Lecture 2 Last part Flashcards
What is a seconary messenger and function ?
Second messengers are small intracellular molecules that mediate the effects of first messengers, i.e., neurotransmitters and hormones.
Some of the important second messengers in the nervous system are
cAMP, cyclic guanosine monophosphate (cGMP), diacylglycerol (DAG), inositol trisphosphate (IP3), and Ca2 + ions.
These are chemical substances that relay signals
from an activated receptor to a target molecule in
the cell, and so altering the physiology of the cell.
The binding of drug receptor can inhibit inhibits in the case of antagonists) either an
enzyme or a series of secondary messengers.
What are G proteins ?
They are also known as also known as guanine nucleotide-binding proteins
Activated by binding of Guanosine-5’-triphosphate (GTP) ,
Two pathways include cAMP and Phostinyol pathway .
When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF).
First Piece of G proteins
One of these pieces increases levels of an enzyme
called adenylate cyclase, which in turn increases
cellular production of cAMP (cyclic adenosine
monophosphate).
Adenylyl cyclase is a 12-transmembrane glycoprotein that catalyzes ATP to form cAMP with the help of cofactor Mg2+ or Mn2+. The cAMP produced is a second messenger in cellular metabolism and is an allosteric activator of protein kinase A.
Second Piece
cAMP is a common intracellular secondary messenger
used in many different cellular processes throughout the
body.
• It amplifies the signal so that one ligand molecule binding
to one receptor can result in the generation of hundreds
of secondary messengers in the cytoplasm within
nanoseconds.
• These hundreds of secondary messengers can bind to
thousands of target molecules and the signal will be
greatly amplified. This process is called signal
transduction.
Used in Hormones like adrenaline and
It is also involved in the activation of protein kinases. In addition, cAMP binds to and regulates the function of ion channels such as the HCN channels and a few other cyclic nucleotide-binding proteins such as Epac1 and RAPGEF2.
What is Therpeutic Index?
A ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is effective.
This is a comparison between the dose
which is effective and the dose that is
toxic to the patient.
It is given as a ratio between two figures:
the ED50 and the TD50.
• TD50/ED50 = TI
What is ED50 and TD50 ?
ED50 is the dose that produces a therapeutic
effect in 50% of the population (ED = effective
dose)
• TD50 is the dose that produces a toxic effect in
50% of the population (TD = toxic dose)
Animal Studies
LD50 (LD = lethal dose). This is used in animal studies, and
describes the dose required to kill 50% of the animal
sample. For obvious reasons, we do not use this in human
studies!
What can Therpeutic Index become quite narrow and when ?
Therapeutic indexes can be quite narrow, such as with some antibiotics such as gentamicin or vancomycin.
These drugs therefore have more potential to do harm if prescribed incorrectly, or blood levels not monitored and doses adjusted accordingly.
What is Drug Half life ?
Half-life (t1/2
): time taken for the drug’s blood or
plasma concentration to decrease from full to onehalf (50%)
• The longer the half-life, the longer the drug remains
in the body.
How do drugs work?
Most work by interacting with
endogenous proteins
-Some antagonize, block or inhibit endogenous proteins
• Some activate endogenous proteins
• A few have unconventional mechanisms of action
Are Drugs that inhibit enzyme Clinically useful ?
YES
Yes
• Cyclooxygenase Inhibitors for pain relief,
particularly due to arthritis (aspirin; ibuprofen [Motrin®])
• HMG-CoA Reductase Inhibitors for hypercholesterolemia
(atorvastatin [Lipitor®]; pravastatin [Pravachol®])
Angiotensin Converting Enzyme (ACE) Inhibitors for
high blood pressure, heart failure, and
chronic renal insufficiency
(captopril [Capoten®]; ramipril [Altace®])
Are Drugs That Inhibit Signal Transduction
Proteins Clinically Useful?
Signal Transduction : Signal transduction (also known as cell signaling) is the transmission of molecular signals from a cell’s exterior to its interior. Signals received by cells must be transmitted effectively into the cell to ensure an appropriate response. This step is initiated by cell-surface receptor
Yes:
• Type 5 Phosphodiesterase Inhibitors for erectile dysfunction
(sildenafil [Viagra®])
• This is a major focus of drug development
Unconventional Mechanisms Of Action?
•Disrupting Structural Proteins
e.g. vinca alkaloids for cancer, colchicine for gout
• Being Enzymes
e.g. streptokinase for thrombolysis
• Covalently Linking to Macromolecules
e.g. cyclophosphamide for cancer
• Reacting Chemically with Small Molecules
e.g. antacids for increased acidity
• Binding Free Molecules or Atoms
e.g. drugs for heavy metal poisoning, infliximab (anti-TNF)
Unconventional Mechanisms Of Action?
Unconventional Mechanisms of Action
•Being Nutrients
e.g. vitamins, minerals
• Exerting Actions Due to Physical Properties
e.g. mannitol (osmotic diuretic), laxatives
• Working Via an Antisense Action
e.g. fomivirsen for CMV retininitis in AIDS
• Being Antigens
e.g. vaccines
•Having Unknown Mechanisms of Action
e.g. general anesthetics
Receptor Regulation
Sensitization or Up-regulation 1. Prolonged/continuous use of receptor blocker 2. Inhibition of synthesis or release of hormone/neurotransmitter - Denervation
