drugs -enzymes & transportrs Flashcards
define enzyme inhibitor
a molecule that binds to an enzyme and decreases its activity. It prevents the substrate from entering the enzyme’s active site and prevents it from catalysing its reaction.
what are the 2 types of enzyme inhibitor
irreversible inhibitors
reversible inhibitors
how do irreversible inhibitors work
react with the enzyme and change it chemically (e.g. via covalent bond formation)
how do reversible inhibitors work
bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind to the enzyme, the enzyme-substrate complex, or both.
can enzymes be drug products
yes
eg steptokinase and tPA clot busters
what are statins also known as
enzymes called HMG-CoA reductive inhibitors
what do statins do
block the rate limiting step in the cholesterol pathway
they are a class of lipid lowering medications that reduce the levels of bad cholesterol
for the primary prevention of cardiovascular disease
what is angiotensin converting enzyme inhibitor caused for
to regulate blood pressure
it does this by increasing blood pressure by increasing the amount of salt and water the body retains
inhibiting ACE reduces ATII production and therefore causes a reduction in blood pressure
where is angiotensin converting enzyme predominately found
kidney and liver
how is angiotensin converting enzyme hijacked
SARS-Cov2 uses ACE2 as an entry receptor to get into body cells
because ACE 2 has a diff distribution to ACE
symptoms of parkinson’s
• Hypokinesia – motor movement↓
• Tremor at rest
• Muscle rigidity, Motor inertia
• Cognitive impairment
• Degenerative disease of basal ganglia
Major dopaminergic pathways in CNS (red)
dopamine
• Early degeneration of dopaminergic neurones in the nigrostriatal pathway leading to autonomic dysfunction and dementia
what is L dopa produced from
produced from the amino acid L - Tyrosine as a precursor for neurotransmitter biosynthesis
it crosses the blood brain barrier
what is the blood brain barrier
a highly selective semi permeable membrane barrier that separates the circulating blood from the brain
what does peripheral DDC INHIBITOR DO
blocks DDC in the periphery generating more for the CNS pathway
if you block this more L -DOPA transfers into the brain - less dopamine being produced - has no effect outside of the brain
what does the peripheral COMT inhibitor do
prevents breakdown of L DOPA generating more for the CNS Pathway
what does central COMT INHIBITORS DO
FUNCTION WITHIN THE cns TO keep dopamine levels up
what do mono amino oxidase B inhibitors do
prevent dopamine breakdown and increases availability
what do central dopamine receptor agonists d
antagonise dopamine receptors ( not enzyme inhibitors )
what are the 2 categories of transporters
passive - no energy
active - require energy
2 types of passive transporters
symporter - Na/K/2Cl, NaCl
channels - Na, Cl, Ca, K
what is transport
when molecules move across a cell membrane
what is active transport
when ions move from a lower concentration to a higher concentration
allows cells get wat they need eg ions, glucose & amino acids
needs energy - usually from ATP
ATP —> ADP/AMP
3 types of protein ports
uniporters
symporters
anitporters
how do uniporters work
use energy from ATP to pull molecules in
how do symporters work
use the the movement in of one molecule to pull in
another molecule against a concentration gradient.
how do antiporters work
one substance moves against its gradient, using
energy from the second substance (mostly Na+, K+ or H+) moving down its gradient.
example of 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 hypertension and edema) Acts by inhibiting the luminal NKCC
in the thick ascending limb of the loop of Henle
Binding to the NKCC causes sodium, chloride, and potassium loss in urine
examples of ion channels
• Epithelial (Sodium) – heart failure
• Voltage-gated (Calcium, Sodium) – nerve, arrhythmia
• Metabolic (Potassium) – diabetes
• Receptor Activated (Chloride) - epilepsy
describe the epithelial (sodium) channel (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)
what can block enac channels
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
define heterotrimeric
two set of three proteins
describe voltage gated calcium channels
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.
what causes voltage gated calcium channels to open
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.
define action potential
A momentary change in electrical potential on the surface of a nerve or muscle cell, that occurs when it is stimulated, resulting in the transmission of an electrical impulse.
what inhibits voltage gated calcium channels
Amlodipine is an angioselective (Why is that important?) Ca channel blocker that inhibits the movement of Ca ions 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
describe voltage gated sodium channe;s
Conducts Na+ through plasma membrane.
how are voltage gated sodium channels classified
according to the trigger that opens them
voltage gated or ligand gated
what are the 3 main conformational states in excitable cells of voltage gated sodium channels
closed, open, inactivated
what causes activation ages to open in voltage gated sodium channels
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
what can block voltage gated sodium channels
Lidocaine (anaesthetic) blocks transmission of the action potential.
Also blocks signaling in the heart reducing arrhythmia.
define action potential
A momentary change in electrical potential on the surface of a nerve or muscle cell, that occurs when it is stimulated, resulting in the transmission of an electrical impulse.
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describe voltage gated potassium channels
Voltage-gated K+ channels are selective for K+ over other cations such as Na+.
>40 known human voltage-gated potassium channel alpha subunits.
Present in many “excitable” tissues Also have three conformational
states: closed, open and inactivated. An electric current (action potential)
allows the activation gates to open eliciting a downstream effect.
what do voltage gated potassium channels do
Regulate insulin in Pancreas: B Islets of Langerhans
Increased glucose leads to block of ATP dependent K+ channels.
Repetitive firing of action potentials increases Ca+ influx
and triggers insulin secretio
what can block voltage gated potassium channels
Repaglinide, nateglinide and
sulfonylureal lower blood glucose levels by blocking K+ channels to stimulate insulin secretion.
Used for treatment of type II diabetes
describe Receptor-mediated (Chloride) channels
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
describe the Sodium Pump (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.
what can inhibit the sodium pump
digoxin
mainly inhibits the pump in tbe myocardium
used for atrial fibrillation, atrial flutter and heart failure
causes an increase in intracellular Na resulting in decreased activity of the Na-Ca exchanger and increases intracellular Ca.
This lengthens the cardiac action potential, which leads to a decrease in heart rate
what is the protopump of the stomach
the gastric hydrogen potassium ATPase or H+/K+ ATPase
it is a heterodimeric protein - the product pf 2 genes
it exchanges potassium from the intestinallumen with cytoplasmic hydronium
what is the stomach proton pump responsible for
responsible for the acidification of the stomach and the activation of the digestive enzyme pepsin
define hydronium
the form in which hydrogen ions are found in aqueous solution
what blocks the stomach proton pump
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)
what are organophosphate
Irreversible inhibitors of cholinesterase)
examples of organophosphate
- insecticides (Diazinon)
- Nerve gases (Sarin)
what is pharmacokinetics
the sticky of drug metabolism
how does the metabolic breakdown of drugs occur
through specialised enzymatic systems
it works through bio transformation
Generate compounds that are more readily excreted (work in liver and kidney)
what does the rate of metabolism determine
the duration and intensity of a drugs pharmacologic action
what are xenobioptics
compounds foreign to an organisms norma biochemistry eg drug or poison
what are the main enzymes involved in drug metabolism
CYPs (e.g. cP450) are the major enzymes involved in drug metabolism (75%)
Most drugs undergo deactivation by CYPs, either directly or by facilitated excretion from the body.
