Pharmacology Lecture Notes

Pharynx

• Connects nasal cavity and mouth to larynx and esophagus.

Sinuses

• Resonators for sound.

• Aid in mucus production.

• Help lighten the skull.

Larynx

• Primary function: phonation (voice production).

• Structure adapted for vibration due to vocal folds and cords.

Vocal Cords

• Breathing: vocal cords remain open.

• Phonation: vocal cords move together, and airflow causes vibration.

• Pitch is determined by the stretch of the vocal cords.

  • High pitch: Sharp edges.

  • Bass pitch: Blunt edges.

Mucus and Cilia

Mucus

• Secreted by goblet cells.

• Traps particles, preventing them from reaching the alveoli.

Cilia

• Epithelial wall is lined with ciliated epithelium (200 cilia per cell).

• Power stroke in the direction of the pharynx.

• Mucus and trapped particles are either swallowed or coughed out.

Cough Reflex

• Bronchi and trachea are sensitive to light touch, with the larynx and carina being the most sensitive.

• Afferent nerve impulses pass through airways via the vagus nerves to the medulla.

Steps

1. 2.5L of air is inspired rapidly.

2. Epiglottis closes, and vocal cords shut tightly, trapping air.

3. Abdominal muscles contract, increasing lung pressure by 100 mmHg.

4. Vocal cords and epiglottis suddenly open widely, expelling air at high pressure (75-100 miles/hr).

Histamine

• Endogenous amine involved in immediate allergic responses, such as bronchoconstriction and vasodilation (H1 receptor).

• Gastric acid secretion (H2 receptor).

• Neurotransmitter release from granules on mastocytes.

• Antigen I-gE interaction on mast cell surface.

Histamine Receptors

• Four receptors: H1-H4.

Agonists

• Activate the receptor to its maximum capacity.

Partial Agonists

• Activate the receptor, but only partially, not to its maximum capacity.

• Prevent the activity of full agonists.

Antagonists

• Prevent the activity of agonists and partial agonists.

• Do not produce any action on the receptor itself.

Inverse Agonists

• Prevent the constitutive activity of the receptor, making it inactive.

• The resultant effect is opposite to the constitutive activity of the receptor.

First Generation Antihistamines

Chlorpheniramine

• Most potent H1 antagonist.

• Less prone to induce drowsiness.

• CNS effects are more common.

Diphenhydramine

• Ethanolamine class.

• Antimuscarinic activity.

• Pronounced sedation.

Second Generation Antihistamines

Loratadine

• Active metabolite: desloratadine.

• No anticholinergic actions.

• No penetration to the CNS.

• Mast cell stabilizing and anti-inflammatory properties.

Fexofenadine

• Replaced terfenadine due to toxic side effects.

• No sedation.

• Antiallergic.

Cetirizine

• Minimal anticholinergic effect.

• More associated with drowsiness than other 2nd generation piperazines.

• Mast cell stabilizing and anti-inflammatory properties.

Terfenadine and Astemizole

• May cause arrhythmia (Torsade de pointes).

• Terfenadine metabolized by CYP3A4 to fexofenadine.

• Not used anymore.

Triple Response of Lewis

1. Localized reddening: direct vasodilating effect.

2. Flare: slower onset (1cm), indirect vasodilation.

3. Wheal: appears in 1-2 minutes, increased capillary permeability.

Side Effects of Antihistamines

• Sedation, dizziness, tinnitus, fatigue, incoordination, blurred vision, diplopia, mood changes.

• GI: Nausea, vomiting, epigastric distress (can improve when taken with meals).

• Cyproheptadine may increase appetite and cause weight gain.

• Anticholinergic (antimuscarinic) effects: Dry mouth, dry respiratory passages, urinary retention or frequency, dysuria (less common in 2nd generation).

• Allergic reactions: Allergic dermatitis, drug fever, photosensitivity.

• Hematologic effects: Leukopenia, agranulocytosis, hemolytic anemia.

Acute Poisoning with First Generation H1 Antagonists

• Danger: Central excitatory effects.

• Resemble atropine poisoning (hallucinations, tachycardia, flushing).

• Progression can lead to coma, cardiorespiratory collapse, and death within 2-18 hours.

Precautions

• Second-generation H1 antagonists are preferred for elderly patients, especially those with impaired cognitive function.

• First-generation antihistamines are not recommended for use in children, sedative effects can impair school performance.

Additional Medications

• NSAIDs and acetaminophen.

• Glucocorticoids (e.g., betamethasone, mometasone, fluticasone) for allergic disease of limited duration.

• Supplementary therapy: Allergic rhinitis (intranasal steroids).

Beta-Lactams

Mechanisms of Resistance

1. Alterations in the PBP target.

2. Reductions of the concentration at the target site.

3. Enzymatic degradation of the beta-lactam itself.

Beta-Lactamase Inhibitors

• Protect beta-lactams from beta-lactamases by binding to them.

• Prevent enzymes from hydrolyzing beta-lactam agents in the vicinity.

• Examples: Clavulanic acid, Tazobactam, Sulbactam, Avibactam, Baborbactam.

Amoxicillin

• Aminopenicillin.

• Useful activity against more gram-negative organisms.

• Hydrolyzed by beta-lactamases.

• Formulated with beta-lactamase inhibitors.

Spectrum

• S. aureus, H. influenzae, E. coli, Klebsiella, Proteus, B. fragilis

• Bactericidal for gram-positive and gram-negative bacteria.

ADME

• Oral absorption via GI tract.

• Food does not interfere with absorption.

• 20% bound to plasma.

• Excreted in urine.

• Dose adjustment in renal dysfunction needed.

• Treatment of choice for community-acquired pneumonia (1g every 8 hours).

• Alternative Tx for bacterial pharyngitis.

Macrolides

Clarithromycin

ADME

• Absorbed in GI, 55% bioavailability, liver first pass.

• Active metabolite = 14-hydroxy clarithromycin.

• Metabolized in the liver.

• Dose: Adults with mild-moderate infection 250 mg every 12 hrs/500mg every 12 hrs

Azithromycin

• Orally or IV

• Distributed widely throughout the body.

• High drug concentrations within cells.

• Half-life: 40-60 hours.

• Dose: 250-500 mg oral/IV every 24 hours.

• In community-acquired pneumonia in low ambulatory risk patients, a macrolide is commonly added to an anti-pneumococcal beta-lactam for coverage of atypical respiratory pathogens, mycoplasma, legionella.

• Allergy to penicillins: azithromycin 500mg VO day 1 then 250mg daily x days

Adverse Effects

• GI distress.

• Cardiac arrhythmias.

• Hepatotoxicity.

• Strong CYP3A4 inhibition.

Alpha-Adrenergic Receptor Agonists

• Sympathomimetic effects of alpha-1 adrenergic receptors in vascular smooth muscle.

• Peripheral vascular resistance is increased.

• Blood pressure is maintained or elevated.

• Used as nasal decongestants in patients with allergic or vasomotor rhinitis and acute rhinitis in upper respiratory infections

Limitation of therapy

• Loss of efficacy

• Rebound hyperemia/congestion: nasal spray, px use it excessively, worsening of symptom with chronic use or if stopped, because of receptor desensitization and mucosa damage, a-1 receptor agonist are less prone to damage

• Vasoconstrictors to the local nasal mucosa or eye

  • Naphazoline

  • Oxymetazoline
    Most common oral preparations for the relief of nasal congestions

• phenylephrine
  Precautions Hypertension/ischemic heart disease

• Prostatic enlargement

• Contra if taking MAO inhibitors Serotoninergic/hypertensive crisis

Antitussives

• Cough is a common symptom of airway disease, treatment is largely ineffective

  • Viral infections are the most common cause (upper tract)

  • Post Viral cough is usually self limiting and patient medicated

  • Over the counter meds are largely ineffective

  • Cough is a defensive reflex.

  • Suppression of cough may be inappropriate (Bacterial lung infection)

  • Treat the underlying cause, not the cough itself

Dextromethorphan

• N-methyl-D aspartate receptor antagonist.

• Causes: hallucinations, abuse potential because of opioid

Benzonatate

• Local anesthetic.

• Acts peripherally by anesthetizing stretch receptors located in respiratory passages, less cough cough.

Oxolamine

• For use in Mexico only

Expectorants

• Supposed to enhance clearance of mucus.

• No sirven, solo Guaifenesin.

• Better approach: adequate hydration and steam inhalation.

Mucolytics

• Reduce viscosity of mucus.

• N-acetylcysteine, derivative of cysteine that reduces disulfide bridges that bind glycoproteins to proteins, ONLY IN THE US.

• Others: Bromhexina/ ambroxol.

Anti-Influenza Agents

Amantadine

• Tricyclic amine.

• Inhibits early viral replication and late-step viral assembly.

• Primary locus of action is influenza A virus M2 protein.

• TX Influenza A viruses only, all H3N2 strains of influenza worldwide are resistant, because of overuse, vaccine more cost effective.

• Alternative medication for antipsychotic induced parkisons

Bronchodilators

• Relax airway smooth muscle or blocks bronchoconstriction effects of neurotransmitters

• B2 adrenergic agonist (sympathomimetics)

• Theophylline (Methylxanthine)

• Anticholinergic agents (muscarinic receptor antagonists)

B2 Agonists

• Activation of G protein, Gs-adenylyl cyclase-5’5’ cyclic adenosine monophosphate (cAMP) protein kinase A PKA pathway

• Phosphorylative events, bronchial smooth muscle relaxation

• Indirect bronchodilation (theory)

• Prevention of mediator release from mast cells

• Prevention of microvascular leakage and edema from mediator exposure

• Increase mucus secretion and ion transport

• Reduction in neurotransmission of ACh release

• Tx of choice for asthma

• SABA= acute severe asthma Nebulized route

• LABA= COPD

12h bronchodilator action, improve asthma control give 2x a day, combined them with corticosteroids

• Labas are more effective given in combination tx with ICS than increasing ICS dose when asthma is not controlled at low doses Improve symptoms and exercise tolerance, reduces both air trapping and exacerbations.

Antimuscarinic Agents

• Competitive antagonists of ACh at muscarinic receptors.

• Direct inhibition of constrictor effect on bronchial smooth muscle.

• M3-Gq-PLC-IP3-Ca^{2+} pathway

• Parasympathetic regulation of bronchial tone and mucus secretion.

Clinical Use

• Asthma: Less effective than B2 agonists; LAMAs (Long-acting Muscarinic Antagonists) used as additional bronchodilators.

• COPD: More effective than B2 agonists; inhibit vagal tone, potentially the only reversible element of obstruction.
  Medications

SAMA (Short-Acting Muscarinic Antagonist)

• Ipratropium bromide.

• Slow onset of bronchodilation (max 30-60 min after inhalation).

LAMA (Long-Acting Muscarinic Antagonist)

• Tiotropium bromide.

• Once-daily dose.

Combination Therapy

• SABA/SAMA: Albuterol/ipratropium.

Adverse Effects

• Ipratropium may precipitate glaucoma in elderly patients (prevented by mouthpiece nebulization).

• Paradoxical bronchoconstriction is possible with ipratropium bromide.

• LAMAs cause dryness of the mouth in 10% to 15% of patients; urinary retention is occasionally seen in elderly patients.

Methylxanthines

Theophylline

• Related to caffeine and theobromine.

• Add-on therapy in severe asthma and COPD.

Bronchodilator Action

• Nonselective inhibition of PDEs

• Adenosine receptor antagonism (adenosine causes histamine and LT release; Al receptors).

• Arrhythmias

• Seizures

• Il-10 release

• Broad anti inflammatory effect

• Reduced secretion in asthma/COPD

• Gene transcription

• Prevents translocation of pro-inflammatory transcription factor nuclear factor- KB (NF-KB)

• Reduced expression of inflammatory genes

• Apoptosis (A2 receptors)

• Eosinophils and neutrophils Pharma

• Therapeutic range 5-15 mg/L plasma concentration

• Large variances in clearance

• Hepatic metabolism

• CYP1A2

• For continuous treatment, twice-daily therapy (~8 mg/kg twice daily) is needed

• For nocturnal asthma, a single dose of slow-release theophylline at night is often effective Clinical use ASTHMA

• Acute asthma

• On pxs that failed to respond to inhale B2 agonists.

• Used as a controller in mild-persistent asthma

Side Effects

• Related to plasma concentration (>15 mg/L): Headache, nausea, and vomiting (Most common)

• Inhibition PDE4

• Increased acid secretion

• Diuresis

• Schoolchildren: Behavioral disturbances and learning difficulties.

• High concentrations: Cardiac arrhythmia (PDE3 inhibition and cardiac Al receptor antagonism).

• Very high concentrations: Seizures (Central Al receptor antagonism).

Chromones

Disodium Cromoglycate

• Derivative of khellin (Egyptian herbal medicine).

• Allergy protection without bronchodilator effect.

• Not used as much anymore for asthma therapy.

Term 1: Pharynx
Definition 1: Connects nasal cavity and mouth to larynx and esophagus.
Term 2: Sinuses
Definition 2: Resonators for sound, aid in mucus production, help lighten the skull.
Term 3: Larynx
Definition 3: Primary function is phonation (voice production).
Term 4: Mucus
Definition 4: Traps particles, preventing them from reaching the alveoli.
Term 5: Cilia
Definition 5: Epithelial wall lined with ciliated epithelium, power stroke in the direction of the pharynx.
Term 6: Histamine
Definition 6: Endogenous amine involved in immediate allergic responses, gastric acid secretion, neurotransmitter release.
Term 7: Agonists
Definition 7: Activate the receptor to its maximum capacity.
Term 8: Partial Agonists
Definition 8: Activate the receptor, but only partially, not to its maximum capacity; prevent activity of full agonists.
Term 9: Antagonists
Definition 9: Prevent activity of agonists and partial agonists; do not produce any action on the receptor itself.
Term 10: Inverse Agonists
Definition 10: Prevent the constitutive activity of the receptor, making it inactive; resultant effect is opposite to constitutive activity of the receptor.
Term 11: Chlorpheniramine
Definition 11: Most potent H1 antagonist; less prone to induce drowsiness; CNS effects are more common.
Term 12: Diphenhydramine
Definition 12: Ethanolamine class; antimuscarinic activity; pronounced sedation.
Term 13: Loratadine
Definition 13: Active metabolite: desloratadine; no anticholinergic actions; no penetration to the CNS; mast cell stabilizing and anti-inflammatory properties.
Term 14: Fexofenadine
Definition 14: Replaced terfenadine due to toxic side effects; no sedation; antiallergic.
Term 15: Cetirizine
Definition 15: Minimal anticholinergic effect; more associated with drowsiness than other 2nd generation piperazines; mast cell stabilizing and anti-inflammatory properties.
Term 16: Terfenadine and Astemizole
Definition 16: May cause arrhythmia (Torsade de pointes); terfenadine metabolized by CYP3A4 to fexofenadine; not used anymore.
Term 17: Triple Response of Lewis
Definition 17: Localized reddening: direct vasodilating effect; Flare: slower onset (1cm), indirect vasodilation; Wheal: appears in 1-2 minutes, increased capillary permeability.
Term 18: Mechanisms of Resistance
Definition 18: Alterations in the PBP target; reductions of the concentration at the target site; enzymatic degradation of the beta-lactam itself.
Term 19: Beta-Lactamase Inhibitors
Definition 19: Protect beta-lactams from beta-lactamases by binding to them; prevent enzymes from hydrolyzing beta-lactam agents in the vicinity; e.g., Clavulanic acid, Tazobactam, Sulbactam, Avibactam, Baborbactam.
Term 20: Amoxicillin
Definition 20: Aminopenicillin; useful activity against more gram-negative organisms; hydrolyzed by beta-lactamases; formulated with beta-lactamase inhibitors.
Term 21: Clarithromycin ADME
Definition 21: Absorbed in GI, 55% bioavailability, liver first pass; active metabolite = 14-hydroxy clarithromycin; metabolized in the liver.
Term 22: Azithromycin
Definition 22: Orally or IV; distributed widely throughout the body; high drug concentrations within cells; half-life: 40-60 hours.
Term 23: Alpha-Adrenergic Receptor Agonists
Definition 23: Sympathomimetic effects of alpha-1 adrenergic receptors in vascular smooth muscle; peripheral vascular resistance is increased; blood pressure is maintained or elevated.
Term 24: Dextromethorphan
Definition 24: N-methyl-D aspartate receptor antagonist; causes hallucinations, abuse potential because of opioid.
Term 25: Benzonatate
Definition 25: Local anesthetic; acts peripherally by anesthetizing stretch receptors located in respiratory passages.
Term 26: Mucolytics
Definition 26: Reduce viscosity of mucus; N-acetylcysteine, derivative of cysteine that reduces disulfide bridges that bind glycoproteins to proteins.
Term 27: Amantadine
Definition 27: Tricyclic amine; inhibits early viral replication and late-step viral assembly; primary locus of action is influenza A virus M2 protein.
Term 28: Bronchodilators
Definition 28: Relax airway smooth muscle or blocks bronchoconstriction effects of neurotransmitters
Term 29: Antimuscarinic Agents
Definition 29: Competitive antagonists of ACh at muscarinic receptors; direct inhibition of constrictor effect on bronchial smooth muscle.
Term 30: Theophylline Bronchodilator Action
Definition 30: Nonselective inhibition of PDEs; adenosine receptor antagonism (adenosine causes histamine and LT release; Al receptors).