NURS 6242: SESSION II

Transporters, Receptors & Enzymes

The 5 Molecular Targets of Psychotropic Drugs Include:

• 12-t________ R____ T_______ (~30% of psychotropic drugs)

• 7-t_________ R____ G p____-l____ (~30% of psychotropic drugs)

• E_____ (~10% of psychotropic drugs, MAOI’s)

• 4-t___________ Region L____-G____ I__ Channel (~20%)

• 6-t_________ region v____-G____ I__ Channel (~10%)

• 12 transmembrane region transporter

• 7 transmembrane region G protein-linked

• enzyme

• 4 transmembrane region
  ligand-gated ion channel

• 6 transmembrane region
  ~ 10% of psychotropic drugs voltage-gated ion channel

Sodium/Chloride Coupled Transporters

S____ is pumped INTO the cell, a n_______ follows (i.e. serotonin, dopamine etc) P_______ is pumped OUT by ATPase. When medications i.e. Fluoxetine is administered, it takes the place of the neurotransmitter - reducing serotonin from reaching the presynaptic neuron

Sodium

Neurotransmitter

Potassium

T/F: The most common action of psychotropic drugs is to modify the ion channels

FALSE! It is to modify the G-protein linked receptors (7 membrane regions)

G-Protein Linked Receptors have a wide range of modifications/actions including:

• m____

• b____

• partially b___

• fully b____

the neurotransmitter function

mimic

block

partially block

fully block

G-Linked Protein 7-membrane receptor actions changes the downstream of molecular events, such as:

• Phosp_______ act______ or inact______

• Modify i__ ch_____

  • Modify G___ expression

Phosphoproteins activated or inactivated

Ion channels are modified

Gene Expression

T/F: Agonist and antagonist are opposites of one another.

FALSE!

Agonists & inverse agonists

A_____ S_______: a pharmacological model that classifies how different drugs and molecules bind to cell receptors and change their functional activity.

Agonist Spectrum

T/F: If an agonist is not present, there is no activity during a signal transduction cascade

FALSE! There is still constitutive activity

What occurs when a full agonist is added to maximum signal transduction?

FULL STEAM AHEAD! 2ND messanger and protein kinase are moving along

T/F: An antagonist is the same as not having an agonist because activity is back to baseline and not amplified.

TRUE

P____ A_____: partially enhanced signal transduction; anxiolytics

Partial Agonist

How is the inverse agonist beyond antagonist??

Even constitutive activity is halted, there is no activity AT ALL going on. 2nd messenger isn’t produced AT ALL

___-3 has been considered a possible target for Lithium and other mood stabilizers. When it is stopped by lithium (possible ECT, Lithium), symptoms such as mood instability and m____ can be reduced. Therefore, lithium can be considered n_________.

GSK-3

mania

neuroprotective

T/F: Lithium is the gold standard for treating bipolarity

TRUE!

After a s_____ binds to an enzyme, it turns into a product that is then released by the enzyme.

substrate

What is the point of CYP enzymes?

They allow our body to change a drug from its original form to a bioavailable form

When assessing a CYP enzyme name, we look at it like:

1 = f____

A = s_____

1 = g___ p_____

family

subtype

gene product

CYP 1A2:

major l___ enzyme responsible for breaking down caff___, certain prescription m______ and environmental t____.

Inhibitors Include:

• flu_____

  • cip_______

Substrates of CYP1A2 include:

• THeo_______

• Cloz____ and Olanz____

• Dul_______

• Mirt_______

• Tizan______

• Phenace_____

• Mela____

• Prop_____

• Lidoc_______

liver

caffeine

medications

toxins

• fluvoxamine

  • ciprofloxacin

• theophylline (treats asthma, lungs(

• Clozapine and olanzapine (tx schizophrenia)

• Duloxetinie (antidepressent)

• Mirtazepine (helps iwth sleep, depresson)

• tizanidine (muscle relaxer)

• Phenacetin (older pain reliever used in research to test enxyme activity)

• Melatonin (sleep supplement)

• Propanolol

• Lidocaine

CYP-2D6 - no hydroxylation

A l___ enzyme that helps to “unpack” medications, it can be f___ or s___. If the medications are “unpacked” too quickly, the s___ l____ can SKYROCKET. If they “unpack” too slowly, they s___ l____ does not reach therapeutic levels.

Substrates include: T__, c_____, some b___ b_____, ris_____, ven______

Inhibitors include: par_______, flu_____, bup____, qui_____

liver

fast or slow

serum level

serum level

substrates: TCA, codeine, beta blockers, risperidone, venlafaxine

inhibitors: paroxetine, fluoxetine, bupropion, quinidine

CYP-2C9

CYP-2C19

CYP-___- heavy lifter, the single most common and active enzyme in your body, crushing through roughly 50% of all prescription meds, the absolute boss

• found in both small intestine + liver

• grapefruit contain sneaky chemicals that act like permanent superglue inhibitors to this enzyme

• without your “Absolute Boss” there to guard the door, your body absorbs WAY too much!!

• Subtrates include - s_____, b____ p_____ (amlo_____), aller__, many anti_____ (eryt______)

3A4

statins

blood pressure amlodipine

allergy

many antibiotics (erythromycin)

If a patient receives both a substrate and an inhibitor of enzyme CYP- IA2, what are we concerned about?

Increased bi-product of a drug (increased substrate due to enzyme not present to do its job)

Thus, substrate dose may need to be lower if inhibitor is in place

S_____ is a common inducer for enzymes such as CYP1A2, causing less biproduct. These patients may need a higher dose of medication if they are smokers.

Smoking

T/F: If a patient is taking clozapine and smoking, they will need a smaller dose.

FALSE!!!

If a patient quits smoking, they have to let you know because the plasma concentration can increase by ~18%

S_____ and c_____ and both considered inducers of CYP-1A2

smoking ; caffeine

A s_____ is the target, something to be “chopped up”, where an i______ is the blocker, a medicine slowing things down.

substrate ; inhibitor

Clinical Example: A patient presents after being stable for multiple months on an atypical antipsychotic (i.e. clozapine), and needs a mood stabilizer such as Depakote. What would be the long term concern?

Because depakote is an inducer of 3A4, we need to be mindful that the brain & blood level of other medications may be lowered, requiring increased doses. Labs and close monitoring of symptoms are recommended.

Ligand-Gated Ion Channels:

• Regulated by n_________ & act as a g______

  • N________ binds to the g______ receptor, and causes a conformational change that opens ion channel

Regulated by neurotransmitters and act as a gatekeeper

neurotransmitter binds to the receptor