Pharmacology

Question 1

What is the difference between pharmacokinetics and pharmacodynamics?

Answer 1

• Pharmacodynamics- what a drug does to the body

* Pharmacokinetics- what the body does to a drug

Question 2

Define agonist and antagonist

Answer 2

1) Agonists- drug that binds to a receptor to produce a cellular response
2) Antagonist- drug that reduces or blocks the actions of an agonist by binding to the same receptor

Question 3

Define affinity and efficacy in agonist binding

Answer 3

• Affinity is the relationship between binding and unbinding rate.
• The more bonds and the higher the strength of the bonds, the higher the affinity.
• Efficacy is the ability of an agonist to evoke a cellular response

Question 4

What do antagonists possess?

Answer 4

Only affinity

Question 5

Explain potency

Answer 5

• Potency is a measure of drug activity.

* A drug is less potent if you need a bigger range of concentrations to produce the same biological effect

Question 6

Explain competitive antagonism

Answer 6

• Binding of agonist and antagonist both of which are reversible occur at the same time (orthosteric) site and is thus competitive and mutually exclusive.
• Reversible competitive antagonism can be overcome by increasing the concentration of agonist.
• Antagonists and agonists compete for the same binding site.

Question 7

Explain non-competitive antagonism

Answer 7

• Agonist binds to the orthosteric site and antagonist binds to a separate allosteric site and this is not competitive.
• Both may occupy the receptor reversibly and simultaneously but activation cannot occurs when antagonist is bound.

Question 8

Explain ligand gated ion channels

Answer 8

These are located at the plasma membrane and targeted by hydrophilic signalling molecules. Action is on a millisecond time scale.

Question 9

Explain G-protein coupled receptors

Answer 9

These are located at the plasma membrane, targeted by hydrophilic signalling molecules. Action is on a signal on a second time scale. G proteins activated by agonist binding to their receptor then producing series of reactions resulting in desired response.

Question 10

Explain kinase linked receptors

Answer 10

These are located at the plasma membrane and targeted mainly by hydrophilic protein mediators. Binding by agonist triggers a series of phosphorylation events eventually producing desired response. They work on an hours time scale.

Question 11

Explain nuclear receptors

Answer 11

These are located intracellularly in the nucleus (or cytoplasm), targeted mainly by hydrophobic signalling molecules. They have very slow action on an hours/day time scale. These are ligand gated transcription factors. Binding will either promote or inhibit transcription of specific genes.

Question 12

What Physicochemical Factors control drug absorption?

Answer 12

1. Solubility: The drug (within a medication) must dissolve (dissolution) in order to be absorbed.
2. Chemical stability: Some drugs are destroyed by acid in the stomach, or enzymes in the gastrointestinal tract.
3. Lipid to water partition coefficient: Absorption of a drug commonly occurs by simple diffusion across membranes (importantly, some agents are transported). For a given drug concentration gradient across a membrane, the rate of diffusion increases with the lipid solubility of the drug.
4. Degree of Ionisation: Many drugs exist as weak acids (e.g. aspirin) or weak bases (e.g. morphine), existing in both ionised (A-, BH+) and unionised (AH, B) forms. Only unionised forms readily diffuse across the lipid bilayer unaided (the factors are embodied in Fick’s law).

Question 13

When does the pH equal the pKa of the drug?

Answer 13

When 50% of the drug is ionised and 50% unionised.

Question 14

Describe the absorption of acids and bases

Answer 14

• Absorption of weak acids is facilitated by the pH of the stomach lumen. Bases are not readily absorbed until they reach the small intestine
• The overwhelming majority of absorption (even weak acids) occurs in the small intestine due to the large surface area.
• Weak acids and weak bases are well absorbed, strong acids (pKa < 3) and strong bases (pKa > 10) are poorly absorbed.
• Acidic drugs become less ionised in an acid environment, basic drugs become less ionised in a basic environment.

Question 15

What are factors affecting gastrointestinal absorption?

Answer 15

• Gastrointestinal motility: The rate of stomach (gastric) emptying and movement through the intestines. This can be modified by several pathologies such as migraines, it can also be altered by drugs and the presence of food.
• pH at the absorption site: This varies along the gastrointestinal tract.
• Blood flow to the stomach and intestines: This is increased by food.
• The way in which the tablet, capsule etc. is manufactured: This can be customised to release drugs at different rates and sites.
• Physicochemical interactions: For example, the rate of absorption of some drugs is modified by calcium-rich foods.
• The presence of transporters: These are found in the membranes of epithelial cells of the G.I tract and can facilitate drug absorption

Question 16

What is the difference between enteral and parenteral routes?

Answer 16

Enteral is via the GI tract, parenteral is not

Note to read over the advantages and disadvantages of the routes

Question 17

What are the four main body water compartments drugs can be distributed in?

Answer 17

1. Interstitial water
2. Intracellular water
3. Plasma water
4. Transcellular water

Question 18

What is Vd and how do you interpret the value?

Answer 18

• Volume of distribution Vd Is is the volume into which a drug appears to be distributed with a concentration equal to that of plasma.
• Vd < 10 L implies that the drug is largely retained in the vascular compartment. It occurs for drugs extensively bound to plasma protein (e.g. aspirin, warfarin), or too large to cross capillary wall (e.g. heparin).
• Vd between 10 and 30 L suggests that the drug is largely restricted to extracellular water. It occurs for drugs with low lipid solubility (e.g. gentamicin, amoxicillin).
• Vd > 30 L may indicate distribution throughout total body water, or accumulation in certain tissues. It occurs for highly lipid soluble drugs (e.g. ethanol, amitriptyline, thiopentone), or those that bind extensively to tissue proteins (e.g. digoxin).

Question 19

How do most drugs leave the body?

Answer 19

In the urine as a chemically transformed compound rendered more polar by metabolism

Question 20

What is the main organ of drug metabolism?

Answer 20

The liver

Question 21

Explain Phase One reactions

Answer 21

Phase 1 reactions are catabolic, and the products sometimes are more toxic/carcinogenic than the original drug. Reactions aim to introduce a functionality that can serve as a point of attack for Phase 2 conjugation systems.

Question 22

Explain Phase Two reactions

Answer 22

Conjugation adds an endogenous compound increasing polarity. This usually results in inactive products.

Question 23

What is the major organ involved in drug excretion

Answer 23

Kidneys

Question 24

Explain the three basic processes involved in drug excretion

Answer 24

1) Glomerular filtration- only drugs that are unbound and have a low molecular weight can enter the filtrate via glomerular filtration (about 20% of plasma flow is filtered this way)
2) Active Tubular Secretion- plasma flow not filtered through the glomerulus is delivered to the peritubular capillaries of the proximal tubule. Epithelial cells of the proximal tubule contain two, independent, transporter systems that actively secrete drugs into the lumen of the nephron, the organic anion transporter for acidic substances and the organic anion transporter for basic substances.
3) Passive Reabsorption by Diffusion (across the tubular epithelium)- there will then be passive reabsorption of many drugs across the distal tubule by diffusion. Factors that will influence reabsorption include: lipid solubility, polarity, urinary flow rate and urinary pH.

Question 25

Explain the therapeutic ratio

Answer 25

• To achieve an effect, a drug must reach a critical concentration in the plasma known as the Minimum Effective Concentration (MEC) but, ideally be well below that causing significant unwanted effects or the Maximum Tolerated Concentration (MTC).
• The therapeutic ratio is MTC/ MEC.
• If the therapeutic ratio is high then the drug is safe, unsafe drugs have a low ratio.

Question 26

What is first order kinetics

Answer 26

The rate of elimination is directly proportional to drug concentration.

Question 27

What does clearance refer to and why is it important?

Answer 27

The term clearance refers to the volume of plasma cleared of drug in unit time. Clearance is important as CL determines the maintenance dose rate (the dose per unit of time required to maintain a given plasma concentration).

Question 28

Explain dosing to a steady state with an IV

Answer 28

• At steady state (ss) the rate of drug administration = rate of drug elimination. For drugs that exhibit first order kinetics, the steady state (ss) plasma concentration (Css) is linearly related to the infusion rate. The time to reach Css is determined by t½, but not the infusion rate. Css is reached after approximately 5 half-lives. You just have more drug at steady state but time to reach that is the same. 5 half lives

Question 29

Explain dosing to a steady state orally

Answer 29

Dosing to steady state with intermittent oral administration involves the same principles as continuous infusion, but plasma concentration fluctuates about an average steady state value (Css (average))

Question 30

What is a loading dose?

Answer 30

A loading dose (LD) is an initial higher dose of a drug given at the beginning of a course of treatment before stepping down to a lower maintenance dose. It is employed to decrease time to steady state for drugs with long half lives. It can be estimated from the Vd of the drug.

Question 31

Explain zero order kinetics

Answer 31

A few drugs of clinical significance are initially eliminated at a constant rate, rather than at a rate that is proportional to their concentration

Question 32

Explain the difference between depolarisation and hyper polarisation

Answer 32

• Depolarization – the membrane potential becomes less negative (or even positive)
• Hyperpolarization – the membrane potential becomes more negative

Question 33

Explain the upstroke and downstroke of an action potential

Answer 33

• Sodium ions will diffuse into the neuron when channels are open and if the membrane potential reaches a threshold level all voltage gated sodium channels will open resulting in the upstroke and depolarisation.
• When depolarisation reaches a critical level the potassium channels will open resulting in repolarisation and the downstroke.
• The undershoot is due to delayed closure of voltage-activated K+ channels

Question 34

Explain the absolute and relative refractory period

Answer 34

• Absolute refractory period – no stimulus, however strong, can elicit a second action potential (all Na+ channels inactivated). Puts a limit on the frequency that nerve fibres can generate action potential.
• Relative refractory period – a stronger than normal stimulus may elicit a second action potential (mixed population of inactivated and closed channels, plus the membrane is hyperpolarized)

Question 35

Explain the difference in the propagation of action potentials in myelinated and unmyelinated axons

Answer 35

• In un-myelinated axons there is only passive spread of current
• In myelinated axons there is decreased leak of current across the axons and the action potential jumps from one Node of Ranvier to the next, this known as saltatory conduction.

Question 36

Explain pre and post ganglionic neurons

Answer 36

Preganglionic neurons, originate in the brainstem or the spinal cord, and the second set, postganglionic neurons, lies outside the central nervous system in collections of nerve cells called autonomic ganglia.

Question 37

What is always the transmitter of pre ganglionic neurons

Answer 37

Acetylcholine

Question 38

What is the different transmitters of post ganglionic neurons in the para sympathetic and sympathetic divisions?

Answer 38

• The transmitter of post ganglionic neurons in parasympathetic is acetylcholine
• The transmitter of post ganglionic neurons in sympathetic division is noradrenaline

Question 39

Explain the lengths of pre and post ganglionic neutrons in the sympathetic and para sympathetic nervous system

Answer 39

• Sympathetic preganglionic neurones synapse with postganglionic neurones in either paravertebral ganglia, or prevertebral ganglia, both of which are close to the spinal cord. Their axons (fibres) are typically short. Sympathetic postganglionic neurones innervate effector cells in organs distant to the sympathetic ganglia. Their axons (fibres) are generally long
• Parasympathetic preganglionic neurones synapse with postganglionic neurones in terminal ganglia that are distant to the CNS and often located in the walls of the target organ. Their axons (fibres) are thus long. Correspondingly, the fibres of the postganglionic neurones are short.

Question 40

Explain chemical transmission in the autonomic nervous system

Answer 40

Sympathetic Division
• Action potential originating in the CNS travels to the presynaptic terminal of the preganglionic neurone triggering Ca2+ entry through voltage-gated ion channels and the release of Acetylcholine by exocytosis
• ACh binds to and opens ligand-gated ion channels (nicotinic ACh receptors) in the postganglionic neurone, causing depolarization and the initiation of action potentials that propagate to the presynaptic terminal of the neurone, triggering Ca2+ entry and the release, usually, of noradrenaline
• Noradrenaline activates G-protein-coupled adrenoceptors in the effector cell membrane to cause a cellular response via ion channels/enzymes

Parasympathetic Division
• This process is very similar to that described for the sympathetic division, with the important exceptions that:
- ACh is always the classical transmitter used by postganglionic neurones
- ACh activates G-protein-coupled muscarinic acetylcholine receptors in the effector cell membrane to cause a cellular response via ion channels/ enzymes

Question 41

Describe cholinoreceptors

Answer 41

Ach is the agonist of nicotinic, or muscarinic receptors: Cholinergic fibres release ACh as transmitter that activates cholinoceptors that are either ligand-gated ion channels (nicotinic), or G-protein-coupled receptors (GPCRs, muscarinic)

Question 42

Describe adrenoreceptors

Answer 42

Adrenergic fibres release NA as transmitter that activates adrenoceptors, all of which (α and β) are G-protein-coupled receptors

Question 43

What beta receptors are in the airways and the heart

Answer 43

Beta 1 receptors in the heart and beta 2 in the airways

Question 44

Describe nicotinic acetylcholine receptor structure of the ganglia

Answer 44

Three beta4 subunits and two alpha 3 subunits.

Question 45

How may blocking of cholinergic transmission at ganglia be achieved?

Answer 45

• Depolarization block by high concentrations of agonists (e.g. nicotine)
• competitive antagonism (e.g. trimetaphan)
• Non-competitive antagonism
• All ganglionic transmission (sympathetic and parasympathetic) is selectively blocked by hexamethonium which non-competitively blocks the channel.

Question 46

What will agonists and antagonists do to release of transmitters in post ganglionic neurons?

Answer 46

• Agonists decrease release as they will produce a response

* Antagonists increase release as they produce no response