Drugs, enzymes and transporters Flashcards
Enzyme inhibitor
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.
What are the two types of enzyme inhibitors?
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.
Enzymes themselves can be drug products
Streptokinase and tPA
Statins
Block the rate limiting enzyme in the cholesterol pathway (HMG-CoA reductase inhibitors).
For primary prevention of cardiovascular disease.
ACE inhibitors for BP
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).
ACE can be hijacked
SARS-CoV-2 - ACE2 as an entry receptor.
Enzymes can target multiple steps in biosynthetic pathways.
PD - early degeneration of dopaminergic neurones in the nigrostriatial pathway - leading to autonomic dysfunction and dementia.
L-DOPA
Synthesised from L-Tyrosine as a precursor for neurotransmitter biosynthesis.
Carbidopa
Peripheral DDC Inhibitor Blocks DDC in the periphery generating more for the CNS pathway.
Catechol-O-methyl-transferase COMT inhibitor - Entacapone
Peripheral COMT Inhibitorprevents breakdown of L-DOPA generating more for the CNS pathway
Tolcapone
Central COMT InhibitorsFunction within the CNS to keep Dopamine levels up.
Selegiline/Rasagiline
Mono Amine Oxidase B InhibitorsPrevents Dopamine breakdown and increases availability.
D1 Bromocryptine, Pergolide
D2 Pramipexole, Ropinirole, Rotigotine
Central Dopamine Receptor AgonistsAntagonise dopamine receptors (not enzyme inhibitors).
Drugs and Ion transport
Passive (no energy required)
Symporter
Na/K/2Cl , NaCl
Channels
Na, Ca, K, Cl
Active (requires energy)
ATP-ases
Na/K, K/H
Active transport
Moves ions from a lowerconcentrationto a higher concentration. Allows cells get what they need, such asions,glucoseandamino acids.
Needs energy (normally fromadenosine triphosphate(ATP).
Three main types of protein ports in cell membranes
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.
Example of a symporter
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
Ion channels
Exist in many tissues.
Epithelial (Sodium) – heart failure
Voltage-gated (Calcium, Sodium) – nerve, arrhythmia
Metabolic (Potassium) – diabetes
Receptor Activated (Chloride) - epilepsy
ENaC
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
VGCC
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
VGCC inhibition
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.
VGSC
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.
VGPC
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.
VGPC and insulin secretion
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.
Receptor-mediated channels (Chloride)
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.
GABA
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 !!!
NA/K ATP-ase
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.
Digoxin
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
K/H ATP-ase in stomach
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.
PPIs
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.
Irreversible enzyme inhibitors
Organophosphates (insecticides, nerve gases) act on muscarinic, nicotinic and CNS.
Irreversible enzyme inhibitors
Omeprazole
Aspirin
Xenobiotics
Compounds foreign to an organism’s normal biochemistry, such any drug or poison.
