Transcript of the video narration:

“Although nicotine can interact with a variety of receptor at numerous tissues, it is its interaction with specific receptors in the brain that creates the dependence associated with smoking.

Within the midbrain, nicotine interacts with the alpha 4 beta 2 nicotinic acetylcholine receptor. Acetylcholine is the natural ligand for this receptors. However, nicotine also an acetylcholine receptor agonist, has a higher affinity for the α4β2 (alpha 4 beta 2) receptors. Located on postsynaptic neurons, these receptors are comprised by two α4 and three β2 subunits that form a channel for transporting ions through the membrane.

When two molecules of nicotine or another ligand engage binding sites within the ionotropic receptor, the ion channel is activated. Looking into the receptor, we see that it is closed, but activation by ligand triggers channel opening for the passage of calcium, sodium and potassium ions.This generates action potentials to the reward area of the brain. Here, the impulse stimulates the release of neurotransmitters including dopamine. Dopamine triggers additional signaling events that stimulate the reward circuit generating short feelings of well-being, increased attention and improved mood. Every time tobacco is used, dopamine levels surge. However, nicotine is eliminated rather rapidly, causing dopamine levels to decline. The result: a craving for more nicotine.

With continued use, α4β2 (alpha 4 beta 2) nicotinic receptors undergo complex adaptive changes including up regulation and desensitization. Over time, these and other downstream changes contribute to a stronger need for nicotine stimulation to achieve the rewards of smoking.”

Geriatric drug therapy. By Linda Farho, Pharm.D

Lecture outline

• Pharmacokinetics recall: Absorption, Distribution, Metabolism, Elimination. Bioavailability.
• Effects of Aging on: absorption, metabolism, volume of distribution and the kidney.
• Estimating GFR in the Elderly.
• Determining creatinine clearance.
• Pharmacodynamics.
• Concepts related to an optimal pharmacotherapy.
• Consequences of overprescribing.
• Adverse drug events (ADE): most common medications, Beers criteria, patient risk factors for ADE.
• Drug – drug interactions (DDI).
• Drug – disease interactions.
• Principles of prescribing in the elderly.
• Preventing polypharmacy.
• Enhancing medication adherence.
• Clinical cases.

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Clinical Pharmacological Issues in the Elderly. By Charles A. Cefalu, MD

Lecture outline

• Factors related to adverse drug reactions.
• Changes of aging: liver, renal clearance, CNS.
• Normal physiological changes in the organ systems.
• Pharmaceutical agents that require hepatic metabolism.
• The cytochrome system.
• Drugs eliminated in the kidneys requiring dosage adjustment.
• Aminoglycoside dosing in the elderly with impaired renal function.
• Practical rule of thumb for dose adjustment.
• Anticholinergic agents.
• Clinical conditions that necessitate dosage adjustment in the elderly.
• Anorexia and aging.
• Screening for potential toxicity of prescription drugs: H2 blockers, beta blockers.
• Innapropriate drugs: anticholinergics, indomethacin, propxyphene, trimethobenzamide and many others.

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The Bagful of Pills: Polypharmacy in the Elderly. By Oana Marcu, DO

Lecture outline

• Definitions: polypharmacy, adverse drug reaction.
• Economic consequences.
• Geriatric prescription principles.
• High risk medications in the elderly: Beers and Canadian criteria as consensus data.
• High risk medications: analgesics (NSAIDs, narcotics, muscle relaxants) and narrow therapeutic index (digoxin, phenytoin, warfarin, theophylline, lithium) cardiovascular (antihypertensives, calcium channel blockers, propanolol, diuretics – see indications and mechanism of action- ), psychotropics (TCAs, antipsychotics, benzodiazepines , sedatives).
• Avoiding polypharmacy: adjust the dose, review regimen regularly, educate.
• Personal Health Records.
• Clinical cases.

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Polypharmacy in the Elderly. By Rosemary D. Laird, MD

Lecture outline

• Overview of polypharmacy.
• The brown Bag.
• Medications and the elderly.
• Polypharmacy and the non-adherence.
• Adverse drug reactions.
• The role of the PCP.
• Prescribing pearls.

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Recommended reading

• Pocket Guide: Pharmacokinetics Made Easy (2009)
• Basic Clinical Pharmacokinetics (2009)
• Concepts in Clinical Pharmacokinetics (2010)
• Clinical Pharmacokinetics, 4th Edition (2008)

• Dose-effect relationships
• What determines the dose-effect relationship?
• What is the relationship between [drug] and [drug receptor]?
• What is the concentration-effect relationship?
• EC50
• Spare receptors
• Potency
• Full agonist
• Partial agonist
• Surmountable antagonist
• What is the effect of blocking drugs on concentration-response curves?
• Characteristics of insurmountable antagonists
• What is a quantal concentration or dose response curve?

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1. Ion channels:

• Ligand gatedace

• Voltage gated

• Second messenger regulated

2. G protein coupled receptors

3. Receptor tyrosine kinase

4. Intracellular hormone receptors: like  the glucocorticoid receptor

The video animation below shows the activation of a ionotropic receptor or ligand-gated ion channel (LGIC):

An excerpt on the topic from Katzung’s textbook:

Ligand-Gated Channels

Many of the most useful drugs in clinical medicine act by mimicking or blocking the actions of endogenous ligands that regulate the flow of ions through plasma membrane channels. The natural ligands include acetylcholine, serotonin, GABA, and glutamate. All of these agents are synaptic transmitters.

Each of their receptors transmits its signal across the plasma membrane by increasing transmembrane conductance of the relevant ion and thereby altering the electrical potential across the membrane. For example, acetylcholine causes the opening of the ion channel in the nicotinic acetylcholine receptor (AChR), which allows Na⁺ to flow down its concentration gradient into cells, producing a localized excitatory postsynaptic potential-a depolarization.

Latent Period or Latency:

The period of time that must elapse between the time at which a dose of drug is applied to a biologic system and the time at which a specified pharmacologic effect is produced. In general, the latent period varies inversely with dose; the relationship between dose and latent period for a given agent is described by a time-dose or time-concentration curve.

The copyright of the text is hold by Trustees of Boston University. Permission has been granted for its use in this blog.

You can download the power point file of this pharmacology lecture.

Note: the words underlined don’t mean right answer but link to another page.

9 – Pharmacodynamics: Receptor Theory and Dose Response
1.1) Which of the following occurs on the extracellular domain of the lipid bilayer and
not the cytoplasmic domain, with regard to drug action?
a) Ligand binding
b) Coupling with membrane associated molecules
c) Trafficking
d) Signaling

1.2) Which of the following drug targets involves inhibitors, false substrates, and a pro-
drug type?
a) Receptors
b) Ion channels
c) Enzymes
d) Carriers
1.3) What is the correct order of bond strength, from strongest to weakest?
a) Van der Waals > Hydrogen > Ionic > Covalent
b) Ionic > Covalent > Hydrogen > Van der Waals
c) Covalent > Hydrogen > Ionic > Van der Waals
d) Covalent > Ionic > Hydrogen > Van der Waals
e) Van der Waals > Hydrogen > Covalent > Ionic
2) On a graded dose-response curve (or drug-receptor curve in a laboratory), at what
point does response increase the most rapidly?
a) Initially

b) At EC50

c) At LD50
d) At 90% maximal response efficacy (Emax)
e) At steady-state
3.1) Which of the following is the equilibrium dissociation constant, where the
concentration of free drug is at half-maximal binding?
a) EC50
b) Emax
c) Kd
d) Bmax
e) LD50
3.2) What kind of graph scaling is often used to compare EC50 to Kd?
a) Linear
b) Exponential
c) Semilog
d) Inverse
e) Proportional
3.3) Clinical effectiveness of a drug depends on its potency.
a) True
b) False

3.6) Intrinsic activity is a drug’s ability to elicit:
a) Strong receptor binding
b) Weak receptor binding
c) Response
d) Excretion
e) Distribution
4.4) A competitive antagonist affects the agonist ____ and a non-competitive antagonist
affect the agonist ____.
a) Potency; Efficacy
b) Efficacy; Potency
c) Duration; Speed
d) Speed; Duration
4.5) In which of the following cases could a dose-response curve be constructed?
a) Prevention of convulsions
b) Prevention of arrhythmias
c) Reduction of death
d) Reduction of fever
e) Relief of headache
5.1) For most drugs, a frequency distribution of the response plotted against the log of the
dose (quantal) produces what kind of curve?
a) Linear
b) Exponential
c) Logarithmic
d) Gaussian (normal) distribution
e) Poisson distribution
5.2) Generally, which of the following is the correct order as dosage is increased?
a) ED50 < LD50 < TD50
b) ED50 < TD50 < LD50
c) LD50 < TD50 < ED50
d) LD50 < ED50 < TD50
e) TD50 < LD50 < ED50
5.3) Which of the following is the median effective dose, or the dose at which 50% of the
individuals exhibit the specified quantal response?
a) LD50
b) ED50
c) EC50
d) TD50
e) T.I.
6.1) Which of the following is considered the therapeutic index (or ratio)?
a) T.I. = TD50 / ED50

b) T.I. = LD50 / ED50
c) T.I. = ED50 / TD50
d) T.I. = ED50 / LD50
e) A & B
6.2) Which of the following can be used as a relative indicator of the margin of safety of
a drug?
a) LD50
b) ED50
c) EC50
d) TD50
e) T.I.
6.3) Which of the following is the most relevant use of therapeutic index?
a) Guide for toxicity in therapeutic the setting
b) Multiple measures of effectiveness are possible (e.g. aspirin)
c) Measure of impunity with which an overdose may be tolerated
d) Toxicities may be idiosyncratic (e.g. propranolol in asthmatics)
7.1) Which of the following refers to an increased intensity of response to a drug?
a) Idiosyncratic
b) Hyporeactive
c) Hyperreactive
d) Hypersensitive
e) Tolerance
7.2) Tachyphylaxis refers to which of the following?
a) Responsiveness increased rapidly after administration of a drug
b) Responsiveness decreased rapidly after administration of a drug
c) Responsiveness increased rapidly after maintenance of a drug (hypersensitive)
d) Responsiveness decreased rapidly after maintenance of a drug (desensitized)

10 – Receptor-Effector Coupling
1) Which of the following would occur with an antagonist binding to a receptor and not
an agonist?
a) Ion channel closed
b) Enzyme inhibited
c) Endogenous mediator blocked
d) Ion channel modulated
e) DNA transcription
2.1) Nicotinic ACh receptors (ligand-gated) involve the movement of what ion across the
membrane?
a) K+
b) Ca++
c) Cl-
d) Na+
e) Mg++
2.2) The nicotinic receptor requires one molecule of ACh to bind to each of the two ____
receptors in order to activate the receptor and open the channel.
a) α (alpha)

b) β (beta)
c) γ (gamma)
d) δ (delta)
2.3) GABA A receptors (ligand-gated) involve the movement of what ion across the
membrane?
a) K+
b) Ca++
c) Cl-
d) Na+
e) Mg++
2.4) Which of the following is increased in intracellular concentration due to second
messengers such as IP3?
a) K+
b) Ca++
c) Cl-
d) Na+
e) Mg++
Match the G protein with the action it causes:
2.5) Activates phospholipase C (PLC) a) Gs
2.6) Activates K+ channels b) Gi
2.7) Inhibits Ca++ channels c) Go
2.8) Activates Ca++ channels d) Gq
2.9) Which of the following signaling mechanisms involves phosphorylation of substrate
proteins and has receptors that are polypeptides with cytoplasmic enzyme domains
(tyrosine kinase, serine kinase, guanylyl cyclase)?
a) Intracellular receptors for lipid soluble ligands
b) Transmembrane receptors
c) G-protein coupled receptors
d) Ligand-gated ion channels
2.10) Regulated by cytokines and growth factors, the Janus-Kinase JAK-STAT pathway
results in which of the following?
a) Ion channel closing
b) Enzyme inhibition
c) Endogenous mediator blocking
d) Ion channel modulation
e) Gene transcription
2.11) Which of the following describes the pathway of nitric oxide (NO)?
a) Stimulates guanylyl cyclase, increase cGMP concentration, vasodilation
b) Stimulates guanylyl cyclase, decreases cGMP concentration, vasodilation
c) Stimulates guanylyl cyclase, increase cGMP concentration, vasoconstriction
d) Inhibits guanylyl cyclase, increase cGMP concentration, vasodilation
e) Inhibits guanylyl cyclase, decreases cGMP concentration, vasoconstriction
2.12) Which of the following signaling mechanisms can involve heat-shock protein
(hsp90)?
a) Intracellular receptors for lipid soluble ligands

b) Transmembrane receptors

c) G-protein coupled receptors
d) Ligand-gated ion channels
3.1) All of the following interact with ligand-gated ion channels EXCEPT:
a) Benzodiazepines
b) Insulin
c) Glutamate
d) Aspartate
e) Glycine
3.2) Which of the following is NOT a second messenger associated with G proteins?
a) DAG
b) GDP
c) IP3
d) cAMP
e) cGMP
3.3) Muscarinic ACh receptors and adrenergic receptors are associated with which of the
following?
a) Intracellular receptors for lipid soluble ligands
b) Transmembrane receptors with enzymatic cytosolic domains
c) G-protein coupled receptors
d) Ligand-gated ion channels
3.4) In smooth muscle and glandular tissue, ACh binds to what muscarinic receptor,
leading to the DAG cascade?
a) M1
b) M2
c) M3
d) M4
e) M5
3.5) In the heart and intestines, what muscarinic receptor inhibits adenylyl cyclase
activity?
a) M1
b) M2
c) M3
d) M4
e) M5
3.6) Adrenergic α2 receptors ____ adenylyl cyclase and β receptors ____ adenylyl
cyclase.
a) Stimulate; Stimulate
b) Stimulate; Inhibit
c) Inhibit; Inhibit
d) Inhibit; Stimulate
3.7) Which of the following is NOT a ligand-regulated transmembrane enzyme (agent)?
a) Insulin
b) EGP
c) PDFG
d) ANP
e) NO

3.8) Which of the following cytokine receptors (transmembrane enzyme) is antagonized
by anakinra (Kineret), for treatment of rheumatoid arthritis?
a) Growth hormone
b) Erythropoietin
c) Interferons
d) Interleukin-1
3.9) Which of the following is NOT an intracellular receptor for lipid-soluble agent,
which stimulates gene transcription in the nucleus by binding to DNA sequences?
a) Steroids
b) Vitamin A
c) Vitamin D
d) Thyroid hormone
e) Nitric oxide
Match the receptors with their time scale:
4.1) Insulin receptor a) Miliseconds
4.2) Muscarinic ACh receptor b) Seconds
4.3) Estrogen receptor c) Minutes
4.4) Nicotinic ACh receptor d) Hours

Complete PDF file with answers

More USMLE pharmacology questions

Technorati : General pharmacology: pharmacodynamics, MCQs, affinity pharmacology definition, drug metabolism, flashcards, quizzes, tolerance

Efficacy:

Broadly, efficacy refers to the capacity of a drug to produce an alteration in a target cell/organ after binding to its receptor. A competitive antagonist, that occupies a binding site without producing any alteration in the receptor, is considered to have an efficacy of zero.

Efficacy is generally independent of potency/affinity, and is related to the maximum effect that a particular drug is capable of producing.

As originally formulated by Stephenson (1956), binding of an agonist A to its receptor R is considered to result in a “stimulus” S=? A x P AR where ? A is the efficacy of A and PAR is the proportion of the receptors occupied. The effect of the drug on the cell or tissue is given by Effect = f (S), where f is an unspecified monotonic function that is dependent upon the nature of the receptor and its interaction with the cell or tissue. Efficacy is both agonist and tissue-dependent.

Efficacy is related to Intrinsic Activity, which was originally defined by Furchgott (1966) as e=?/R T , i.e. as the efficacy per receptor. In practice, the two terms are sometimes loosely used synonymously

The copyright of the text is hold by Trustees of Boston University. Permission has been granted for its use in this blog.

Equipotent:

Equally potent, or equally capable of producing a pharmacologic effect of a specified intensity. The masses of the drugs required to produce this degree of effect may be compared, quantitatively, to yield estimates of ” potency” of the drugs. Obviously, if two drugs are not both capable of producing an effect of a given intensity, they cannot be compared with respect to potency; i.e., drugs with different intrinsic activities or ceiling effects cannot be compared with respect to potency in doses close to those producing the ceiling effect of the drug with the greater intrinsic activity.

The copyright of the text is hold by Trustees of Boston University. Permission has been granted for its use in this blog.