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FALL 2022 > PHARM Block 1 > Flashcards

PHARM Block 1 Flashcards

1
Q

Pharmacology

A

The science of drug action on biological systems
Pharmaco = medicine / drug
logy = study

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2
Q

Pharmacy

A

clinical practice devoted to the formulation, proper and safe distribution and use of drug

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3
Q

Pharmaceutical Drug

A

chemical substance for medical diagnosis, treatment, or prevention of disease

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4
Q

Discuss the first recordings of drug action

A

China: Chen Nog in 200 B.C was a divine farmer and Chinese herbal medicine
Egypt: The book of Thoth is the world’s oldest preserved medical and pharmacological record

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5
Q

What did Galen introduce

A

The study of anatomy and described the actions of agonists and antagonist

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6
Q

During the Islamic Golden Age, scientists developed an understanding of

A

drug quantities and formulations

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7
Q

Who is Swiss-German physician-scholar Paracelsus

A

The father of toxicology, the dose makes the poison

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8
Q

Who is William Withering and what is his connection to Tucson

A

An English botanist that discovered digitalis treat congestive heart failure
digitalis (fox glove) is native to Tucson
but if you use the Nerium oleander then it is poisonous to humans

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9
Q

What did the Lewis and Clark expedition discover

A

willow bark tea to treat fever and pains because salicilin is metabolized to aspirin

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10
Q

Who is Friedrich Serturner

A

Isolated alkaloid from opium and over dosed
named morphine from the Greek god of dreams, Morpheus

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11
Q

Who is Friedrich Wohler

A

founded synthetic organic chemistry

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12
Q

Who is Hippocrates

A

The Father of Western Medicine and began the separation of medicine from religion and superstition

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13
Q

Who is Claude Bernard

A

Founded the concept of homeostasis

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14
Q

Pharmacodynamics

A

The mechanism of drug action

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15
Q

How do drugs act on receptors

A

usually proteins which result in a change in the system

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16
Q

What are effectors

A

molecules that translate the receptor - drug interaction into a change in cellular activity

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17
Q

Discuss the misleading nature of the Lock and Key model of molecular pharmacology

A

it is not simply turned on or turn off
Instead, think of receptors as fluctuating between favored and disfavored energy states constantly

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18
Q

R*

A

disfavored, active, high-energy state

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19
Q

R

A

favored low - energy state

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20
Q

What do agonists do

A

lower the free energy of the activated state and this will make it more favorable than the baseline state.
*cycling between states still continues

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21
Q

Binding of a ligand can

A

cause an induce fit which is a conformation shift of the receptor that can cause effector signaling

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22
Q

Are receptors ever completely on or completely off

A

No, even some imperfect agonists can still stimulate the receptor given enough concentration

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23
Q

Discuss the Saturation Radioligand Binding as a key method for measuring the binding of a drug to a receptor

A

-Membrane preparation of tissue or cells with target
-Increasing concentrations of radiolabeled drug
-Non‐specific binding component
-Saturating concentrations of cold selective ligand
-Reaction proceeds to equilibrium

-you have your ligand (drug) and it is radiolabled and its going to bind and saturate it (high affinity low capacity systems) and you can use it to measure how well the drug binds to its binding site

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24
Q

Competition Radioligand Binding

A

A known amount of radiolabeled established drug is competed off of a receptor by a non - radiolabeled drug with unknown affinity
-two drugs competing for a binding site and they compete by affinity and concentration
- the less it takes for the drug to compete away to higher the affinity
*Allosteric sites are a problem

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25
Q

Bmax

A

Total number of binding sites

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26
Q

Kd

A

Binding constant (affinity) of the drug

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27
Q

Why do you not want to use Saturation Binding?

A

Because you do not want to radiolabel a bunch of drugs, therefore you would use Competition Radioligand Binding

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28
Q

IC50

A

Concentration at 50% inhibition

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29
Q

The data obtained is the IC50. IS this the same as the drug affinity?

A

No, this is not the drug affinity because if you double the radio labeled drug then you have twice as much drug to compete away .

IC50 is depended upon the concentrations of the two drugs

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30
Q

Ki

A

Binding Constant (affinity) of our experimental, unlabeled drug

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31
Q

Assumptions of the experiment

A

-Bound concentration is negligible compared to free
-No binding cooperativity
-At equilibrium
-Binding is reversible and follows Law of Mass Action

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32
Q

Most drug binding to receptors involve

A

non - covalent interaction with key amino acids

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33
Q

Efficacy

A

E max

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34
Q

Potency

A

EC50, ED50

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35
Q

Can a partial agonist be more than a full agonist

A

A full agonist reaches the maximal response capability of the system, and a partial agonist does not (even at full receptor occupancy)

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36
Q

How are affinity and potency different

A

Affinity defines the strength of attraction between the drug and its receptor. A high affinity is generally associated with a lower dose requirement (compared to low affinity for the same receptor). Potency describes the relationship between the drug dose and the magnitude of the effect

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37
Q

Can antagonists be competitive and non competitive

A

Yes, competitive and reversible binding and non competitive is irreversible which will reduce the total amount of receptors available to bind agonist

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38
Q

Antagonists

A

bind to the target but do not cause a conformation shift , therefore baseline activity is still the same
*cause agonist to not be able to bind so you can only see the effects of an antagonist when an agonist is present

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39
Q

Agonists

A

a substance which initiates a physiological response when combined with a receptor

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40
Q

Inverse agonists

A

bind to the receptor, but shift the energy landscape baseline (R) is lower and / or the active state (R*) is higher so the receptor spends even less time in the active state than before

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41
Q

Drug selectivity

A

Selectivity deals with how well your drug binds to your preferred target vs other targets.

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42
Q

Side effects

A

“Side effects” can come from both the actions of your drug on its key target and from actions on other targets

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43
Q

Can antagonists be competitive and non competitive

A

Yes, competitive and reversible binding and non competitive is irreversible which will reduce the total amount of receptors available to bind agonist

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44
Q

Pharmacokinetics

A

how the body deals with the drug

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45
Q

Important phases of how the drug move in and out of our tissues/bodies

A

ADME
A= Absorption
D= Distribution
M= Metabolism
E= Excretion
T= Toxicity (sometimes)

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46
Q

Absorption

A

Many factors influence absorption, especially route of administration.
-I.V. route bypasses most barriers to get to plasma
-Oral -> gut-> liver -> plasma -> kidney -> urine
-All drugs must eventually interact with plasma (central compartment)
-Diffusion can always go both ways between compartments
EX = muscle <-> plasma, gut <-> plasma

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47
Q

Passive transport Verse Active transport

A

Passive = no ATP, diffusion
Active = Facilitated diffusion, drug transporters

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48
Q

Discuss key characteristics of the drug that affect absorption

A

lipid solubility
molecular size & weight
pKa

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49
Q

Discuss key characteristics of the tissue that affect absorption

A

membrane permeability
membrane thickness
pH
local blood flow
local surface area/anatomy
transport mechanisms

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50
Q

Frick’s Law of Diffusion

A

most drugs move down their concentration gradient (passive diffusion)

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51
Q

How do orally administered drugs move through body?

A

Must pass through the gut and all blood from the gut passes through the portal vein into the liver before general circulation
- This is an issue because the liver has many CYP’s

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52
Q

Bioavailability

A

the fraction of drug absorption into the systemic circulation.
AUC (Area under the curve) of plasma concentration verse time for the i.v route compared to that for the test route (oral)

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53
Q

Drug pKa

A

pH at which 50% of the molecules are ionized

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54
Q

Acids verse Bases

A

Acids are increasingly ionized in a basic environment, bases increasingly ionized in an acid environment

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55
Q

How does pKa affect drug diffusion

A

because difference in pH in body fluids an lead to “trapping” of drugs in certain compartments
-this can affect absorption/elimination
-Trapping can help eliminate drugs through the urine

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56
Q

how do you trap a weak base

A

acidify the urine with ammonium chloride

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57
Q

how do you trap a weak acid

A

alkalinize the urine with sodium bicarbonate

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58
Q

Distribution

A

depends on size of the organ, blood flow, solubility, binding

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59
Q

Distribution

A

depends on size of the organ, blood flow, solubility, binding

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60
Q

Drugs are distributed in different phases

A

starting with high flow ares then low flow ares

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61
Q

binding to albumin in plasma dramatically affects what

A

percent of drug available to distribute to tissue
-adding a second albumin-binding drug can change the “bound verse free” percentage of drug 1. This can contribute to drug side effects

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62
Q

How is blood - brain barrier an extra challenge for drug distribution

A

-Tight junctions between capillary endothelial cells verse fenestrated
-maintains homeostasis and restricts access to toxic xenobiotics / metabolites

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63
Q

Volume of distribution (Vd)

A

the volume that relates the amount of drug given to the body to the plasma concentration
Vd = amount of drug in body / plasma drug concentration
*if drug distributes throughout the body well Vd is large, if drug stays in plasma Vd is small

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64
Q

What can Vd be used to calculate

A

therapeutic does by multiplying by plasma concentration (Cp)

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65
Q

Metabolism

A

biotransformation
this is how the body changes the drug in order to eliminate it

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66
Q

Phase I of metabolism

A

typically uses Cytochrome P-450 family members to add or expose a functional group on the drug, making it more polar

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67
Q

Phase II of metabolism

A

conjugates a bulkier functional group onto the drug in order to further increase water solubility and excretion

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68
Q

Several drugs and natural products are known to induce or inhibit the expression/activity of Cyp enzymes. How can
this be a problem?

A

Cyp enzymes are a group of enzymes encoded by P450 genes and are expressed as membrane bound proteins mostly found in the endoplasmic reticulum of the liver.
-If expressed CyP then this could increase the metabolism of drugs so they never reach receptor
-If inhibited CyP then this could decrease the metabolism of drugs

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69
Q

Excretion

A

enterohepatic circulation =
conjugated drugs in the liver can be carried in the bile into the gut for excretion
-most drugs excreted through the urine by action of kidneys
-Quantified using renal clearance value (CL)
*high CL = fast clearance

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70
Q

Zero order kinetics

A

A fixed amount of drug can be handled at one time (alcohol)

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71
Q

First order kinetics

A

constant fraction of the drug is metabolism per unit of time
-more drug = faster metabolism

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72
Q

Half life

A

time to excrete half of the drug

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73
Q

Use half-life and kinetics in order to know how to dose patients to achieve steady-state levels of drug.

A

Typically takes
4-5 half-lives to reach steady-state.

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74
Q

Sex

A

as a classification, generally as male or female, according to the reproductive organs and functions that derive from the chromosomal complement

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75
Q

Gender

A

person’s self representation as male or female or how that person is responded to by social institutions on the basis of the individual’s gender presentation

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76
Q

Describe strategies to address gender differences in PK/PD across in vitro to post - approval stages

A
  1. Report sex/age of cells/subjects in studies
  2. Stratify findings by sex and/pr hormone levels
  3. Dose by weight
  4. Dose by hormone concentrations / weight or body composition
  5. Study pharmacogenomics
  6. study hormone drug interactions
    -include aged and pregnant persons
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77
Q

How PK contribute to sex/gender differences

A
  1. Drug absorption is influenced by body composition, including body weight, lean mass, free water, and total body fat
  2. Distribution is impacted by organ size, blood flow, and total plasma volume are lower in female bodies which is coupled to increased resting heart rates and longer OT intervals
  3. Metabolism/excretion, renal and liver functions is lower in women. Males and females have a different constellation of CYP enzyme
  4. poly pharmacy
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78
Q

How PK contribute to sex/gender differences

A
  1. Hormone fluctuations over life span (In utero through menopause/age matched males)
  2. Exogenous administration of hormones (Birth control, hormone replacement, gender affirming therapies, lifestyle)
  3. Formulation responsively, changes in half life
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79
Q

The autonomic nervous system (ANS)

A

provides involuntary, subconscious regulation of all organs and glands, controlling for example the blood pressure, heart and lung function, digestion, body temperature, metabolism, sweating, pupil size and secretions of certain glands

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80
Q

What does the ANS consists of

A

-The sympathetic division (SNS) that is activated during the “fight and flight” response to stress
-The parasympathetic division (PSNS) that promotes conservation and restoration of energy “rest and digest” response

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81
Q

Enteric nervous system

A

works in parallel to the sympathetic and parasympathetic systems to regulate the peristalsis of gut wall and activity of GI tract

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82
Q

What does the anatomical organization of the ANS consists of

A

preganglionic neurons residing in the CNS that extend to the peripheral peripheral autonomic ganglion where they synapse on postganglionic neurons. Postganglionic neurons innervate the target organ

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83
Q

What do the neurotransmitters of the ANS include

A

1) acetylcholine, release from all preganglionic neurons and from parasympathetic postganglionic neurons
2) norepinephrine released from sympathetic postganglionic neurons
3)epinephrine released upon sympathetic activation from the adrenal medulla

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84
Q

What do norepinephrine and epinephrine act on what

A

α and β adrenergic receptors of sympathetic
targets.

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85
Q

Acetylcholine acts on nicotinic ACh receptors on

A

all postganglionic cells and on muscarinic ACh receptors expressed on target organs of the PSNS

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86
Q

Blood vessels

A

receive mostly only sympathetic innervation
-Activation of smooth muscle α1-adrenergic receptors causes vasoconstriction.
- Activation of β2-adrenergic receptor in skeletal muscle and liver vasculatures produces vasodilation

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87
Q

Heart

A

-receives dual sympathetic and parasympathetic innervation with opposing roles.
- Sympathetic stimulation increases the natural pacemaker activity of the heart cells through effects on the ß1 receptors resulting in increased heart rate.
- Parasympathetic stimulation decreases the heart rate through effects on M2 muscarinic receptors

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88
Q

Lungs

A
  • Sympathetic activation increases the diameter of bronchioles (bronchodilation), increasing the air flow.
  • Parasympathetic activity produces bronchoconstriction
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89
Q

Eye

A
  • Activation of the M3 muscarinic receptors causes ciliary muscle contraction to accommodate the lens for near vision. There is no significant sympathetic innervation of the ciliary muscle.
  • Sympathetic activation constricts the dilator (radial) pupillae muscle of the iris resulting in pupil dilation (mydriasis).
  • Parasympathetic activation constricts the sphincter (circular) pupillae muscle causing the pupil to constrict (miosis)
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90
Q

The German-Swiss Renaissance physician, botanist, alchemist and astrologer Paracelsus was famous for which of the following sayings:

A

“The dose makes the poison.”

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91
Q

What ligand type does NOT change the energy landscape of the receptor?

A

Neutral Antagonist

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92
Q

What ligand type does NOT change the energy landscape of the receptor?

A

Neutral Antagonist

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93
Q

Your drug is a weak base with a pKa of 7.0. What compartment will cause the highest level of drug trapping?

A

Stomach, pH 2.0

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94
Q

Sex Differences in drug distribution can be influenced by:

A

a) Organ size, blood flow, and total plasma volume

b) Increased resting heart rates and longer QT intervals in female

c) Gastric motility

d) Transporter expression patterns and levels

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95
Q

Which neurotransmitter(s) are released by preganglionic sympathetic neurons?

A

acetylcholine

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96
Q

Epinephrine is used therapeutically in all of the following situations EXCEPT:
a) Severe allergic reactions (Epipen)

b)Bronchial dilator

c) Cardiac stimulant in emergencies

d) Post-operative ileus and bladder retention

A

) Post-operative ileus and bladder retention

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97
Q

Side effects of direct and indirect cholinergic medications include all of the following EXCEPT:

a) Runny nose

b) Salivation

c) Decreased urge to use the bathroom

d) Sweating

A

Decreased urge to use the bathroom

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98
Q

What is the primary vascular effect of treatment with beta 2 adrenergic receptor agonists?

A

vasodilation resulting in decreased blood pressure

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99
Q

A 60 year old man had a MI (heart attack) in the past. His lipids are abnormal: High total and high LDL cholesterol. Which of these drugs would be prescribed?

A

Atorvastatin

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100
Q

Which of the following drug classes are useful in the control of hypertension?

A

a) Calcium channel blockers

b) Angiotensin receptor blockers (ARBs)

c) Thiazide diuretics
beta
RAAS
vasodilators

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101
Q

What is the first substance demonstrated to function as a neurotransmitter

A

Acetylcholine

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102
Q

Can Acetylcholine derivates be non-selective and selective?

A

Yes, derivates like methacholine, carbachol, bethanechol are non-selective which can be nicotinic and muscarinic ot selective muscarinic receptor agonist that mimic physiological effects of acetylcholine

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103
Q

What are plant alkaloids

A

muscarine and pilocarpine are selective muscarininc acetylcholine receptor agonist

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104
Q

What are cholinesterase inhibitors?

A

neostigmine and physostigmine that block degradation of acetylcholine as the synapse, acting as indirect cholinergic agonists

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105
Q

What are direct and indirect cholinergic agonists used to treat

A

glaucoma, muscle weakness in myasthenia gravis and to stimulate GI and urinary function

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106
Q

What is muscarinic cholingeric overdose

A

it is characterized by SLUDGE or PUDDLES response
-miosis, salvation, lacrimation urination, defecation, GI upset, emesis and can be life threatening (coma)

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107
Q

are selective nicotinic agonist limited in therapeutic use?

A

Yes, use in nicotine addiction

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108
Q

What is nicotine overdose with organophosphates

A

involved in muscle weakness, fatigue, ad at high doses tachycardia, bronchoconstriction and paralysis

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109
Q

What are muscarinic acetylcholine antagonist

A

atropine, scopolamine, ipratropium, which block the parasympathetic effects of acetylcholine

110
Q

What are muscarininc antagonists used to treat

A

overreactive urinary and GI function, and as bronchodilators for the treatment of asthma ad chronic obstructive pulmonary disease (COPD)

111
Q

What can nicotinic antagonists be used as?

A

skeletal muscle relaxants during surgeries (intubation) or mechanical ventilation

112
Q

What are side effects of muscarinic antagonists

A

Dry mouth and skin, mydriasis, constipation, urinary retention, tachycardia and may be severe with high doses producing hallucinations and coma

113
Q

Acetylcholine

A

Released from all sympathetic and parasympathetic preganglionic cells (nAChR)
From postganglionic cells of the parasympathetic system (mAChR)
From motor neurons (nAChR)

114
Q

Norepinephrine

A

Released from postganglionic cells of the sympathetic system (α, β AR)

115
Q

Epinephrine

A

Released from adrenal medulla (α, β AR)

116
Q

Epinephrine

A

Released from adrenal medulla (α, β AR)

117
Q

Endogenous adrenergic neurotransmitters differ in their release and receptor selectivity

A

Epinephrine= is released from chromaffin cells of the adrenal medulla into the blood stream and binds to all alpha and beta receptors
Norepinephrine= is released from the posganalionic neurons of the sympathetic nervous system and binds to all alpha and beta1 receptors but NOT b2 receptors

118
Q

alpha 1 receptors

A

activation produces vasoconstriction leading to increase blood pressure

119
Q

alpha 1 agonist

A

phenylephrine is used as a nasal decongestant and to improve circulation in hypotensive shock

120
Q

alpha 1 receptor antagonist

A

prazosin can be used in the management of hypertension

121
Q

alpha 2 receptors

A

mostly presynpatic, their stimulation inhibits norepinephrine release

122
Q

alpha 2 agonists

A

clonidine used as antihyertensive drugs

123
Q

beta 1 receptors

A

activation stimulates the heart

124
Q

beta 1 receptor agonist

A

dobutamine used to stimulate the heart in cases of cardiogenic shock

125
Q

selective beta 1 antagonists

A

cardio selective beta blockers metroprolol are used for management of hypertension, angina, cardiac arrhythmias, and other cardiac disorders

126
Q

beta 2 receptors

A

mediate vasodilation and bronchodilation

127
Q

beta 2 receptor agonists

A

albuterol are used to dilate bronchial airways in the management of airway diseases (COPD, asthma)

128
Q

indirect sympathomimetics

A

the main action is by increasing the release of norepinephrine or by blockade of norepinephrine reuptake (NE transport)

129
Q

cocaine

A

is the only local anesthetic that produces vasoconstriction and can be used locally in some surgical procedures requiring vasoconstriciton and local anesthesia and to control excessive nose bleeds because cocaine is a CNS stimulate it is used to blockade of monoamine transporters and increase and arenergic, dopaminergic an serotonergic neurotransmission

130
Q

Myocardial
Infarction

A

death of heart muscle die to sudden blockage of blood flow to the area, almost always caused by atherosclerosis buildup allowing for a blood clot to form

131
Q

Stoke

A

a brain infarction, blockage of blood flow to/in the brain leading to death of brain tissue. Also caused by atherosclerosis, or a clot can also be formed in the heart and move to the brain

132
Q

Stoke

A

a brain infarction, blockage of blood flow to/in the brain leading to death of brain tissue. Also caused by atherosclerosis, or a clot can also be formed in the heart and move to the brain

133
Q

Risk factors for heart attack or stroke

A

high LDL, low HDL, cigarette smoking, hypertension, increased age, diabetes, estrogen, physical inactivity
-male gender, obesity, hostile personality, family history

134
Q

vulnerable verse stable plaques features

A

vulnerable = fibrous cap thickness is small lipid core size is large
stable= fibrous cap thickness is large lipid core size is small

135
Q

what is the leading cause of death in the US

A

cardiovascular disease

136
Q

what is the leading risk factor of CVD

A

abnormal cholesterol and lipids in blood

137
Q

statin

A

the leading drug used to prevent heart attach
-work by blocking HMG-coA reductase in the liver, leads to reduce liver cholesterol synthesis, increased LdL receptors in the liver and cholesterol uptake

138
Q

other CVD therapies

A

bile acids sequestrants, nicotinic acid, fibric acid derivatives, cholesterol absorption inhibitors, omega 3 fatty acids

139
Q

Why do statins cause a significant reduction in coronary events

A

increase certain liver enzymes
decrease in cholesterol with stain treatment show largest effect with initial dose then diminish returns
-but they can cause myopathy
-can be combined with other therapies

140
Q

what does combing statins with fibrate therapy do

A

may increase chance of rhabdomyolysis

141
Q

what do fish oils do

A

prescription fish oils help lower triglycerides, but they need high dose to have mild effects

142
Q

omega 3 therapy effects

A

increase in bleeding
purchased from reputable source that uses purification methods
Omega 3 = icosapent ethyl did show reduction in cardiovascular events over time

143
Q

pcsk9 inhibitor

A

praluent, repatha
work by increasing LDL reuptake receptors on liver cells
-very expensive

144
Q

what do statins and nicotinic acid both increase

A

HDL to be protective against cardiovascular events

145
Q

If a patient presents at the hospital with acute MI, the initial therapeutic goals are to

A

improve blood flow
into the heart (thrombolytic agents, antigoagulants, anti-platelet drugs, angioplasty), prevent new clot formation,
decrease work of the heart, correct risk factors later.

146
Q

Anticoagulants

A

block clotting cascade. Heparin (injectable), warfarin (oral) are classic anticoagulants, but can be too slow to work in the acute setting.
Newer anticoagulants = Dabigatran, etc. Usually used to prevent stroke or
thrombosis in high-risk patients, not in acute MI setting

147
Q

Anti-platelet agents

A

Classic = aspirin. Blocks platelet activation, therefore reducing clot formation.
Is known to reduce
risk of CVD/death, but can cause some side effects at higher doses.
81mg/day (“baby aspirin”) sufficient to protect very
well.
Recommended for patients with known CVD, adults with diabetes, other cardiovascular risk factors (should check
with physician)

148
Q

To decrease the work of the heart what would you use

A

use either beta blockers (reduce heart rate and bp), Ace inhibitors/ARBs, or nitrates.

149
Q

ACEi

A

angiotensin converting enzyme inhibitor
Angiotensin does many things
including increasing blood pressure, so blocking its synthesis (ACEi) or blocking its receptor (ARB) can reduce bp. Side
effects = cough, dizziness, too low BP.

150
Q

ARB

A

angiotensin-receptor blocker.
Angiotensin does many things
including increasing blood pressure, so blocking its synthesis (ACEi) or blocking its receptor (ARB) can reduce bp. Side
effects = cough, dizziness, too low BP.

151
Q

Beta blockers

A

decrease heart rate, bp, force of contraction. Can cause tiredness, dizziness, impotence. (which beta
receptor is the primary target here?) B1 because agonist stimulate HR but antagonist decreased HR and B2 relate to lung and bronchodilation

152
Q

Hypertension Risk Factors

A

-age
-weight
-gender
-race
-diet (high sodium intake)
-alcohol and tobacco use

153
Q

normal blood pressure

A

less than 120/80 mm Hg

154
Q

what does starting hypertensives following a cardiac event do

A

reduces future morbidity and mortality

155
Q

what drugs make controlling BP difficult

A

NSAIDS, normal contraceptives, chemotherapeutic agents (sorafenib) and various herbal compounds (guarana)

156
Q

why are diuretics good at controlling hypertension

A

because the act to increase urine production and decrease BP by decreasing blood volume (furosemide), also thiazide diuretics (chlorothiazide and hydrocholorothiazide: HCTZ), and K+ sparing diuretics (spironolactone) also called aldosterone antagonists

157
Q

why are RAAS good at controlling hypertension

A

Renin antiotensin aldosterone system blockers block conversion or angiotensin I into angiotensin II via ACE OR block the angiotension II receptor (ARB). Both reduce BP by relaxing blood vessels across the body
-ACE inhibitors = captopril
-ARB = losartan

158
Q

why are Beta Blockers good at controlling hypertension

A

because they inhibit beta-1, beta-2 and occasionally alpha-1 activity to reduce cardiac contractility, heart rate, and cardiac conduction to lower overall BP
-Nonselective [propranolol], cardio-selective via beta-1 [metoprolol], and w/alpha-1 blocking activity [carvedilol])
-Normally used as first line therapy for angina and heart failure, second to third line for hypertension control

159
Q

why are Calcium channel blockers good at controlling hypertension

A

because they dilate blood vessels and slow heart rate to reduce BP.
-Dihydropyridine dilates w/o
conduction system effect & Non-dihydropyridine w/conduction system effect.
- (DHP [nifedipine], Non-DHP [verapamil]

160
Q

why are vasodilators good at controlling hypertension

A

because they act directly on blood vessels to rapidly dilates, useful in cardiac and ischemic emergencies
-Nitric Oxides and Nitrates

161
Q

side effects of antihypertensives

A

-dry cough w/ACE inhibitors
-gout,hypokalemia, glucose intolerance w/thiazides
-excessive hypotension and angioedema w/ACE/ARB
-asthma aggravation w/beta blockers

162
Q

current principles about treating hypertension

A

Rule out extraneous causes before starting treatment
(illicit drugs, OTC’s)
* Combining diet and exercise with pharmacotherapy
is critical for successful management
* Diabetes, CHF, CAD, PAD, sleep apnea, obesity
are all commonly associated comorbidities
* Typical regimens for control
are ACE/ARB+diuretic or CCB+diuretic

163
Q

over the counter drug

A

describes drugs that can be purchased without a prescription from a doctor

164
Q

how do OTC drugs compare to prescription drugs

A

tend to have less side effects but are not harmless. Prescription drugs could
require monitoring because they are habit-forming, require frequent check-ins with a doctor, or are new to the
market. Over time, some prescription medications may be deemed safe and moved to the OTC category

165
Q

The most common ingredients in OTC drugs are

A

acetaminophen (ex: Tylenol) and ibuprofen (Advil). Most cold and flu
medications contain acetaminophen + other active ingredients

166
Q

Analgesics

A

pain medications. Acetaminophen, NSAIDS (aspirin, ibuprofen) = Cox2 inhibitors

167
Q

Cox2

A

enzyme which causes the release of prostaglandins, specifically PGE2, which along with other inflammatory agents
can increase the sensitivity of nociceptors (pain receptors) in the spine, causing hyperalgesia and allodynia. Cox1 and
Cox2 are also found on inflammatory cells, so their blockade can reduce inflammation. Blocking Cox enzymes also
inhibits fever, by blocking the effects of prostaglandins on receptors on the thermosensitive neuron in the
hypothalamus.

168
Q

Acetaminophen

A

commonly used OTC, but can be accidentally overdosed and cause liver toxicity

169
Q

Aspirin

A

acetylsalicylic acid. Blocks pain, fever, but need higher doses to fight inflammation. Does block platelet
aggregation in small doses. Problem: causes increased HCl in stomach, can lead to ulcer. Can cause Reye’s syndrome in
kids

170
Q

Ibuprofen

A

often preferred due to less GI side effects. Discussed some newer alternative compounds with longer half-lives

171
Q

comparing the 3 main analgesics

A

Tylenol (Acetaminophen) antidote for OD cysteine
Aspirin (Salicylate) no children antiplatelet
Mortrin (Ibuprofen)
pain relievers reversible Cox inhibitor

172
Q

OTC drugs for allergies are anti-histamines

A

H1 receptor antagonists. Histamines produced in large quantities by mast
cell

173
Q

Stimulation of H1 receptors by histamines released by

A

inflammatory cells can cause an allergic reaction.
Ex: pruritus, vasodilation/permeability, flushing, headache, bronchoconstriction, and pain. Anti-histamines block
these effects. Side effects include sedation, anti-cholinergic activities

174
Q

OTC cough suppressant

A

Anti-Tussives). Can include expectorants (ex: Guaifenesin) or cough suppressants
(Dextromethorphan

175
Q

OTC nasal decongestant

A

alpha-adrenergic agonists. Stimulates contraction of blood vessels in nasal passages, allowing
for better drainage (and breathing). Side effects include damage to the mucosa and desensitization

176
Q

Cyclooxygenase

A

prostaglandin
synthesis
Cyclooxygenase-2 products
Modulate pain perception
Promote fever through receptors in hypothalamus
Modulate inflammatory response

177
Q

Benadryl (Diphenhydramine)

A

Antihistamines
H1 receptor “antagonists” reduce constitutive activity of the receptor
and compete for histamine.

178
Q

PGE2

A

PGE2 can cross the blood-brain barrier and acts on EP3/EP1 receptors in
the thermosensitive neuron.

179
Q

Antipyretic

A

fever reducers

180
Q

OTC drugs can be abuse

A

such as Dextromethorphan, ephedrine, pseudoephedrine (now replaced by phenylephrine)

181
Q

Physical symptoms of depression

A

anhedonia, loss of energy, social withdrawal, psychomotor retardation or agitation, somatic complaints, appetite/weight loss, decreased hygiene,
crying spells

182
Q

Cognitive symptoms of depression

A

Decreased ability to concentration, indecisiveness

183
Q

Emotional symptoms of depression

A

Dysphoric mood, sad thoughts or attempts at suicide, hopelessness, helplessness, worthlessness, guilt, shame

184
Q

what can depression be caused by

A

genetics, brain/neuron damage, or HPA overactivation and CRF hypersecretion

185
Q

what do PET scans show in depression

A

decreased brain activity in patients with depression

186
Q

bipolar disorder

A

marked by unusual shifts in mood with episodes of mania and depression

187
Q

major depressive disorder

A

symptoms of depression most of the day, nearly every day for at least 2 weeks that interfere with your ability to work sleep, study, eat, and enjoy life. An episode can occur only once in a persons lifetime, but more often a person has several episodes

188
Q

persistent depressive disorder (dysthymia)

A

having symptoms of depression that last for at least 2 years. A person diagnosed with this for of depression may have episodes of major depression along with periods of less severe symptoms

189
Q

biogenic amine hypothesis

A

depression caused by deficiency in catecholamines (norepinephrine, NE) and/or indoleamines (serotonin; 5HT)

190
Q

small study on doctors were trying to treat hypertensive patients

A

The patients were tested for depression and treated for hypertension them with Reserpine (VMAT inhibitor). This prevents release of neurotransmitters (it targeted VMAT) leading patients to develop depression

191
Q

Types of Antidepressants

A
  1. SSRI’s: block 5-HT reuptake.
  2. SNRI’s: block 5-HT & NE reuptake, without effects on other receptors.
  3. Tricyclics: block the reuptake of both NE and 5-HT, with effects on a number of other receptors.
  4. MAOI’s: prevent metabolism of the neurotransmitters (elevate synaptic levels).
  5. Atypical: have SSRI effects, 5-HT2 antagonism, and inhibition of norepinephrine reuptake
192
Q

MOIs

A

target MAO to allow more serotonin and norepinephrine to be taken up in vesicles and released in synaptic cleft
-MAOIs are not used much anymore due to drug-drug and drug-food interactions and risk of hypertension crisis (stroke)
-Wine and Cheese: Tyramine does not cross BBB. Unmetabolized tyramine can function as a “false” neurotransmitter, potentiating
catecholamine (NE/DA/5HT) release from terminals, causing vasoconstriction.
-Phenelzine and Tranylcypromine are both still used

193
Q

TCAs

A

have affinity for both SERT and NET. Relative affinity is not equal (e.g., desipramine has higher affinity for NET vs SERT)
-TCAs are still used (Amitriptyline) especially in developing countries, but have anticholinergic effects (dry mouth and eyes, urinary hesitancy or retention, and constipation)
-used for neuropathic pain ( e.g., migraine) and insomnia

194
Q

SSRI

A

block SERT and end up with more serotonin able to bind to 5HT2A
-Excessive levels with serotonin can lead to side effects (ex: lots of binding = anxiety)
-Citalopram, Fluoxetine, Sertraline

195
Q

SNIR

A

block NETs (similar mechanism to SSRIs)
-Side effects include increase blood pressure and heart rate, orthostatic hypotension (stand up and get lightheaded).
-SNRIs are better for treating pain associated with neuropathy and fibromyalgia compared to SSRIs
-Venlafaxine, Duloxetine

196
Q

Mirtazapine

A

blocks α2AR which then allows for release of neurotransmitters, and also blocks 5HT2A receptors allowing for more serotonin in synaptic cleft

197
Q

Bupropion

A

blocks NET and DAT

198
Q

Trazodone & Nefazodone:

A

blocks SERT, NET, 5HT2A receptors, and beta alpha 1 receptors

199
Q

Therapeutic effect is usually not acutely evident but

A

chronically present after the patient has been taking the medication for 4 weeks

200
Q

Mania

A

too much biogenic amine neurotransmission.
- Reduced by Lithium (by reducing IP-3 production) but the issue is that Li is solely eliminated by the kidney and therefore has a very small therapeutic
window

201
Q

seizures

A

Clinical manifestation of abnormal
and excessive excitation and synchronization of a population of neuron

202
Q

epilepsy

A

Disease characterized by spontaneous recurrent seizures

203
Q

Generation of action potential

A

actions potentials are triggered with an influx of sodium through voltage gated sodium channels which lead to an upstroke followed by a downstroke where k channels open and then it gets rest
*potassium channels open and close but sodium channels open inactive and then need to be reactive in order to open again

204
Q

epileptogensis

A

sequence of events that convert a normal neuronal network into an epileptic network

205
Q

Describe in detail the 4 ways that AEDs can decrease neuronal discharge

A

1.Decrease Na+ channel depolarization (carbamazepine, lamotrigine,
oxcarbazepine, phenytoin, topiramate, valproate)
2.Decrease glutamate transmission
*Block presynaptic HVA Ca2+ (topiramate, lamotrigine)
*Block presynaptic α2δ1 (gabapentin, pregabalin)
*Block SV2A (levetiracetam)
3. Decrease Ca2+ permeability
*Block postsynaptic (T-type) Ca2+ (valproate, zonisamide,
ethosuximide)
4. Enhance GABA inhibition
*Facilitating Cl- conductance: barbiturates, benzodiazepines
*Facilitating/stabiling K+ conductance: retigabine
*Blocking GABA reuptake: tiagabine
*Blocking GABA transaminase: Vigabatrin

206
Q

Vigabatrin

A

Blocking GABA transaminase:

207
Q

tiagabine

A

Blocking GABA reuptake:

208
Q

retigabine

A

Facilitating/stabiling K+ conductance:

209
Q

barbiturates, benzodiazepines

A

Facilitating Cl- conductance

210
Q

topiramate, lamotrigine

A

Decrease glutamate transmission
*Block presynaptic HVA Ca2+

211
Q

levetiracetam

A

Decrease glutamate transmission
Block SV2A

212
Q

gabapentin, pregabalin

A

Decrease glutamate transmission
Block presynaptic α2δ1

213
Q

Valproate

A

give to patient three abscess motor but do not want to give to a female who is pregnant because can lead to spina bifida

214
Q

Phenytoin

A

Dilantin
Zero-Order Kinetics
side effects of toxicity
Gingival hyperplasia (overgrowth of gums)
Hirsutism(excess hair)
Nystagmus (eyes moving)

215
Q

motor drugs do what to action potential

A

SLOWS the Inactivation….NOT the Activation

216
Q

carbamazepine

A

Induces microsomal enzymes, =
speeding its own metabolism.
Toxicity: toxic
epidermal necrolysis (STOP
DRUG!), cardiac arrhythmias if see this give Lamotrigine could see Stevens–Johnson
syndrome (SJS) /
Toxic epidermal
necrolysis:

217
Q

carbamazepine, lamotrigine,
oxcarbazepine, phenytoin, topiramate, valproate

A

Motor problem seizures
Decrease Na+ channel depolarization

218
Q

Describe mechanism of action & toxicity associated with drug treatments for patient 1

A

lipsmacking
focale (because still aware)
motor (because moving against will)
carbamazepine
phenytoin
lamotrigine
valproate
benzodiazepines
NOT ethosuximide because thats for absence seizures

219
Q

Describe mechanism of action & toxicity associated with drug treatments for patient 2

A

absence without motor symptoms
ethosuximide
lamotrigine

220
Q

Describe mechanism of action & toxicity associated with drug treatments for patient 3

A

absence with motor symptoms (tonic clonic)
ethosuximide
lamotrigine
valproate

221
Q

Describe mechanism of action & toxicity associated with drug treatments for patient 4

A

generalized absence tonic clonic
phenytoin
valproate
ethosuximide

222
Q

difference between benzo and barbs

A

benzos: increase the frequency

barbs: the make it so the GABA receptors cannot close as quickly -do not change the frequency

223
Q

Describe mechanism of action & toxicity associated with drug treatments for patient 5

A

tonic clonic seizure over 5 minutes = status epilepticus
benzodiazepines
Klonopin
Valium
Diazepam

224
Q

Describe the non-linear relationship of dose and plasma concentration of phenytoin

A

zero order kinetics
so everyone has a different therapeutic range

225
Q

Describe the alternative treatments for patients who are unresponsive to treatment or require adjunct therapy

A

patient 1 & 4 = Zonisamide, Levetiracetam, Topiramate
patient 2 & 3 = Levetiracetam

226
Q

There are many forms of viruses, in 2 main classes

A

DNA viruses and RNA viruses (retroviruses carry RNA but must convert the genome to DNA before replication).

227
Q

Stages of viral replication

A

Cell entry (attachment, penetration), Uncoating, transcription of viral genome, translation of viral proteins, post-translational modifications (cleavage), assembly of new virion components, release (budding)

228
Q

First antiviral drug was Acyclovir

A

discovered by Gertrude Elion and George Hitchings in the 1960s. Used for treatment of Viral herpes. Is a nucleoside analog. Acyclovir is unique in that it must be metabolized by herpes thymidine kinase in order to be used

229
Q

Anti-influenza virus

A

drugs include Arantadine and Rimantadine, which inhibit viral uncoating. Or Tamiflu (Oseltamivir) or Relenza (Zanamivir) which inhibit the neuraminidase enzyme of influenza A or B viruses, causing viral aggregation at the cell surface so the new particles can’t be released.

230
Q

COVID-19 vs the Flu

A

both viruses spread similarly, have similar symptoms, and can be mild or severe. Differences: sometimes delayed onset of symptoms for COVID-19, which is often more severe/deadly than the flu

231
Q

Several treatments are currently being investigated/used in special cases to treat patients with COVID-19

A

At home, at-risk patients may be prescribed Lagevrio (molnupiravir – nucleoside analogue, can cause mutations
in viral DNA), or Paxlovid (combination of 2 protease inhibitors, nirmatrelvir and ritonavir)

232
Q

Hospitalized patients may also be prescribed:

A

1) The monoclonal antibody Bamlanivimab
2) The viral RNA-polymerase inhibitor Remdesivir
3) Dexamethasone: steroid that helps reduce systemic inflammation, found to reduce mortality for some patients

233
Q

Heptatitis

A

Caused by viruses spread by fecal matter (HPV A), or bodily fluids (HPV B, HPV C). Can cause liver damage, weaken the immune system, cause liver cancer, failure, death. Often no early symptoms

234
Q

Interferons

A

are naturally occurring, immune stimulatory proteins that, when used as drugs, are purified and injected
into the patient to stimulate specific immune responses. Work as anti-virals in many different ways.
Downsides:
expensive, nasty side effects, can only be used in a relatively healthy subset of patients, and don’t always work.

235
Q

Raltegravir

A

binds to HIV DNA Integrase and blocks its ability to insert the HIV genome into the host genome.

236
Q

HIV protease inhibitors

A

(peptidomimetic) can block the cleavage of precursor HIV proteins into their mature, functional
forms.
* Prophylactic (PrEP) drugs are now available for individuals who may be at high risk of HIV exposure that can reduce the risk
of infection by 90%, but must be taken daily. Truvada can be used for PrEP.

237
Q

Reverse transcriptase inhibitors

A

can either mimic nucleotides/nucleosides and block further DNA replication, or bind
elsewhere on the reverse transcriptase enzyme and block its activity

238
Q

HIV binds to CD4+ immune cells by binding to the CD4 receptor

A

ith help from the CXCR4 and CCR5
co-receptors. HIV is a retrovirus, which is an RNA virus that needs to reverse-transcribe its genome to DNA, then
it integrates its genome into the host DNA before using host machinery to replicate

239
Q

Discussed the need for constant turnover of cells in the body

A

thus constant DNA replication and opportunities for
for mutations to occur that aren’t repaired (in addition to environmental mutagens). In normal conditions, cell
proliferation, differentiation and death are well-orchestrated to keep our bodies at homeostasis

240
Q

hallmarks of cancer cells

A

involves loss of normal control mechanisms governing cell survival,
proliferation and differentiation, capable of metastasis, can undergo clonal expansion, often contain mutations
and chromosomal abnormalities.

241
Q

intracellular signaling networks

A

are keys to allowing for operations of the cancer cell. They rely on
dysregulation of normal signaling to survive

242
Q

Oncogene

A

a gene having the potential to cause cancer. Often mutated or expressed at high levels in cancer.
- Growth factors, growth factor receptors, signaling molecules, anti-apoptotic genes, transcription factors for cell
proliferation (see examples on slide 7). Can be stimulated by translocation/transposition, gene amplification, or point
mutations (in promoter or within the gene)

243
Q

Tumor Suppressor Gene

A

Protect cells against becoming cancerous. Often they are inhibitors of cell growth that become
mutated or lost in cancer. Examples: p53, Rb, PTEN

244
Q

Log-kill hypothesis

A

If cancer cells are undergoing logarithmic growth, it is much more effective to treat
them early when there are orders of magnitude fewer cells to kill. But this requires early diagnosis and
treatment. Also, chemotherapeutic drugs only kill a certain fraction of tumor cells each cycle, so multiple rounds of
chemotherapy are required to achieve significant reduction in tumor burden

245
Q

Antimetabolites

A

Inhibit DNA or RNA synthesis. Purine analogs, pyrimidine analogs, folate analogs

246
Q

Alkylating agents

A

Chemically modify DNA, RNA or proteins by adding an alkyl group

247
Q

Natural products

A

There are many, but we discussed vinca alkyloids (disrupt microtubule formation), taxanes (enhance
tubulin polymerization and don’t allow them to resolve for the next phase of the cell cycle), Etoposide ( inhibits
DNA topoisomerase II), camptothecins (inhibits DNA topoisomerase I), anthrocyclines (inhibits DNA topoisomerase
II, intercalates DNA, makes free radicals), mitomycin (cross links DNA), bleomycin (binds DNA, causes strand breaks).

248
Q

Hormones and analogues

A

for hormone-dependent cancers. Can induce apoptosis

249
Q

tyrosine kinase inhibitors

A

can work through binding to the ATP binding site (e.g.: Lapatinib), but this can also have
off-target effects.
There are many of these inhibitors being used, with varying effects. Monoclonal antibodies are also available
to target tyrosine kinases. They can block the ligand for the receptor, bind to the receptor itself, or prevent
dimerization of the receptor – each of which inhibits downstream signaling

250
Q

Neurominidase

A

inhibits influenza an enzyme on the surface of viruses
enabling the virus to be released from the host cells.

251
Q

Herceptin

A

(Trastuzumab) is an antibody against the HER2 receptor which can be overexpressed in breast cancer

252
Q

Combination therapy

A

Helpful to treat the cancer while reducing the
risk of developing resistance
The combination called R-CHOP is often used for Non-Hodgkins Lymphoma.
R = Rituximab (antibody against cancer cells)
C = cyclophosphamide (alkylating agent which binds DNA)
H = Doxorubicin Hydrochloride (an anthracycline, blocks topoisomerase II)
O = Oncovin (Vincristine Sulfate, a vinca alkyloid)
P = Prednisone (corticosteroid)

253
Q

Three main types of immune stimulatory therapies

A

1) Blocking the CTLA-4
immune checkpoint, 2) Blocking the PD-1/PD-L1 immune checkpoint, 3) T-cell transfer

254
Q

Pyrimidine analogue

A

Purine or Pyrimidine Analogs
Foscarnet=pyrophosphate analog
anti herpes drugs that target virus

255
Q

General Structure of Viruses

A

1) Core: single or double stranded DNA or RNA
2) Capsid: protein shell
3) Envelope: phospholipids and proteins

256
Q

Integrase

A

Raltegravir binds to hIV integrase and prevents DNA strand transfer

257
Q

Herpes Simplex virus

A

DNA virus

258
Q

Acyclovir (zovirax)

A

first antiviral drug
for viral herpes
analog of nucleoside
adds phosphate groups and gets stuck

259
Q

Viral protease

A

inhibitor peptidomimetic

260
Q

Hepatitis B

A

usually no symptoms pases vua blood or body fluids vaccine preventable

261
Q

Mechanisms of resistance

A

1) Inactivation by b-lactamases (over hundreds)- inactivate beta-lactam antibiotics by hydrolyzing the peptide
bond of the characteristic four-membered beta-lactam ring rendering the antibiotic ineffective
2) Modification of Penicillin-bind proteins (PBPs, transpeptidase)- mutation of PBPs
3) Impaired penetration of drug to target PBPs- can’t get into cell
4) efflux- get kicked out

262
Q

Gyrase

A

DNA gyrase
quinolones

263
Q

50S ribosomal inhibitors

A

targeted by macrolides, clindamycin, linezolid

264
Q

30S ribosomal inhibitors

A

targeted by tetracyclines and aminoglycosides

265
Q

Macrolide

A

Erythromycin, Clarithromycin, Azithromycin
Binding to 50S ribosomal RNA near the peptidyltransferase center

266
Q

Beta-lactam antibiotic

A

mimic D-Ala-D-Ala and inhibit
activity of the transpeptidase that uses them.
mimic the bacteria cell wall and then puts a cephalosporins to stop bacteria from making cell wall
Resistance

1) Inactivation by b-lactamases (over hundreds)
2) Modification of Penicillin-bind proteins (PBPs, transpeptidase)
3) Impaired penetration of drug to target PBPs
4) efflux kicking drug back out

267
Q

Louis Pasteur

A

diseases were caused by germs

268
Q

gram positive

A

bacteria with big cell walls

269
Q

gram negative

A

small cell wall

270
Q

Streptomycin

A

its an aminoglycoside and best for gram neg
makes RNA not be able to read correctly
binds to 30s

271
Q

gabapentin, pregabalin

A

Block presynaptic α2δ1

272
Q

gabapentin, pregabalin

A

Block presynaptic α2δ1

FALL 2022 (5 decks)

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