Category Archives: The Basics of Pharmacology

Receptors vs. Targets

In pharmacology, we often talk about targets instead of receptors.  Targets are simply the place on the cell or in the body that a drug affects.  This can be a receptor (or receptors), or it can be a general region.  In some cases, like with certain drugs that affect the kidneys and CNS, it is far more helpful to memorize the target than the receptor.

For example, hydrochlorothiazide, a thiazide diuretic, increases urine excretion from the kidneys by blocking sodium reabsorption in the distal convoluted tubule.  This process begins with the blocking of a receptor, but then starts a very long chain of events that culminate in a net effect.  If you know what the distal tubule does, however, and how variations in its contents affect the rest of the body, then you know that a thiazide diuretic…

1.  Is a mild-moderate diuretic

2. Will cause potassium loss

3.  Will lower your blood pressure

So remember to eat your bananas (unless you are taking spironolactone), and go study some physiology!

Our Friends the Receptors

Why do we love receptors? Because if we know what the receptor does, we know what the drug does!  Seriously:

To know a drug you MUST know the receptor.

This will save you many, many sympathetic responses.  Trust me.

Receptors are usually proteins that are embedded in the cell membrane, floating in the cytoplasm, or part of the nuclear envelope.  There are many subtypes that are very important to know.  For now, let’s look at the main categories so you get an idea how they work.

There are a few different categories of receptors.  It’s not necessary to know these in ridiculous detail to get how drugs work, but here’s a little bit of an overview to familiarize yourself with these important characters:

Ligand-gated Ion Channels: These are protein channels that are activated to open or close when a certain type of molecule attaches to it.  These molecules, called ligands, work a little bit like keys activating a lock.  This activation causes a change in the shape of the protein, which allows ions (usually sodium, potassium, chloride or calcium) to flow along their concentration gradient.  This produces a change in the cell!

Voltage-gated Protein Channels: Without these guys, we really couldn’t do anything.  This is the type of receptor that activates an action potential–the firing of a neuron–and also the type involved in muscle contractions.  VGPC’s act by responding to a change in the positive-negative electricity balance on either side of the cell membrane.  When the voltage switches from positive to negative, the channels open.  These are often responses to the initial actions of a ligand-gated channel!

G-Protein Coupled Receptors: A great many receptors are of this type.  When a molecule binds to the receptor, the receptor actually changes its shape.  This change causes a series of proteins to be activated in what is called a signalling cascade. This chain reaction causes a certain process to occur in the cell, thus causing the cell to do or not do something.

Transcription Factors: What?  Transcription?  Yes, it’s true.  There are these little guys floating around in the cytoplasm, waiting for a hormone or other uncharged lipid-soluble drug to scream through the cell membrane!  Certain drugs go inside the cell and activate transcription factors, thereby executing a direct effect on DNA transcription.  Crazy!

Transport Proteins: There are some drugs that act within the cells that just cannot be formulated to either diffuse across the cell membrane or fit through an existing channel by themselves.  This is usually because they are too big, move against the concentration gradient, or not lipid-soluble.  Sigh.  Luckily, there are transport proteins!  Not only do these proteins help get drugs across the cell membrane (or even the nuclear envelope!), but they also help kick toxins (and medications, before they become toxic) out of the cell.

There are other categories of receptors, but this should give you a good start.

Pharmacodynamics: Hey Baby, Let’s Interact

 

Pharmacodynamics (PHARM-a-ko-dy-NA-micks) are how drugs affect the body.  This boils down to how drugs interact with their receptors. 

 

Receptors are the parts of cells that block, accept, or manage the access of substances to the cell itself.  These little guys are very complex, and for many we can only speculate how they work!  What we do know is that chemical compounds affect receptors in different ways.  This is the essence of pharmacodynamics.

 

Drugs interact with receptors in several ways.

 

Agonists:  Drugs that act as agonists make a receptor do what it normally does, OR enhance what it does already.  For example, if you take dextroamphetamine (Adderall), the drug activates the same receptors as your body does when it is in “fight or flight” mode.  So it makes you more alert, speeds up your heart rate, and might give you the sweats and cold feet.

 

Antagonists: As you may have guessed, drugs that are antagonists stop the receptor from doing what it usually does.  It can either block the receptor directly or compete with endogenous agonists to stop their action.  For example, when you take a beta blocker like propanolol (Inderal), the drug blocks the receptors in your heart that speed up the heart rate and increase stroke volume.  It also blocks the receptors that control the release of renin from your kidneys.  These three blockades effectively lower your blood pressure!

 

Partial Agonist: I call this type of drug “Let’s Just Be Friends”.  Partial agonists have a lesser effect (but still an effect!) than full agonists. The cool thing is that while they are attached to receptors, agonists can’t get there, so in that way they can act both as agonists and antagnoists!  Woot!  An example of this that I have borrowed from my favorite pharmacology book is pentazocine, a pain killer.  Pentazocine is a partial agonist of opioid receptors, so when it is attached to those receptors, a mid-range amount of pain-killing is accomplished.  However, when you give someone pentazocine, and then decide to give them, say, meperidine (a full opioid agonist) pentazocine is like, “This is my turf, beeyotch” and blocks meperidine from attaching to the receptors!  Amazing!

 

So all of this is under the umbrella of pharmacodynamics.  These three types of drugs–agonists, antagonists, and partial agonists–are the first thing you should memorize.  Then, when you learn the receptors, you will have no trouble figuring out how a drug will affect the body!

 

Pharmacokinetics: Go Forth, Multiply, Do Your Thing, Get the Hell Out

There are two major things that make drugs do what they do, and to what degree.  The first one is Pharmacokinetics (PHARM-a-ko-kin-EH-ticks) or, how drugs move around the body.

Like I said in the title, pharmacokinetics is how a drug gets in, spreads out, gets to working, and gets out.  So there are four big parts of pharmacokinetics.  Let’s break them down.

1.  Absorption: You already know that some drugs are given by mouth, some squirted up your nose, some in an IV, and others in places we may not like to remember.  These different routes all have to do with absorption, or how a drug gets to where it needs to be.  You will find as you study that based on their potency, toxicity, and chemical properties, certain drugs have to be given certain ways in order to absorb properly into the body.  This is the first principle of pharmacokinetics.

2. Distribution: Drugs can be carried through the body in many different ways.  When you get an injection of Novacaine at the dentist’s office, that drug is only affecting the immediate surrounding area.  If you get an IV of morphine in the hospital, your whole body is affected almost immediately. When you take a pill, it has to absorb through the linings of your digestive tract before it gets to work.  All of this has to do with how the drug is carried and how far it can go.

3. Metabolism: You already know that metabolism is how cells in your body process things.  Cells can break down compounds and turn them into simpler ones (catabolism), or they can put compounds together to make bigger ones (anabolism).  They do the same things with drugs.  In fact, some drugs are even formulated so that they don’t do anything until your cells metabolize them into something else!  Genius!  The most common sites of metabolism are the liver, kidneys, gastrointestinal tract, and the lungs.

4. Excretion:  Poop, pee, sweat, tears, and breast milk!  There are others too, but those are my personal favorites.  Excretion is how the body eliminates drugs.  As you may have guessed, the most famous modes of excretion are through the kidneys in the form of urine, and through the GI tract in the form of feces.  Fun fact:  Alcohol (Ethanol) is excreted through the kidneys AND GI tract AND exocrine (sweat) glands AND the lungs.  This is why last weekend, when you came home, you totally reeked.

In pharmacology class, the phrase First Pass Effect may be frequently thrown around.  Medical professionals are likely familiar with the drugs that are not usually given by mouth, or have to be started with a loading dose.  This is often due to the first pass effect, which is the super fast metabolism of the drug by the liver. To get around this snag, we either give susceptible drugs by a route that bypasses the liver (like IV or sublingual), or we give a higher dose at first to start building the drug up in the body.

The Best Drug Ever!

If we had the opportunity to make the BEST DRUG EVER what qualities would it have?

You may say it would cure the ill it was meant to cure.  So, it would have to be Effective.

You may also say that while it’s doing it’s thing it probably shouldn’t be killing you or hurting you in the process.  So, it would have to be Safe.

It would be nice if it only did the thing it was supposed to do, and nothing else.  So, it would have to be Selective.

Remember ‘ESS’!  For Super Drug!

There are many other qualities that would make a drug completely ideal, like reversibility, predictability, low cost, and no interactions with other drugs!

Well, what are we waiting for?  As you may have guessed, the BEST DRUG EVER doesn’t exist.  There isn’t a drug that is completely effective, safe or selective all the time.  But we can use these guidelines to make the safest drugs possible.  We call these guidelines the Therapeutic Objective.

The Therapeutic Objective is to get the most out of a drug while doing the least amount of harm.