Pharmacology I

A.Y. 2021/2022
Overall hours
Learning objectives
The course intends to provide medical students with basic information on drugs' action, focusing on the general principles of pharmacodynamics and pharmacokinetics. To this aim, students will learn about the cellular and molecular targets of drug actions, with emphasis on how the pharmacological interference with these targets can produce a therapeutic outcome. Students will also learn on how a drug reaches its target in the body, crossing physiologic barriers, distributing into peripheral tissues, and eventually being metabolized and excreted.
Expected learning outcomes
Students will develop the aptitude to establish the appropriate pharmacotherapy on the basis of:
- Pathogenetic mechanisms of disease
- Mechanism of action of the drugs
- Pharmacokinetic parameters for the choice of the dose, posology, administration routes
-I ndividual characteristics of the patient (comorbidity, possible drug-drug interactions, pharmacogenetics).
Course syllabus and organization

Single session

More specific information on the delivery modes of training activities for academic year 2021/22 will be provided over the coming months, based on the evolution of the public health situation.
Course syllabus
TOPIC 1 Pharmacodynamics. Classification of drug targets
· Describe membrane receptors

TOPIC 2 Pharmacodynamics. Classification of drug targets
· Describe intracellular receptors

TOPIC 3 Pharmacodynamics. Classification of drug targets
· Describe voltage-gated ion channels, pumps and transporters

TOPIC 4 Pharmacodinamics. Quantitative drug-receptor interactions (ASYNCHR)
· Describe binding curves
· Define the concept of affinity and Bmax.

TOPIC 5 Pharmacodinamics. Quantitative drug-receptor interactions (ASYNCHR)
· Describe dose-response relationships.
· Define the concepts of potency and efficacy.
· Define the concepts of agonist, antagonist, inverse agonist, partial agonist, biased agonist

TOPIC 6 Pharmacodinamics- Clinical applications (ASYNCHR)
· Define the concepts of therapeutic index and therapeutic window
· Describe receptor desensitization and down-regulation
· Describe mechanisms of drug toxicity

TOPIC 6 Nitric Oxide (NO)
· Enzymes
· Functions in endothelial, neuronal and inflammatory cells

TOPIC 6 Arachidonic acid cascade
· Eicosanoids pathways
· COX1 and COX2
· Lipoxigenase and leukotriens
· Lipoxins, Resolvins, Protectins and Marensins

TOPIC 7 Biologic drugs (ASYNCHR)
· Recombinant protein
· mAbs
· Decoy

TOPIC 8 Proton Pump Inhibitors and drugs affecting gastrointestinal functions
· Classification of drugs affecting gastric pH.
· PPI: mechanism of action
· Drugs for gastrointestinal motility, constipation, diarrhea, emesis.

TOPIC 9 Pharmacology of Autonomic Nervous System (ANS)
· Anatomical organization
· Neurochemistry
· Receptor distribution
· Drugs modulating ANS responses

TOPIC 10 Pharmacogenetics and pharmacogenomics.
· Polymorphisms classification
· Genetic variations and PK
· Genetic variations and PD

TOPIC 11 Pharmacokinetics-Absorption
· Describe Physiologic barriers
· Describe physicochemical properties of biological membranes
· Describe administration routes and rationale

TOPIC 12 Pharmacokinetics-Distribution
· Define the concept of Volume of distribution
· Describe plasma protein binding
· Describe the role of transporters in drug distribution
· Describe the blood-brain-barrier

TOPIC 13 Pharmacokinetics-Metabolism
· Describe Oxidation/Reduction Reactions
· Describe Conjugation/Hydrolysis Reactions

TOPIC 14 Pharmacokinetics-Excretion
· Describe renal excretion
· Describe biliary excretion

TOPIC 15 Pharmacokinetics-Clinical applications (ASYNCHR)
· Define bioavailability
· Define Clearance
· Describe Metabolism and excretion Kinetics
· Define the concept of elimination half-life

TOPIC 16 Pharmacokinetics- Clinical applications (ASYNCHR)
· Factors altering the half-life
· Describe therapeutic dosing and frequency
· Describe pharmacokinetic parameters in special populations (e.g. elderly, children, chronic kidney diseases, liver diseases)

· Membrane receptors as drug targets
· Membrane receptors structures and their transduction systems.
· ligand-gated ion channels (nicotinic receptors, glutamate receptors, GABAa receptors, glycine receptors, 5HT3 serotonin receptors), and the mechanism of action of relevant drugs acting on them.
· GPCR receptors. classification of different G-proteins.
· GPCR for classic neurotransmitters (cholinergic, adrenergic, dopaminergic receptors) and their relevant drugs
· Receptors with intrinsic enzymatic activity and their relevant drugs:
Receptor Tyrosine kinases, receptor tyrosine phosphatase, receptor serine/threonine kinases, receptor guanylyl cyclases. Tyrosine-kinase associated receptors.
· Drugs affecting second messenger levels (e.g phosphodiesterase inhibitors)
· Receptor desensitization and down-regulation. Clinical implications.
· Intracellular receptors as drug targets
· Gene transcription as a drug target
· Intracellular receptor structures and their action as transcription factors.
· Steroid hormone receptors as drug targets (glucocorticoids, mineralcorticoids, androgens, estrogens, progestins)
· Glucocorticoid receptor and the NFkappaB system. The role in inflammation
· Voltage-gated ion channels as drug targets
· Voltage-gated ion channels (sodium, potassium, calcium) as targets for drugs used in: epilepsy, arrythmia, pain, hypertension, anesthesia
· Pumps and transporters as drug targets
· ATPases pumps as drug targets: Na+/K+ pumps, Ca++ pumps, ABC transporters
· Physiological and pathological secretion of H+ in the stomach.
· The H/K pump as target of PPI. Mechanisms of action.
· Enzymes as drug targets
· Classification of NOS enzymes and their regulation.
· Effects of NO in endothelial cells, in central and autonomic neurons, and in inflammatory cells.
· Hormonal regulation of NOS.
· Drugs modifying NO system in the cardiovascular system: NO donors.
· Physiology of eicosanoids metabolism
· Generation of arachidonic acid and omega-3 fatty acid
· Cycloxygenase pathway: prostaglandins, thromboxane and prostacyclin
· COX-1 and COX-2 and NSAIDs
· Therapeutic use of NSAIDs
· Aspirin in the cardiovascular system
· NSAIDs ADR: GI, cardiovascular system, kidney
· Lipoxygenase pathways: leukotriens
· Leukotriens synthesis inhibitors
· Leukotriens receptor antagonist
· Lipoxygenase pathway and the resolution of inflammation: Lipoxins, Resolvins, Protectins and Marensin.
· Epoxygenase pathway
· Pharmacology of Autonomic Nervous System (ANS)
· Functional organization and neurochemistry of parasympathetic nervous system
· Ach synthesis, storage and release
· Cholinergic muscarinic receptors in the target organs
· Degradation of Ach
· Drugs affecting parasympathetic functions and their clinical uses.
· Cholinergic nicotinic receptors at the neuromuscular junction. Drugs and clinical uses.
· Functional organization and neurochemistry of sympathetic nervous system
· Catecholamine synthesis, storage and release
· Adrenergic receptors in the target organs
· Reuptake and metabolism of catecholamines
· Drugs affecting sympathetic functions and their clinical uses.
· NANC (non-adrenergic non-cholinergic fibers). Distribution and functions.
· Pharmacogenetics and pharmacogenomics
· The genetic bases of individual drug response
· Polymorphisms classification (SNP, CNV)
· Polymorphisms in drug transporters and their effects on absorption, distribution and elimination.
· Polymorphisms in drug metabolizing enzymes and their effects on metabolism
· Polymorphisms in drug targets and their effects on pharmacodynamics
· Pharmacodinamics: quantitative drug-receptor interactions
· How to study drug-target interaction
· Binding curves and the concept of Kd and Bmax.
· Dose-response relationships.
· The concepts of potency and efficacy.
· The concepts of agonist and partial agonist
· The concept of antagonist: competitive and non-competitive antagonists
· Receptor basal activity and inverse agonists
· The definition of drug intrinsic activity
· Definition of biased agonist
· Spare receptors
· Drug safety and toxicity
· The concepts of therapeutic index and therapeutic window
· The general mechanisms of drug toxicity
· Biologic drugs
· Recombinant protein.
· Heterologous systems for the production of recombinant protein
· Recombinant proteins as modulators or for the replacement therapies
· mAbs
How mAbs are produced: murine, chimeric, humanized and fully human mAbs
· Mechanisms of action
· Adverse drug reactions
· Bispecific antibodies .
· Decoy

· the cellular bases of pharmacokinetics
· the characteristics of the main cellular barriers that the drug must overcome in order to reach its target
· how the drug can cross membranes and cell barriers to move between the various compartments of the body including the characteristics of the main barriers and permeability in the various capillary districts
· the different routes of administration and their characteristics, in terms of absorption rate, passage to the systemic circle, times and peak values of plasma concentration
· the variables that may interfere with drug absorption
· the concept of absorption kinetics
· the absorption differences according to the route of administration used
· the concept of apparent volume of distribution
· the binding of drugs to plasma and tissue proteins
· the factors influencing the rate of drug distribution in the various compartments
· To familiarize with models to understand pharmacokinetics
· the concept of elimination and the concept of total and organ clearance
· renal excretion, tubular passive reabsorption, active secretion and reabsorption at tubular level including the transport system of organic anions and cations
· renal clearance in particular categories (e.g. newborn)
· the hepatic excretion and entero-hepatic circulation and biliary and fecal excretion
· perfusion, plasma protein binding, enzyme activity and liver clearance
· the relationship between metabolism and excretion as well as the drug metabolism including phase I and phase II enzymatic reactions
· the extra-hepatic biotransformations including the role of intestinal microbial flora
· the concept of induction and inhibition of drug metabolism
· the concept of personalized pharmacokinetics including the temporal trends of drug plasma concentration after single or repeated administrations.
· how to calculate the absorbed fraction, the apparent distribution volume and the clearance of a drug
· To familiarize with theoretical calculation of the plasma concentration curve including the assessment of peak of plasma concentration
· the effect of closer administration on plasma concentration trend
· how the interval between administrations may influences the fluctuations of the plasma concentration at equilibrium
· the concept of accumulation doses
· the kinetic relevance of plasma protein binding
· the particular case of the placenta
· the distribution of drugs and drugs redistribution between different compartments
· the drug administration by inhalation
· the specificities of the antibiotic therapy regimen
· the therapeutic regime corrections
· the dosage variations as a function of body weight and physical constitution
· the age-dependent dosage changes
· the dosage corrections during liver or kidney diseases
Prerequisites for admission
To take the Pharmacology 1 exam, students must have already passed all the exams of the first year (Fundamentals of Basic Sciences, Cells, Molecules and Genes 1 and 2, Human Body) and the exam of Functions.
Teaching methods
Synchronous learning: lectures
Asynchronous learning: pre-recoreded audio-video;

Attendance is required to be allowed to take the exam. Unexcused absence is tolerated up to 34% of the course activities. University policy regarding excused illness is followed. During the aa 2020-21 higher tolerance for absence considering the development of the pandemic and the related current difficult conditions for students.
Teaching Resources
· "General and Molecular Pharmacology. Principles of drug action" Edited by Francesco Clementi and Guido Fumagalli. Wiley.
· Goodman & Gilman's. "The pharmacological basis of therapeutics". 12th Edition. The McGraw-Hill companies

Additional material, in particular original articles and online contents, will be made available during the course.
Assessment methods and Criteria
Students' assessment is based on an oral exam.
The examination contents are to be considered those listed in the EXPECTED OUTCOMES sections.

Registration to the exam through SIFA is mandatory.
BIO/14 - PHARMACOLOGY - University credits: 3
Lessons: 36 hours