the influx of Ca2+ ions through the open channel
   a) In the presence of the non-competitive antagonist blockade of the channel, an agonist cannot cause Ca2+ movement to elicit muscle contraction

Question 23

What is an allosteric modulator?

Answer 23

1. The binding of the drug at the second site causes a conformational change in the shape of the protein receptor molecule, either causing reduced affinity of the primary agonist or potentiating the effect of the primary agonist
2. E.g. some benzodiazepines bind to the GABA receptor causing a change that increases the affinity of the receptor for the endogenous inhibitory neurotransmitter GABA = increased sedation and hypnosis

Question 24

What is receptor desensitisation and turnover?

Answer 24

1. Receptor populations are not static
2. Receptors may undergo several changes, including loss of responsiveness or a decrease or increase in the number of receptors
3. Tachyphylaxis = diminished responsiveness after repeated exposure to the same concentration of the drug that stimulates the receptor
   a) e.g. transdermal glyceryl trinitrate in treatment of angina requires intermittent dosing schedule to limit the problem of tachyphylaxis

Question 25

What is downregulation of receptors?

Answer 25

1. The total number of receptors in the cell membrane can change
2. A decrease in receptor number is called downregulation and can contribute to desensitisation and loss of response

Question 26

What is upregulation of receptors?

Answer 26

1. An increase in receptor number is referred to as upregulation and can cause receptor super-sensitivity
2. E.g. upregulation of receptors often occurs after chronic use of drugs that block receptors; when the drug is abruptly removed the person experiences increased responsiveness to stimuli