Drugs, enzymes and transporters

Question 1

Enzyme inhibitor

Answer 1

A molecule that binds to an enzyme and (normally) decreases its activity.

Prevents the substrate from entering the active site thus from catalysing the reaction.

Question 2

What are the two types of enzyme inhibitors?

Answer 2

Irreversible: usually reach with the enzyme and change it chemically (via covalent bond)

Reversible: bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind to the enzyme, enzyme-substrate complex, or both.

Question 3

Enzymes themselves can be drug products

Answer 3

Streptokinase and tPA

Question 4

Statins

Answer 4

Block the rate limiting enzyme in the cholesterol pathway (HMG-CoA reductase inhibitors).

For primary prevention of cardiovascular disease.

Question 5

ACE inhibitors for BP

Answer 5

Inhibiting ACE reduces ATII production and therefore reduces BP.

First generation - Captopril (blocks proteolytic residues on 9 His and 10 Leu)

Second generation (Enalaprilat - blocks the active site).

Question 6

ACE can be hijacked

Answer 6

SARS-CoV-2 - ACE2 as an entry receptor.

Question 7

Enzymes can target multiple steps in biosynthetic pathways.

Answer 7

PD - early degeneration of dopaminergic neurones in the nigrostriatial pathway - leading to autonomic dysfunction and dementia.

Question 8

L-DOPA

Answer 8

Synthesised from L-Tyrosine as a precursor for neurotransmitter biosynthesis.

Question 9

Carbidopa

Answer 9

Peripheral DDC Inhibitor Blocks DDC in the periphery generating more for the CNS pathway.

Question 10

Catechol-O-methyl-transferase COMT inhibitor - Entacapone

Answer 10

Peripheral COMT Inhibitorprevents breakdown of L-DOPA generating more for the CNS pathway

Question 11

Tolcapone

Answer 11

Central COMT InhibitorsFunction within the CNS to keep Dopamine levels up.

Question 12

Selegiline/Rasagiline

Answer 12

Mono Amine Oxidase B InhibitorsPrevents Dopamine breakdown and increases availability.

Question 13

D1 Bromocryptine, Pergolide
D2 Pramipexole, Ropinirole, Rotigotine

Answer 13

Central Dopamine Receptor AgonistsAntagonise dopamine receptors (not enzyme inhibitors).

Question 14

Drugs and Ion transport

Answer 14

Passive (no energy required)
Symporter
Na/K/2Cl , NaCl
Channels
Na, Ca, K, Cl

Active (requires energy)
ATP-ases
Na/K, K/H

Question 15

Active transport

Answer 15

Moves ions from a lowerconcentrationto a higher concentration. Allows cells get what they need, such asions,glucoseandamino acids.
Needs energy (normally fromadenosine triphosphate(ATP).

Question 16

Three main types of protein ports in cell membranes

Answer 16

Uniporters: use energy from ATP to pull molecules in.

Symporters: use the movement in of one molecule to pull in another molecule against a concentration gradient.

Antiporters: one substance moves against its gradient, using energy from the second substance (mostly Na+, K+ or H+) moving down its gradient.

Question 17

Example of a symporter

Answer 17

The Na-K-Cl co-transporter (NKCC) is a protein that transports Na, K, and Cl into cells.
Move ions in the same direction
Functions in organs that secrete fluids.
Furosemide (a so-called loop diuretic - used for hypertensionandedema)
Acts by inhibiting the luminalNKCC in thethick ascending limbof theloop of Henle
Binding to the NKCC causes sodium, chloride, and potassium loss in urine

Question 18

Ion channels

Answer 18

Exist in many tissues.

Epithelial (Sodium) – heart failure

Voltage-gated (Calcium, Sodium) – nerve, arrhythmia

Metabolic (Potassium) – diabetes

Receptor Activated (Chloride) - epilepsy

Question 19

ENaC

Answer 19

An (apical) membrane-bound heterotrimeric* ion channel selectively permeable to Na+ ions
Causes reabsorption of Na+ ions at the collecting ducts of the kidney’s nephrons (also in colon, lung and sweat glands)
Blocked by the high affinity diuretic amiloride (often used with Thaizide).
Thaizide targets Na+Cl− cotransporter that reabsorbs Na and Cl from tubular fluid
Used as a anti-hypertensive

Question 20

VGCC

Answer 20

Voltage-gated ion channels (VDCC) are found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.)
At physiologic or resting membrane potential, VDCCs are normally closed.
They are activated (i.e., opened) at depolarized membrane potentials (action potential)*.
Ca2+ enters the cell, resulting in activation of Ca-sensitive K channels, muscular contraction, excitation of neurons etc

Question 21

VGCC inhibition

Answer 21

Amlodipine - angioselective (inhibits movement of Ca into vascular smooth muscle cells and cardiac muscle cells.

This inhibits the contraction of cardiac muscle and vascular smooth muscle cells

Amlodipine inhibits Ca ion influx across cell membranes, with a greater effect on vascular smooth muscle cells

Causes vasodilation and a reduction peripheral vascular resistance, thus lowering blood pressure

Also prevents excessive constriction in the coronary arteries.

Question 22

VGSC

Answer 22

Conducts Na+ through plasma
membrane.
Classified according to the
trigger that opens them-
“Voltage-gated” or “ligand-
gated”.
In excitable cells voltage-gated Na+channels have three main conformational states: closed, open and inactivated.
An action potential allows the activation gates to open, allowing Na+ions to flow into the cell causing the voltage across the membrane to increase – transmits a signal
Lidocaine (anaesthetic) blocks transmission of the action potential. Also blocks signaling in the heart reducing arrhythmia.

Question 23

VGPC

Answer 23

Selective for K+ and Na+.

Present in many excitable tissues.

Three conformational states: closed, open, inactivated.

An electric current (action potential) allows the activation gates to open eliciting a downstream effect.

Question 24

VGPC and insulin secretion

Answer 24

Regulate insulin in Pancreas:  Islets of Langerhans
Increased glucose leads to block of ATP dependent K+ channels.
Repetitive firing of action potentials increases Ca+ influx and triggers insulin secretion
Repaglinide, nateglinide and sulfonylureal lower blood glucose levels by blocking K+ channels to stimulate insulin secretion.
Used for treatment of type II diabetes.

Question 25

Receptor-mediated channels (Chloride)

Answer 25

Ligand-gated ion channels (ionotropic receptors), open to allow ions to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand) such as a neurotransmitter an example is GABA -A Receptor.

Question 26

GABA

Answer 26

Endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the CNS.

GABA A receptor is post-synaptic, opens Cl- channel - induces hyperpolarisation.

Drugs can enhance activation of GABA A receptor by GABA
ie produce greater inhibition.

Barbiturates increase the permeability of the channel to chloride

As with many receptors many drugs can block the GABA-A complex !!!

Question 27

NA/K ATP-ase

Answer 27

Pumps Na out and K into cells, against their concentration gradients.
This pumping is active (energy comes from ATP).
It has antiporter-like activity (moves both molecules against their concentration gradients.
Pump 3 Na ions out for every 2 K ions in and creates a electrochemical gradient between a cell and its exterior.
The reverse process (unlike the forward) is spontaneous.

Question 28

Digoxin

Answer 28

The sodium pump is another ATP-ase converting ATP-ADP. It pumps 3Na out of the cell for2K going into the cell.
It is used to re-establish membrane potential in excitable tissue. This Atp ase is inhibited by digoxin. Two consequences are
Firstly sodium retention (NA transient). Na is then swopped for Ca by a Na/Ca antiporter. The increased free calcium produces
The inotropic action of the cardiac glycoside.

Digoxin is used for atrial fibrillation, atrial flutter, and heart failure

Question 29

K/H ATP-ase in stomach

Answer 29

The gastric hydrogen potassium ATPase or
H+/K+ ATPase is the proton pump of the stomach.

H+/K+ ATPase is a heterodimeric protein
(the product of 2 genes)

It exchanges potassium from the intestinal
lumen with cytoplasmic hydronium (hydrogen ion form in aqueous solution).

responsible for the acidification of the stomach and the activation of the digestive enzyme pepsin.

Question 30

PPIs

Answer 30

Blocked by Proton-pump inhibitors (PPIs), they are the most potent inhibitors of acid secretion available
Omeprazole (1st in class) - inhibits acid secretion independent of cause.
Irreversible inhibition of H/K ATP-ase - drug half-life 1h, but works for 2-3 days
Omeprazole metabolised at acid pH – enteric coated granules (alters own bioavailability)

Largely superseded by H2-receptor antagonists.

Question 31

Irreversible enzyme inhibitors

Answer 31

Organophosphates (insecticides, nerve gases) act on muscarinic, nicotinic and CNS.

Question 32

Irreversible enzyme inhibitors

Answer 32

Omeprazole
Aspirin

Question 33

Xenobiotics

Answer 33

Compounds foreign to an organism’s normal biochemistry, such any drug or poison.