Pharmacology

Question 1

Partiel agonist

Answer 1

Promotes a stimulatory respons, that is lower than the maximal respons (elicited by the full agonist). The partial agonist is an antagonist compared to the full agonist.

Question 2

Invers agonist

Answer 2

A drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. (<12%)

Question 3

Affinity

Answer 3

How well the ligand is binding to the receptor. Is expressed as KD and/or Bmax.

Question 4

KD

Answer 4

The dissociation constant, is commonly used to describe the affinity between a ligand and its receptor. Therefore, Kd can be used as a measure of binding affinity (how tightly a ligand binds to a receptor).
The ligand concentration (X-axis) that gives 50% of the maximum specific binding. A higher KD means that you require a higher concentration of ligand to bind 50% of the target (high KD = low affinity)

Question 5

IC50

Answer 5

Antagonist concentration that inhibits 50% of the max agonist response.

Question 6

Bmax

Answer 6

Maximal binding capacity ( fx the number of receptors per cell or per mg membrane protein) - only important in experimental conditions.

Question 7

Potency

Answer 7

The amount of agonist needed for a given response. Measured as EC50 (the agonist concentration that elicits 50% of max. activation)

Question 8

EC50

Answer 8

The concentration of an agonist that produces 50% of the maximal response for that agonist.

Question 9

Efficacy

Answer 9

The degree of activation (effect).
The maximum response that can be achieved with a drug. Expressed as Emax (the maximal achievable response for a given agonist).

Question 10

Therapeutic window/index

Answer 10

Describes the dosage range between a minimum effective therapeutic concentration, and the minimum toxic concentration.
Is calculated by TD50/ED50.

Question 11

ED50 and TD50

Answer 11

ED50: the dose required to produce a therapeutic effect in 50% of the population
TD50: the dose required to produce a toxic effect in 50% of the population.

Question 12

Therapeutic range

Answer 12

The plasma drug concentration that has the intended therapeutic effect with minimal side effects.

Question 13

Allosteric binding

Answer 13

When an effector molecule binds to a site that is different from the agonist binding site.

Question 14

Competitive antagonist

Answer 14

A competitive antagonist binds to the same site as the agonist but does not activate it, thus blocks the agonist’s action. (If there are both an agonist and competitive antagonist present, then there will be a change in potency, but no change in Emax).

Question 15

Noncompetitive antagonist

Answer 15

A non-competitive antagonist binds to an allosteric (non-agonist) site on the receptor to prevent activation of the receptor. (If there are both a agonist and a noncompetitive antagonist present, then there will be bo change in potency, but a change in Emax).

Question 16

Tachyphylaxis

Answer 16

A rapid response to a large initial dose of a drug. To protect itself, the cell desynthesizes itself to how much drug is out there. The cell can do this by:
1. Decrease the synthesis of the receptor (less receptor to bind to).
2. Enzymes can phosphate residues to the receptors, and thereby inhibit or inactivate the receptor.
3. Endocytosis of the receptor.

Question 17

Tolerance

Answer 17

A chronic response to a drug, the signal is weakened within days and weeks.
The cell protects itself by endocytosis of receptors and by stopping the synthesis of receptors.
There is an increase in metabolic enzymes, that work to break down the drug. When they break down the drug, it will reduce the efficacy of the drug, that will reduce the response that the drug will produce in the body. It is possible to overcome the activity of the enzyme if the enzyme gets oversaturated, so an increase in dose, can overcome the decreased response/effect.

Question 18

Desensitization

Answer 18

When the effect of the drug is weakened within minutes after activation.

Question 19

Resistance

Answer 19

When the activity of the drug disappears (e.g. resistance to chemotherapy).

Question 20

First pass effect

Answer 20

The phenomenon where orally administered drugs are eliminated on the first pass by the (1) gut epithelia, (2) liver, or (3) lungs. Majority of the first pass effect are due to the liver.

Question 21

Bioavailability (F)

Answer 21

It is the proportion of the drug that is absorbed and can then be distributed. IV will have a bioavailability of 1 and all other routes are measured compared to this.
(F = AUC p.o. / AUC i.v)

Question 22

Factors that affect the bioavailability

Answer 22

Solubility - hydrophobic and small drugs have a high bioavailability, the opposite has a low.
Instability - drugs can be degraded by e.g. HCl in the stomach.
First pass effect - low first pass effect, increased bioavailability

Question 23

What can affect the absorption of a drug?

Answer 23

pH - easier to absorb a non polar drug.
Blood flow - a decreased blood flow to a particular organ, results in a decreased absorption.
Total surface area + contact time - diseases that destroy the vili and microvili, the surface area all decrease and decrease the absorption.
P-glycoprotein - this protein will transfer the drug right back to the GIT. Then the drug will not be absorbed.

Question 24

Types of administration

Answer 24

Topical (skin or mucous surface) - slow effect and can cause local irritation.
Oral - easy and convenient, but there is higher first pass effect and can cause irritation.
IV - low first pass effect and fast absorption.
Rectal - absorption can be unreliable but can be rapid and more complete than following oral administration. Less first pass effect than oral.
Sublingual - rapid response, low first pass effect as the drug won’t be degraded by gastric pH or be rapidly metabolized by the liver. Potentially poor absorption.
Pulmonary - fast absorption, high first pass effect.

Question 25

Factos affecting distribution

Answer 25

Blood flow
Capillary permeability
Protein binding
Solubility
Volume of distribution

Question 26

Volume of distribution (Vd)

Answer 26

The amount of drug in the tissues / concentration of drug in the blood plasma.
Vd = (D*F)/C0
D = dose of drug administered
C0 = concentration of the drug at time 0.

Question 27

Phase 1 biotransformation

Answer 27

CYP450 system makes the drug more polar and water soluble by oxidation, reduction, hydrolysis, dealkylation, deamination etc.

Question 28

Phase 2 biotransformation

Answer 28

CYP450 system makes the drug more polar and/ water soluble and/or larger, so it can be excreted. This is done by conjugation reaction (adding methyl, acetyl, sulfa, glutathione, or glucocaronate).

Question 29

Loop diuretics
- Example
- Mechanism
- Usage
- Side effects

Answer 29

Example: furosemide, bumetanide
Mechanism: antagonist for the Na+/K+/2Cl- transport in the loop of Henle.
Usage: (1) oedema - vasodilation of pulmonary veins leads to reduced pulmonary oedema. Removal of edemas in chronic heart failure, cirrhosis and hypertension. (2) Renal failure treatment – reduces O2 consumption (b/c the kidney is reabsorbing less = not working as hard)
Side effects: Hypotension, hypokalemia, hypocalcemia, and hypomagnesia, and increased renin secretion.

Question 30

Thiazides
- Example
- Mechanism
- Usage
- Side effects

Answer 30

Example: HCTZ, chlorothiazide
Mechanism: antagonist for Na+/Cl co-transporter in the early distal tubule.
Usage: (1) hypertension - they have vasodilator action, as well as reducing water reabsorption, however the hypotensive effects are slightly counteracted by an increase in renin secretion. (2) oedema, chronic heart failure cirrhosis, hypertension.
Side effects: hypotension, hypokalemia, increased renin secretion.

Question 31

Potassium-sparing diuretics - aldosterone antagonist
- Example
- Mechanism
- Usage
- Side effects

Answer 31

Example: spironolactone
Mechanism: aldosterone antagonist
Usage: (1) Co-administration with loop diuretics or thiazides to prevent hypokalemia from these drugs. (2) treat hypertension with increased aldosterone secretion.
Side effects: hyperkalaemia.

Question 32

Potassium-sparing diuretics - Enac inhibitors
- Example
- Mechanism
- Usage
- Side effects

Answer 32

Example: amiloride
Mechanism: Enac inhibitor. This reduces Na+ reabsorption from the lumen, reducing the excretion of K+ into the lumen as the lumen becomes less negative.
Usage: Co-administration with loop diuretics or thiazides to prevent hypokalaemia.
Side effects: Hyperkalaemia

Question 33

Osmotic diuretics

Answer 33

Example: mannitol
Mechanism: pharmacologically inert substances that are filtered in the glomerulus but not reabsorbed, thereby increasing the osmolarity of the tubular fluid, increasing the osmotic pressure driving water into the lumen. Therefore, their area of action is where aquaporins and water transport occur.
Usage: increase water secretion in acute renal failure to limit protein deposition as a result of poor filtration.
Side effects: hyponatraemia

Question 34

Carbonic anhydrase inhibitors

Answer 34

Example: acetazolamide
Mechanism: Inhibit carbonic anhydrase in the proximal tubule to increase the excretion of bicarbonate along with accompanying Na+, K+, and water.
Side effects: metabolic acidosis (loss of bicarbonate in urine, so decreased pH in blood), hypotension and hypokalaemia.

Question 35

Cholinergic receptors - Muscarinic receptors

Answer 35

Types and location:
M1 (brain, gastric parietal cells).
M2 (heart, SA node, autoreceptors).
M3 (smooth muscle, glands, eyes).
M4/M5 (CNS).

Class:
M1 - Gq
M2 - Gi
M3 - Gq
M4/M5 - Gi-Gq

Function when receptor is stimulated:
- HCl secretion (M1)
- Temperature regulation (M1)
- Decrease HR (M2)
- Increased GI motility (M3)
- Pupil constriction (M3)
- Accommodation of eye (M3)
- Increased spit secretion (M3)
- Bronchoconstriction and increased secretion (M3)
- Contraction of bladder (M3)
- Increased sweat secretion (M3)
- Decrease BP by NO release (M3)
- M4 and M5 have unknown effects, but likely CNS and related to learning

Question 36

Cholinergic receptors - nicotinic receptors

Answer 36

Ligand-gated ion channels, located in CNS, adrenal gland, autonomic ganglia and neuromuscular end plates.
- when activated by Ach, sodium channels open, ESPS

Question 37

Muscarinic receptor agonists - Pilocarpine

Answer 37

MOA: Is a non-selective agonist for the muscarinic acetylcholine receptor, but it has a bit higher affinity to the M3 subtype -> Stimulates Gq (GPCR) -> IP3 and DAG -> increased intracellular Ca2+

Effect: Is administered as eye drops for a local effect on the eyes -> increased parasympathetic activity in eyes -> smooth muscles in eye are activated and contracts the pupil and accommodates the lens -> intraocular pressure is decreased

Indication: Treatment of glaucoma (too high intraocular pressure). Can also be used locally in the mouth to increase saliva production.

Side-effects: Bradycardia and hypotension, diarrhea, increased salivary production and sweat production, miosis (pupil constriction).

Question 38

Muscarinic receptor antagonists - atropine

Answer 38

MOA: Non-selective competitive antagonist -> inhibits parasympathetic activity by blocking the muscarinic receptors. E.g: Blocks M2 in SA node in the heart -> blocks the parasympathetic effect on the heart (aka blocks the negative effect that parasympathetic innervation has on heart rate) -> heart rate increases

Effect: Is a non-selective antagonist -> blocks all of the different types of muscarinic receptors! AKA. many side effects!

Indication: Parasympathetic-induced bradycardia, pre operation -> to decrease spit, ventricle and bronchial secretion during operation, poisoning with AChE inhibitors. Previously used to dilate pupils and as an adjuvant for anesthetics.

Side-effects: urine retention, reduced vision, dry mouth, obstipation.

Question 39

Nicotine receptor agonists - suxamethone

Answer 39

MOA: Binds the nicotinic receptor at the neuromuscular endplate and is not removed by the acetylcholinesterase in the synaptic cleft -> continuous depolarization, the receptor stays open -> no repolarization is possible (is irreversible!). This results in an initial muscle “twitch” upon binding of the drug to the receptor, followed by a neuromuscular blockage where the muscle is relaxed and cannot be further stimulated because the drug is still bound to the receptor and blocks it. Suxamethone is removed by acetylcholinesterases existing in the plasma, after 10-15 min.

Indication: Used before intubation (as a muscle relaxant) before surgery. Is short-acting.

Side effects: Myalgia (because the initial muscle twitches can give muscle pains), bradycardia (because the drug binds both nicotinic and muscarinic receptors including M2 in the heart)

Question 40

Nicotinic receptor antagonists - rocuronium

Answer 40

MOA: Competitive nicotinic receptor antagonist -> blocks the opening of the receptor -> Ach cannot bind to the active site. Gives a muscle relaxing effect (paralysis). The effect of the drug depends on the amount of Ach, because these two compete on the active site. The effect of the drug is reversible: By increasing the concentration of Ach e.g by giving inhibitors of acetylcholinesterase -> more Ach competes with the drug -> reduced effect of the drug.

Indication: Intubation (paralysis).

Side effects: Few.