Neuropharm active recall

Pharmacokinetics (PK)

How drugs move through the body. Acronym ADME: Absorption, Distribution, Metabolism/Elimination

Pharmacodynamics (PD)

Mechanism of drug action: how a specific drug binds its target and the relationship between [drug] and effect

Bioavailability

How much of a drug is absorbed and reaches general circulation

Bioavailability of an IV drug

1 (100%) because the whole dose goes directly into the blood

Enteral routes

Routes that involve the GI tract (oral, rectal)

Parenteral routes

Routes that do NOT involve the GI tract (IV, inhalation, absorption through skin/mucous membranes)

Pros of oral administration

Easy, safe, economical

First-pass effect

Orally taken drug goes through the digestive system, into the portal vein, then to the liver where part of it is broken down BEFORE entering general circulation

Why oral doses are sometimes higher

To account for drug broken down in the liver by first-pass metabolism (only post-liver drug enters general circulation)

IV route: advantages

Titratable, accurate, fast, 100% of the dose enters circulation

IV route: disadvantages

Risk of infection; irreversible (e.g., can't undo if patient is allergic); costly because skilled healthcare workers are needed to inject correctly

Which form of a drug crosses the phospholipid bilayer more easily?

The UNCHARGED (neutral) form. Charged molecules cannot cross the membrane easily (correction: earlier note said charged form moves more freely, which is wrong)

Weak acid equation

HA

Strong acid vs weak acid dissociation

Strong acid = more dissociation (more charged form); weak acid = less dissociation

Where is a weak acid drug best absorbed?

In an acidic environment (e.g., stomach) because more of it stays in the uncharged HA form, which crosses membranes

Effect of acid/base environment on absorption

The pH changes the ratio of charged to uncharged drug, which changes how well it crosses membranes

Volume of distribution (Vd)

The hypothetical volume of plasma a drug would need to be distributed in if it were only in plasma. A proxy for where the drug goes (plasma vs. elsewhere)

Vd formula

Vd = (bioavailable dose) / ([drug] in plasma) = (bioavailability x dose given) / ([drug] in plasma)

Vd units

L or L/kg (e.g., (mg/kg) / (mg/L) = L/kg)

Reference body volumes (70 kg person)

Plasma 3 L; blood 5.5 L; extracellular fluid 12 L; total body water 42 L

Vd close to plasma volume means

Drug stays mostly in plasma (e.g., furosemide ~0.1 L/kg)

Vd much larger than total body water means

Drug is sequestered in tissues (e.g., fat); it is "unrealistic" as a real volume, and the size of the unrealistic value reflects how strongly it leaves plasma. Fluoxetine ~36 L/kg (reported range ~12-43 L/kg)

Main sites of drug metabolism

Liver first, then kidneys

First-order kinetics

Metabolism removes a constant FRACTION of the drug remaining per unit time (curved decay on a linear plot); most drugs; e.g., aspirin

Zero-order kinetics

Constant AMOUNT of drug metabolized per hour regardless of how much is present (straight line decline); e.g., alcohol

Why can kinetics switch to zero-order at high concentration?

Enzymes become saturated: more drug than enzyme available, so breakdown can only go as fast as the enzymes work

Does enzyme saturation apply to all routes?

Yes (inhalation, oral, IV); it accounts for drug accumulating at the liver/breakdown enzymes

Half-life (t1/2)

Time it takes for half of the drug to be broken down/eliminated from the blood

Drug remaining after n half-lives

Fraction remaining = (1/2)^n (1 half-life = 50%, 2 = 25%, 3 = 12.5%)

Steady state (repeated dosing)

Drug accumulates until amount eliminated per interval equals amount given. Reached after ~5-6 half-lives (per your figure; commonly cited as 4-5)

Time to reach steady state depends on

Half-life only; it is INDEPENDENT of dose

Steady-state concentration is proportional to

Dose / dosing interval

Size of fluctuations (peak to trough) is proportional to

Dosing interval / half-life

Dosing at an interval equal to the half-life

50% of each dose is eliminated before the next dose, so the drug accumulates to steady state; sinusoidal curve shows max and min at start and end of each interval

Passive diffusion vs carrier-mediated transport (flux vs [drug])

Passive diffusion is linear and non-saturable; carrier-mediated transport is saturable (plateaus) because transporters become fully occupied

Which drugs cross membranes by passive diffusion?

Lipophilic drugs

Carrier-mediated membrane crossing

Requires a transporter

Blood-brain barrier (BBB)

Structural barrier that maintains and protects the brain environment; the main constraint on making CNS medications

Factors that determine BBB crossing

(1) Size (small = fast, large = poor) and (2) lipid solubility

Strategies to get a drug past the BBB

Inject into CSF; prodrug (lipophilic group that cleaves off after crossing); mannitol (temporarily disrupts the BBB via osmosis)

Prodrug

A drug with something lipophilic attached so it can cross the BBB; the group cleaves off once it passes the barrier

Mannitol and the BBB

Temporarily disrupts the BBB by osmotic effects that increase permeability

Ligand

Substance that binds a biomolecule

Three ideal properties of drug binding

Reversible, specific (only that target), saturable

Reversible binding

Drug can bind and come off the target

Saturable binding

Once all targets are bound there is no more binding (curve plateaus at Bmax)

Specific vs non-specific binding on a plot

Specific = hyperbolic curve that plateaus; non-specific = increases linearly without plateau

Steady state (binding)

Equilibrium of drug coming on and off target

KD (dissociation constant)

[Drug] at which half of maximal binding (1/2 Bmax) occurs; measures affinity/potency

Low KD means

High affinity/potency (less drug needed to occupy half the targets)

Bmax

Maximum binding (all targets occupied)

Why is KD read at 1/2 Bmax and not at Bmax?

Near Bmax the curve only approaches the limit and never truly reaches it, so it is inaccurate; 1/2 Bmax is where the curve changes clearly

Why use a log dose-response curve?

Log scale stretches out the beginning (the interesting part) and compresses the plateau; gives a sigmoidal curve with KD at the midpoint

Limitation of a plain dose-response curve

Lets you compare relationships between two specific drugs but not details of one drug (e.g., multiple targets)

Scatchard (Eadie-Hofstee-type) plot axes

Y = Bound/Free, X = Bound

Scatchard plot: how to get KD

KD = -1/slope (= -run/rise)

Scatchard plot: how to get Bmax

Bmax = x-intercept (maximum binding)

Scatchard plot: steeper slope means

Smaller KD (higher affinity). Note: slope is negative

Scatchard plot with a kink / two lines

Drug binds two targets, each with its own KD and Bmax (drug mostly binds one target but binds a second at higher concentration)

Scatchard plot: this is more specific than a dose-response curve because

It approaches a set point (x-intercept) not an asymptotic limit

Competition curve axes

Y = bound ligand, X = log [competing drug]; curve falls as competitor displaces ligand

Ki (inhibition constant)

Amount of competing drug needed to kick off half of the ligand/enzyme

Agonist

Mimics the endogenous ligand

Partial agonist

Milder effect than a full agonist (cannot give full response even at saturating dose)

Antagonist

Blocks the endogenous ligand; "zero effect" on its own

Inverse agonist

Produces the OPPOSITE effect of the endogenous ligand (reduces constitutive receptor activity)

Partial inverse agonist

Reduces constitutive activity but less than a full inverse agonist (your guide's definition sounds like a partial agonist; check with your professor)

Competitive antagonist

Binds the same site as the agonist, reversibly, without activating the receptor

Competitive antagonist effect on dose-response curve

Curve shifts to the RIGHT (higher EC50, lower apparent potency); Bmax/max response unchanged because more agonist can overcome it

Non-competitive antagonist

Binds a different (allosteric) site and reduces receptor response; more agonist cannot overcome it

Non-competitive antagonist effect on curve

Bmax (maximal response) is REDUCED

Irreversible antagonist

Binds so strongly it cannot be displaced, even at the agonist site; receptor permanently disabled

Irreversible antagonist: recovery

Requires synthesis of new receptors; effect cannot be overcome by increasing agonist (max response lowered)

Metric prefixes

deci 10^-1; centi 10^-2; milli 10^-3; micro 10^-6; nano 10^-9; pico 10^-12

Acetylcholine (ACh) synthesis

Choline + acetyl CoA -> ACh via choline acetyltransferase (ChAT); acetyl CoA comes from mitochondria (cellular respiration) and is the rate-limiting reagent

ACh vesicular transporter

VAChT packages ACh into vesicles against a strong concentration gradient

ACh breakdown

Acetylcholinesterase (AChE) in the synapse breaks ACh into choline and acetic acid (acetate)

ACh reuptake

Choline transporter takes choline back into the presynaptic neuron to be reused

Nicotinic ACh receptor (nAChR)

Ionotropic; Na+/K+ channel; strong driving force for Na+ entry causes big depolarization if many are activated; agonist = nicotine

Muscarinic ACh receptors (mAChRs)

Metabotropic; M1, M3, M5 (excitatory) and M2, M4 (inhibitory); agonist = muscarine (mushrooms)

M2 receptor (presynaptic)

Autoreceptor; inhibits adenylyl cyclase and can decrease NT release, a mechanism for negative feedback

M1/M3/M5 vs M2/M4

Different G-protein pathways; M1,3,5 and M2,4 grouped on slides (M1,3,5 and M2,4 both noted for memorization)

ACh nicotinic agonist

Nicotine

Alpha-bungarotoxin (ACh)

Nicotinic antagonist; irreversible and non-competitive (note spelling: bungarotoxin)

Curare (poisonous frogs/plants)

Nicotinic antagonist; reversible and competitive

Antidote for curare poisoning

AChE inhibitors, which block the BREAKDOWN enzyme (not reuptake), raising ACh in the synapse

AChE inhibitors

Sarin (nerve gas), galantamine, Alzheimer's disease drugs; raise ACh in the synapse

Sarin gas

Nerve gas; AChE inhibitor

Galantamine / Alzheimer's drugs

Inhibit AChE to increase ACh in the synapse

Pilocarpine

Muscarinic agonist

Atropine

Muscarinic antagonist from the belladonna plant; dilates pupils

Serotonin (5-HT) synthesis

Tryptophan -> (tryptophan hydroxylase, TPH) -> 5-hydroxytryptophan -> (AADC, aromatic amino acid decarboxylase) -> serotonin

Serotonin to melatonin

2 steps

Serotonin vesicular transporter

VMAT (vesicular monoamine transporter)

5-HT3 receptor

The ONLY monoamine receptor that is ionotropic (Na+/K+); all other 5-HT receptors are metabotropic (don't need to memorize 5-HT receptor subtypes)

Serotonin drugs: LSD

Agonizes serotonin receptors non-specifically

Serotonin drugs: psilocybin

Mushroom-derived serotonin receptor agonist

MAOIs

Monoamine oxidase inhibitors; block breakdown of catecholamines and serotonin

Tricyclics

Antidepressants that block monoamine reuptake (primarily NE and 5-HT); a separate class from MAOIs, though grouped near them in your guide

SSRIs

Selective serotonin reuptake inhibitors (e.g., fluoxetine); block the serotonin transporter