Core Pharmacology Concepts

Pharmacodynamics

What the drug does to the body:

receptor interaction, mechanism, and effect

Beta-blocker lowers heart rate

Pharmacokinetics

What the body does to the drug:

absorption, distribution, metabolism, and excretion (ADME).

Pharmacotherapeutics

Rational use of drugs to manage disease.

Choosing a suitable antihypertensive.

Toxicology

Undesirable effects of chemicals on living systems.

Overdose and antidote management

Ligand / affinity

binds a receptor;

is its ability to bind.

Binding alone does not guarantee activation.

Therapeutic index

Relative safety: TD50 / ED50.

A wider TI generally indicates a safer drug.

Bioavailability (F)

Fraction of administered drug reaching systemic circulation.

Structural proteins:

tubulin forms microtubules involved in cell structure, axonal transport, chemotaxis, and mitosis.

Microtubule inhibitors:

• griseofulvin (dermatophytes; absorption increases with fatty food),

• colchicine (acute gout; diarrhea),

• vinca alkaloids (e.g., vincristine; neurotoxicity),

• taxanes (e.g., paclitaxel; promote microtubule polymerization).

Ion channels:

voltage-gated Na+ channels

are blocked by class I antiarrhythmics, local anesthetics, and some anticonvulsants;

Ion channels:

class III antiarrhythmics

act mainly on K+ channels;

Ion channels:

non-DHP CCBs

act on L-type Ca2+ channels in the heart.

• Pumps:

digoxin

PPIs (suffix -prazole)

• inhibits Na+/K+-ATPase;

• inhibit the gastric H+/K+-ATPase

• Enzymes:

corticosteroids

NSAIDs

• inhibit PLA2 pathway upstream;

• inhibit COX

• Enzymes:

; zileuton

ACE inhibitors

inhibits 5-LOX;

end in -pril;

• Enzymes:

COMT inhibitors

include entacapone and tolcapone

Type I: ionotropic

Cell membrane; milliseconds;

ligand-gated ion channels

• GABA-A (Cl−),

• nicotinic ACh receptors

Type II: metabotropic

Cell membrane; seconds;

G-protein/second messengers

• Gs increases cAMP;

• Gi decreases cAMP;

• Gq activates PLC -> IP3/DAG.

Type III: enzyme-linked

Cell membrane; minutes

• Insulin receptor (tyrosine kinase)

Type IV: nuclear

Cytoplasm/nucleus; hours;

gene transcription

• Steroid, thyroid,

• vitamin D receptors alter gene transcription.

• Full agonist:

binds and produces maximal receptor response

(e.g., morphine at mu receptors).

• Partial agonist:

produces a lower maximal response;

may oppose a full agonist when both compete for the same receptor

(e.g., nalbuphine and tamoxifen has tissue-selective estrogen effects.).

• Antagonist:

affinity without intrinsic activity; blocks agonist effect.

Diphenhydramine blocks H1 effects of histamine.

• Inverse agonist:

lowers constitutive/basal receptor activity.

antihistamines

• Competitive/surmountable antagonist:

increasing agonist concentration can overcome blockade;

curve shifts right, Emax generally preserved.

Physiologic antagonist

Opposite effects through different receptors.

Epinephrine counteracts airway narrowing and hypotension in anaphylaxis.

• Noncompetitive/non-surmountable antagonist:

Emax decreases.

Chemical antagonist

Direct chemical interaction/neutralization.

Protamine sulfate neutralizes heparin.

• Potency:

dose needed for an effect (lower ED50 = greater potency).

Efficacy:

maximum effect a drug can produce

TI =

TD50 / ED50

ED50

TD50

is the dose effective in 50% of a population;

is toxic in 50%.

Passive diffusion

No ATP;

high to low concentration.

Most common; favors small, lipophilic, unionized molecules.

Active transport

Energy-dependent;

can move low to high.

Carrier-mediated and saturable;

Na+/K+-ATPase is a classic pump

Facilitated diffusion

No ATP;

high to low with carrier.

Glucose transport; carrier can saturate

Bulk flow / convective

Drug follows solvent through aqueous pores.

Limited by pore size and charge

Ion-pair transport

Charged compounds form a neutral pair to cross membranes.

Example: tertiary amine paired with mucin.

Pinocytosis / phagocytosis

Energy-dependent vesicular uptake.

Fat-soluble vitamins and griseofulvin are examples