Drugs and the BrainPsychotropic Medications - Effects and Adverse EffectsAdonis Sfera, MD

Neurovascular coupling

Why Do We Get Side Effects From Drugs?

The benefits of the medication will often outweigh the cost of the side effects by improving heath or allowing people to function in daily life.

It is up to us to decide.

Any time you alter you body chemistry you will have some form of side effect.

Sometimes The Risks Do Not Outweigh The Benefits

Current Psychotropic Drugs Are Not “Smart” Drugs

They travel to every area of the body including the brain

Let’s Follow the Drug

Brain Compartments

First Compartment: The Brain Vessels

Extracellular Space - Between Capilaries and Cells

Second Compartment: The Space Between The Cells

The Firewall (Blood Brain Barrier) The blood-brain barrier (BBB) is located

between the blood vessels (capilaries) and the extracellular space of the brain.

Blood Brain Barrier (BBB) Endotelial cells Astrocyte endfeet

Trans-cellular passage of drugs

Passage of drugs from the bloodstream to the brain is dependent on the ability of the molecules to penetrate through cell membranes.

Crossing the Membranes

Penetration of a molecule from the bloodstream to the neurons and glial cells is dependent on the compound's liposolubility.

Targets of psychotropic drugs

30% of psychotropic drugs target transporter proteins

30% of psychotropic drugs target G protein linked receptors

20% of psychotropic drugs target ligand-gated ion channels

10% of psychotropic drugs target voltage sensitive ion channels

10% of psychotropic drugs target enzymes

Transporter Protein and G Protein (60% of psychotropic drugs)

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

Ligand Gated Ion Channels, Voltage Sensitive Ion Channels and Enzymes (40% of psychotropic drugs)

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

Transporter ProteinsTransporters are receptors that bind neurotransmitters (they go in and out of the neuronal membrane 12x)

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

All Antidepressants (except MAO inhibitors) Target and Block Transporter Proteins

Serotonin Transporter(SERT); Norepinephrine Transporter(NET);Dopamine Transporter(DAT)

Antidepressants Bind to Transporters1. When Na binds to the transporter, serotonin also binds and renders the transporter ready.

2. When the antidepressantbinds to the transporter it displaces serotonin and Na, blocking the transporter

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

G Protein Linked ReceptorsG protein linked receptors (7 transmembrane regions, one intracellular and one extracellular portion)

Ligand-Gated Ion Channels (20% of Psychotropic Drugs)

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

N Methyl D Aspartate Receptors

GABA Receptors

VOLTAGE SENSITIVE CHANNELS

Voltage -sensitive sodium channels Voltage-sensitive calcium channels

Voltage-Sensitive Sodium Channels

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

Some Mood Stabilizers’ Binding Sites

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

Voltage-Sensitive Calcium Channels

Alpha 2 Delta Ligands

Antihypertensive Calcium Channel Blockers

Enzymes Directly Targeted by Psychotropic Drugs

Some Enzymes Create New Molecules.Others Destroy Existing Molecules.

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

Enzymes as Targets of Psychotropic Drugs

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

Irreversible Enzyme Inhibitor

An irreversible inhibitor of an enzyme binds to the enzyme in such a way that permanently prevents a substrate from binding.

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

Reversible Enzyme Inhibitor

Dopamine Pathways

I wish I could inhibit only the mesolimbic pathway, but I cannotbecause the drugs are not “smart”.

All antipsychotics (typical and atypical) are dopamine D2 blockers, butunfortunately they affect other receptors as well-adverse effects

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

Tardive Dyskinesia (TD) Up regulation of the postsynaptic dopamine

receptors.

5% of patients maintained on typical antipsychotics will develop TD in 1 year (25% in 5 years).

TD in elderly can be as high 25% in the first year of treatment

Kane JM in Bloom FE, Kupfer DJ, Psychopharmacology: The fourth generation of progress. Philadelphia Raven 1996National Alliance on Mental illness. Tardive dyskinesia Available at www.nami.org/ContentGroups/Helpline1/Tardive_Dyskinesia.html

QuestionWhich of the following risk factors for thedevelopment of TD is most important? Age Gender Mood disorders Substance abuse

QuestionThe estimated annual rate of TD inolanzapine treated patients is: 0.5% 1.0% 2.0% 3% 4%

What happens in the Tuberoinfundibular pathway? With D2 blockade

With 5HT2A blockade

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

Cardiometabolic SyndromeWeight gain is mediated by: 5HT2C H1 M3

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011

Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4th ed 2011