Pharmacology Chapter 1: General Pharmacology

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Chapter 1: General Pharmacology

• Pharmacology is the science dealing with drugs.
• There are two branches:
  • PharmacoKinetics (PK): Effect of Body on Drug
  • PharmacoDynamics (PD): Effect of Drug on Body

PharmacoKinetics (PK)

• Aka ADME Study
• Includes:
  • Absorption (A)
  • Distribution (D)
  • Metabolism (M)
  • Excretion (E)
• Bioavailability: Fraction of given dose that reaches the systemic circulation in unchanged form
  • IV route: Bioavailability = 100%
  • First Pass metabolism/pre-systemic metabolism: Decreases bioavailability

Absorption (A)

• Lipid Solubility is the most important factor in absorption
• When the medium is the same, then the drug will cross:
  • Acidic drugs in acidic medium: Non-ionized, Lipid soluble, and crosses easily
  • Basic drugs in basic medium: Non-ionized, Lipid soluble, and crosses easily
  • Acidic drugs in basic medium: Ionized, Water soluble, and does not cross
  • Basic drugs in acidic medium: Ionized, Water soluble, and does not cross
• Cmax: Maximum concentration obtained by a particular dose
• Tmax: Time in which plasma concentration becomes maximum
• AUC: Total area covered by the graph, tells extent of absorption

Distribution (D)

• Measure of amount of drug in tissues after absorption in the systemic circulation
• Depends on lipid solubility and plasma protein binding
• Acidic drugs bind to Albumin, Basic drugs bind to α1 Acid Glycoprotein
• High PPB drugs have:
  • Low Vd (Volume of Distribution)
  • Long duration of action
  • More drug interactions
• Loading Dose (LD): Initial high dose given to start the action
• Maintenance Dose (MD): Repeated doses given to maintain the plasma concentration

Metabolism (M)

• Aim: To make a drug water soluble (polar)
• Phase I Reactions: Mostly catabolic, includes Oxidation, Reduction, Hydrolysis, Cyclization, and Deamination
• Phase II Reactions: Mostly anabolic, includes Glucuronidation, Glutathione conjugation, Acetylation, Methylation, and Sulfate conjugation
• Purpose of Phase I: Expose the functional group on the drug
• Purpose of Phase II: Makes the drug water soluble
• Enzymes: Divided into Microsomal and Non-microsomal; Microsomal enzymes can be induced or inhibited

Excretion (E)

• Glomerular Filtration: Lipid soluble and water soluble drugs can be filtered
• Tubular Reabsorption: Lipid soluble drugs are reabsorbed, water soluble drugs are excreted
• Tubular Secretion: Due to pumps/transporters in proximal tubules; Lipid soluble drugs are secreted
• Half-life (t1/2): Time in which plasma concentration of a drug becomes half
• Clinical importance of t1/2: Dose cannot be calculated, dosing interval/frequency can be known

PharmacoDynamics (PD)

• Deals with the action of a drug as well as the mechanism of action
• Mechanisms of action:
  • Enzyme inhibition
  • Receptors (Ionotropic, Enzymatic, and G-protein coupled receptors)

Receptors

• Ionotropic Receptors: Present on ion channels, also known as ligand-gated channels
• Enzymatic Receptors: Present on cell membrane with intracellular and extracellular ends (e.g., Tyrosine Kinase Receptors)
• G-protein Coupled Receptors (GPCRs): Works by one out of the three mechanisms ( changing cAMP level, Ca2+ level, or opening ion channels)
• Inracellular Receptors: Only lipid soluble drugs act through these receptors, which are of two types (Cytoplasmic and Nuclear Receptors)

Log Dose Response Curve (Log DRC)

• S-shaped curve (Sigmoid Curve)
• Clinically more useful than DRC
• Three important parameters obtained from log DRC:
  • Potency
  • Efficacy
  • Slope

Quantal Dose Response Curve (Quantal DRC)

• For All or None phenomenon, where grade of response cannot be plotted
• Percentage of subjects responding are kept on Y-axis
• Tells about effect of a drug in population
• ED50 (Median Effective dose): 50% respond to a particular dose
• LD50 (Median Lethal dose): 50% of animals die after receiving a particular dose
• Therapeutic index (TI) = LD50/ED50Here are the study notes based on the provided text:

Autonomic Nervous System

• Origin:
  • Preganglionic parasympathetic and sympathetic neurons release ACh as the neurotransmitter
  • Postganglionic parasympathetic neurons release ACh, while postganglionic sympathetic neurons release NA
• Actions:
  • Heart: Parasympathetic stimulation decreases heart rate (↓), while sympathetic stimulation increases heart rate (↑)
  • Bronchus: Parasympathetic stimulation causes bronchoconstriction, while sympathetic stimulation causes bronchodilation
  • GIT: Parasympathetic stimulation increases peristalsis, while sympathetic stimulation decreases peristalsis
  • Bladder: Parasympathetic stimulation contracts bladder muscles, while sympathetic stimulation relaxes bladder muscles
  • Pupil: Parasympathetic stimulation causes miosis, while sympathetic stimulation causes mydriasis
  • Sexual system: Parasympathetic stimulation causes erection, while sympathetic stimulation causes ejaculation

Cholinergic Drugs

• Directly Acting Cholinergic Drugs:
  • Stimulate parasympathetic system
  • Examples: Pilocarpine, Bethanechol, Carbachol
• Indirectly Acting Cholinergic Drugs:
  • Act by inhibiting AChE
  • Examples: Physostigmine, Neostigmine, Pyridostigmine
• Reversible AChE Inhibitors: Used clinically, e.g., Neostigmine
• Irreversible AChE Inhibitors: Toxic, e.g., Organophosphates

Anticholinergic Drugs

• Organ:
  • Stomach: Blocks M1 receptors, relieving peptic ulcer symptoms
  • Heart: Blocks M2 receptors, increasing heart rate
  • Bronchus: Blocks M3 receptors, relieving bronchial asthma
  • Bladder: Blocks M3 receptors, relieving overactive bladder
  • Eye: Blocks M3 receptors, relieving mydriasis
• Uses:
  • Peptic ulcer
  • Bradycardia
  • Bronchial asthma
  • Overactive bladder
  • Refraction testing
  • Iridocyclitis

Sympathetic Nervous System

• Major neurotransmitter: Noradrenaline (NA)
• Adrenergic Receptors:
  • α1: Vasoconstriction
  • α2: Presynaptic receptor, acting as a brake on sympathetic system
  • β1: Increase heart rate and contractility
  • β2: Relax smooth muscles, causing bronchodilation and vasodilation
  • β3: Lipolysis

Adrenergic Drugs

• Directly Acting Adrenergic Drugs:
  • Stimulate adrenergic receptors
  • Examples: Adrenaline, Noradrenaline, Isoprenaline
• Indirectly Acting Adrenergic Drugs:
  • Act by releasing NA from nerve terminals
  • Examples: Ephedrine, Amphetamine
• α1 Blockers: Used in hypertension, e.g., Prazosin
• β Blockers: Used in hypertension, angina, and cardiac arrhythmias, e.g., Propranolol

Glaucoma

• Characteristics: Increased intraocular pressure (IOP) due to increased aqueous humor production or decreased drainage
• Treatment:
  • β Blockers: Decrease aqueous humor production
  • Prostaglandin analogues: Increase aqueous humor drainage
  • α2 Agonists: Decrease aqueous humor production and increase drainage
  • Carbonic anhydrase inhibitors: Decrease aqueous humor production

Previous Years Questions

• Q1: Muscarinic receptor stimulation leads to erection, increased contraction of cardiac muscles, and bronchodilation.
• Q2: Pinpoint pupils and increased secretions are symptoms of organophosphate poisoning.
• Q3: Topical antiglaucoma drug dorzolamide acts by carbonic anhydrase inhibition.
• Q4: The next line of management for the patient with snake bite symptoms would be to administer atropine and neostigmine.
• Q5: Edrophonium is used to differentiate myasthenia gravis from cholinergic crisis.
• Q6: The patient's symptoms are consistent with cholinergic crisis.
• Q7: The graph shows the effect of ACh on isolated mammalian intestinal tissue.
• Q8: The experiment demonstrates the effect of adrenaline on dog blood pressure.

Quick revision notes on general pharmacology, covering pharmacokinetics, pharmacodynamics, absorption, bioavailability, and first pass metabolism.