Comprehensive Study Guide for Katzung & Trevor's Pharmacology: Basic Principles and Autonomic Drugs

NATURE OF PHARMACOLOGY AND DRUG THEORIES

• General Definitions:

  • Pharmacology: The body of knowledge concerned with the action of chemicals on biologic systems.

  • Medical Pharmacology: The area concerned with the use of chemicals in the prevention, diagnosis, and treatment of disease, especially in humans.

  • Toxicology: The area concerned with the undesirable effects of chemicals on biologic systems.

  • Pharmacokinetics: The effects of the body on drugs, including absorption, distribution, metabolism, and elimination ($ADME$).

  • Pharmacodynamics: The actions of the drug on the body, involving mechanisms of action and therapeutic and toxic effects.

• Physical Nature of Drugs:

  • Drugs include inorganic ions, nonpeptide organic molecules, small peptides, proteins, nucleic acids, lipids, and carbohydrates.

  • Alkaloids: Naturally occurring molecules found in plants or animals that have a basic $pH$ in solution, usually due to amine groups.

  • Molecular Weight ($MW$): Ranges from $7$ (Lithium) to over $50,000$ (thrombolytic enzymes, antibodies). Most drugs fall between $MW\,100$ and $MW\,1000$.

  • Chirality: Many drugs exist as enantiomers; these optical isomers can differ in affinity for receptors by over $1000$-fold and may be metabolized at different rates.

• Drug-Receptor Interactions:

  • Receptor: Specific molecule in a biologic system with which drugs interact to produce changes. Most are proteins.

  • Agonist: A drug that activates its receptor upon binding.

  • Antagonist: A drug that binds without activating its receptor, preventing activation by an endogenous or exogenous agonist.

  • Binding Forces: Range from strong covalent bonds (often irreversible) to weaker electrostatic, hydrogen, van der Waals, and hydrophobic bonds.

• Drug Permeation Processes:

  • Aqueous Diffusion: Movement through watery spaces (extracellular and intracellular). Passive process governed by Fick's law. Capillaries in the brain and testes lack the aqueous pores found elsewhere.

  • Lipid Diffusion: Passive movement through lipid membranes and barriers. Also governed by Fick's law.

  • Special Carriers: Transporters for substances too large or insoluble to diffuse (e.g., $Na^+/K^+\text{ ATPase}$, serotonin reuptake transporters). Capacity-limited and not governed by Fick's law.

  • Endocytosis and Exocytosis: Endocytosis involves membrane infolding to internalize large or lipid-insoluble chemicals (e.g., Vitamin $B_{12}$ with intrinsic factor). Exocytosis is the encapsulated expulsion of material (e.g., neurotransmitter release).

PRINCIPLES OF PHARMACOKINETICS

• Fick's Law of Diffusion:

  • Predicts the rate of molecule movement across a barrier.

  • $\text{Rate} = \frac{(C_1 - C_2) \times \text{Area} \times \text{Permeability Coefficient}}{\text{Thickness}}$

• Solubility and Ionization ($PH$ and $pK_a$):

  • Henderson-Hasselbalch Equation: $\log(\frac{\text{Protonated form}}{\text{Unprotonated form}}) = pK_a - pH$

  • Weak Bases: Become ionized (charged and water-soluble) when protonated. Charged form: $RNH_3^+$; Uncharged form: $RNH_2$.

  • Weak Acids: Become nonionized (uncharged and lipid-soluble) when protonated. Uncharged form: $RCOOH$; Charged form: $RCOO^-$.

  • Ion Trapping: Drugs can be trapped in compartments with a $pH$ that favors the ionized form (e.g., alkalizing urine with $NaHCO_3$ to trap weak acids like aspirin).

• Key Parameters:

  • Apparent Volume of Distribution ($V_d$): $\frac{\text{Amount of drug in the body}}{\text{Plasma drug concentration}}$. Units in Liters ($L$).

  • Clearance ($CL$): $\frac{\text{Rate of elimination}}{\text{Plasma drug concentration}}$. Units in Volume/time (e.g., $mL/min$).

  • Half-life ($t_{1/2}$): $t_{1/2} = \frac{0.693 \times V_d}{CL}$. Time for the plasma concentration to fall by $50\%$.

  • Bioavailability ($F$): The fraction of the administered dose that reaches the systemic circulation.

• Elimination Kinetics:

  • First-Order Elimination: Rate is proportional to concentration; concentration decreases exponentially; $t_{1/2}$ is constant.

  • Zero-Order Elimination: Rate is constant regardless of concentration; occurs when elimination mechanisms are saturated (e.g., ethanol, high-dose aspirin, phenytoin).

• Dosing Calculations:

  • Maintenance Dose: $\text{Dosing rate} = \frac{CL \times \text{Desired Plasma Concentration}}{\text{Bioavailability}}$

  • Loading Dose: $\text{Loading dose} = \frac{V_d \times \text{Desired Plasma Concentration}}{\text{Bioavailability}}$

PHARMACODYNAMICS AND RECEPTOR THEORY

• Graded Dose-Response Relationships:

  • Emax: The maximal effect achieved by a drug.

  • EC50: The concentration at which the effect is $50\%$ of maximum; a measure of potency.

  • Potency: The amount of drug needed for a given effect. Smaller $EC_{50}$ indicates higher potency.

  • Efficacy: The greatest effect ($E_{max}$) an agonist can produce.

• Quantal Dose-Response Relationships:

  • Measures response in a population (all-or-none).

  • ED50: Median effective dose (effective in $50\%$ of the population).

  • TD50: Median toxic dose.

  • LD50: Median lethal dose.

  • Therapeutic Index ($TI$): $\frac{TD_{50}}{ED_{50}}$. A measure of safety.

  • Therapeutic Window: Dosage range between minimum effective concentration and minimum toxic concentration.

• Receptor States and Signaling:

  • Constitutive Activity: Receptor activity in the absence of a ligand.

  • Full Agonist: High affinity for activated state ($R_a$); produces maximal effect.

  • Partial Agonist: Lower maximal efficacy than full agonists even at saturating doses.

  • Inverse Agonist: High affinity for inactive state ($R_i$); reduces constitutive activity.

  • Spare Receptors: When $E_{max}$ is reached at less than $100\%$ receptor occupancy (EC_{50} < K_d).

• Types of Antagonists:

  • Competitive: Reversible; shifts dose-response curve right (increases $ED_{50}$); $E_{max}$ remains unchanged.

  • Irreversible: Non-surmountable; shifts $E_{max}$ downward.

  • Physiologic: Operates on a different receptor to cause opposite effects (e.g., epinephrine vs. histamine).

  • Chemical: Directly binds and inactivates the drug (e.g., chelators).

• Signaling Mechanisms:

  1. Intracellular Receptors: For lipid-soluble agents (steroids, $NO$).

  2. Transmembrane Enzyme Receptors: Outer domain binds ligand, inner domain has enzyme activity (Tyrosine Kinase).

  3. JAK-STAT Receptors: Activate separate cytoplasmic tyrosine kinase molecules.

  4. Ligand-Gated Ion Channels: (e.g., Nicotinic receptors).

  5. G Protein-Coupled Receptors ($GPCRs$): Most common; modulate second messengers ($cAMP, IP_3, DAG$).

DRUG METABOLISM AND PHARMACOGENOMICS

• Metabolic Phases:

  • Phase I Reactions: Oxidation (Cytochrome $P450$), reduction, deamination, and hydrolysis. Adds or unmasks polar groups. $CYP3A4/5$ and $CYP2D6$ are primary.

  • Phase II Reactions: Conjugation (glucuronidation, acetylation, sulfation). Increases water solubility.

• Enzyme Modulation:

  • Inducers: Increase $P450$ synthesis (e.g., carbamazepine, phenobarbital, rifampine, St. John's wort).

  • Inhibitors: Decrease activity (e.g., cimetidine, ketoconazole, erythromycin, grapefruit juice).

  • Suicide Inhibitors: Irreversibly inhibit enzymes (e.g., ethinyl estradiol, spironolactone).

• Acetaminophen Toxicity:

  • Normally metabolized via Phase II (glucuronide/sulfate).

  • Overdose saturates Phase II; Phase I ($CYP$) creates reactive electrophile ($N\text{-acetyl-p-benzoquinoneimine}$).

  • Treated with N-acetylcysteine (glutathione precursor).

• Pharmacogenomics Key Points:

  • CYP2D6: Metabolizes codeine to morphine; polymorphisms lead to poor or ultrarapid metabolizers.

  • CYP2C19: Affects clopidogrel activation; loss of function increases clotting risk.

  • UGT1A1: Clearance of irinotecan bioactive metabolite ($SN\text{-}38$); variants cause bone marrow toxicity.

  • DPD: Responsible for $5\text{-FU}$ clearance; deficiency leads to severe toxicity.

AUTONOMIC NERVOUS SYSTEM (ANS) OVERVIEW

• Anatomy:

  • Parasympathetic ($PANS$): Craniosacral origin ($CN\,III, VII, IX, X$; $S_2\text{-}S_4$). Long preganglionic fibers.

  • Sympathetic ($SANS$): Thoracolumbar origin ($T_1\text{-}L_5$). Short preganglionic fibers.

  • Enteric ($ENS$): Myenteric (Auerbach) and submucous (Meissner) plexuses in the $GI$ tract.

• Cholinergic Transmission:

  • Synthesis: Choline + Acetyl-CoA via Choline Acetyltransferase ($ChAT$).

  • Storage: Vesicular Associated Transporter ($VAT$). Inhibited by vesamicol.

  • Release: $Ca^{2+}$-dependent; involving $SNARE$ proteins ($VAMPs, SNAPs$). Inhibited by Botulinum toxin.

  • Termination: Acetylcholinesterase ($AChE$) hydrolysis to acetate and choline.

• Adrenergic Transmission:

  • Synthesis: Tyrosine $\rightarrow$ DOPA (via Tyrosine Hydroxylase) $\rightarrow$ Dopamine $\rightarrow$ Norepinephrine ($NE$).

  • Storage: Vesicular Monoamine Transporter ($VMAT$). Inhibited by reserpine.

  • Release: Inhibited by guanethidine. Promoted by amphetamines/tyramine.

  • Termination: Reuptake via $NET$ or $DAT$. Inhibited by cocaine/tricyclic antidepressants. Metabolism by $MAO$ and $COMT$.

CHOLINOCEPTOR DRUGS

• Cholinoceptor Types:

  • Muscarinic ($M_1\,M_5$): $GPCRs$. $M_1, M_3, M_5$ use $G_q$ ($\uparrow IP_3, DAG$); $M_2, M_4$ use $G_i$ ($\downarrow cAMP$).

  • Nicotinic ($N_N, N_M$): Ion channels ($Na^+\text{-}K^+$).

• Direct-Acting Agonists:

  • Bethanechol: Muscarinic; used for bladder/bowel atony.

  • Pilocarpine: Muscarinic; used for Sjogren's and glaucoma.

  • Nicotine: Nicotinic; used for smoking cessation.

  • Varenicline: Partial nicotinic agonist for smoking cessation.

• Indirect-Acting (Cholinesterase Inhibitors):

  • Edrophonium: Short-acting ($5\text{-}15\,min$); diagnostic for Myasthenia Gravis.

  • Neostigmine/Pyridostigmine: Carbamates; used for Myasthenia Gravis.

  • Physostigmine: Enters $CNS$; antidote for atropine poisoning.

  • Organophosphates (Parathion, Sarin): Irreversible; treated with Atropine (muscarinic blocker) and Pralidoxime (enzyme regenerator).

CHOLINOCEPTOR BLOCKERS

• Antimuscarinics:

  • Atropine: Prototype nonselective blocker.

  • Scopolamine: Motion sickness.

  • Ipratropium/Tiotropium: $COPD$/Asthma (inhalants).

  • Oxybutynin/Tolterodine: Overactive bladder.

  • Toxicities: "Dry as a bone, hot as a pistol, red as a beet, mad as a hatter." (Hyperthermia, tachycardia, delirium).

• Antinicotinics:

  • Ganglion Blockers: Hexamethonium, Mecamylamine. Rarely used due to profound orthostatic hypotension.

  • Neuromuscular Blockers: Tubocurarine, Succinylcholine.

ADRENOCEPTOR AGONISTS (SYMPATHOMIMETICS)

• Receptor Subtypes and Effects:

  • $\alpha_1$: Vascular contraction, mydriasis.

  • $\alpha_2$: Inhibits $NE$ release, decreases sympathetic outflow ($CNS$).

  • $\beta_1$: Increased heart rate and force, renin release.

  • $\beta_2$: Respiratory/uterine/vascular relaxation, glycogenolysis.

  • $\beta_3$: Lipolysis.

  • $D_1$: Renal vasodilation.

• Selected Drugs:

  • Epinephrine: $\alpha, \beta$ agonist; drug of choice for anaphylaxis.

  • Norepinephrine: $\alpha_1, \alpha_2, \beta_1$; used in shock.

  • Dopamine: Dose-dependent affinity; low ($D_1$), medium ($\beta$), high ($\alpha$).

  • Albuterol: Selective $\beta_2$; acute asthma.

  • Phenylephrine: Selective $\alpha_1$; decongestant and mydriatic.

  • Clonidine: Selective $\alpha_2$; antihypertensive.

ADRENOCEPTOR BLOCKERS

• Alpha Blockers:

  • Phentolamine: Reversible, nonselective; used for hypertensive crisis.

  • Phenoxybenzamine: Irreversible; used for Pheochromocytoma.

  • Prazosin/Tamsulosin: Selective $\alpha_1$; used for hypertension and benign prostatic hyperplasia ($BPH$).

  • Epinephrine Reversal: ${\alpha}$ blockers unmask $\beta_2$ vasodilation, causing a drop in blood pressure when epinephrine is administered.

• Beta Blockers:

  • Propranolol: Nonselective; prototype.

  • Atenolol/Metoprolol: Selective $\beta_1$; safer in asthma.

  • Esmolol: Ultra-short acting; IV only.

  • Labetalol/Carvedilol: Combined $\alpha$ and $\beta$ blockade.

  • Clinical Uses: Hypertension, angina, arrhythmias, chronic heart failure, glaucoma (Timolol).

QUESTIONS & DISCUSSION

• Q: Why speed up weak acid excretion in alkaline urine?

• A: Acids ($RCOOH$) dissociate to the charged form ($RCOO^-$) in alkaline environments, preventing reabsorption from the renal tubule via lipid diffusion.

• Q: How does cocaine affect sympathetic activity?

• A: It inhibits the membrane transporter ($NET$), increasing the concentration of norepinephrine in the synaptic cleft.

• Q: What distinguishes Myasthenic from Cholinergic crisis?

• A: Edrophonium (Tensilon test). If strength improves, it is Myasthenic; if it worsens, it is Cholinergic.

• Q: What triggers "atropine fever"?

• A: Blockade of $\alpha_1$ muscarinic receptors on eccrine sweat glands prevents thermoregulatory sweating.

• Q: Why use Propranolol carefully in diabetics?

• A: It blocks $\beta_2$-mediated glycogenolysis and masks the tachycardia/tremor that warn of hypoglycemia.