1
Q
Pharmacokinetics
A
- description of drug ADME as well as quantitative description of how these processes affect the time course & intensity of response
- what the body does to the drug
2
Q
Pharmacodynamics
A
- the quantitative description of the relationship b/w the drug [ ] time profile and the adverse or therapeutic effect
- What the drug does to the body
3
Q
ADME
A
- Absorption - how the drug gets into the body
- Distribution - where the drug goes in the body
- Metabolism - how to body chemically modifies the drug
- Excretion - how the body gets rid of the drug
4
Q
CMAX
A
maximum [ ] can help predict the likely therapeutic benefit & possible side effects
5
Q
TMAX
A
time where CMAX occurs
6
Q
1/2 Life
A
the time it takes to remove 1/2 the [ ] of drug from the body
7
Q
Area Under the Curve
[ ]-time dependent curve
A
total exposure to the drug
8
Q
Bioavailability
A
- the amount of drug that reaches the systemic circulation compared to the amount of drug administered
9
Q
In the stomach, a weak base is…
A
- protonated
- charged (ionized)
- less water soluble
- less bioavailable
10
Q
In the stomach, a weak acid is…
A
- protonated
- uncharged (unionized)
- less water soluble
- more bioavailable
11
Q
In the SI, a weak base is…
A
- unprotonated
- uncharged (unionized)
- less water soluble
- more bioavailable
12
Q
In the SI, a weak acid is…
A
- unprotonated
- charged (ionized)
- more water soluble
- less bioavailable
13
Q
Non-specific Binding
A
- the drug has an affinity for proteins found in the bloodstream such as albumin
14
Q
Factors affecting brain access of drugs
A
- size
- lipid solubility
- ionization state
- protein binding state
15
Q
Drug Metabolism can do 3 Things
A
- activate drug (L-DOPA -> Dopamine)
- maintain a drug’s stability (ex. Diazepam metabolized to similarly active benzos)
- inactivate a drug
16
Q
Phase I Metabolic Rxn
A
- involves changing 1 functional group
17
Q
Phase II Metabolic Rxn
A
- involves much larger changes to the structure of a drug (adding large group)
18
Q
Portal Vascular System
A
- veins pass through liver, branching into smaller vessels, allowing the liver to remove & process compounds coming from the GI tract
- For orally administered drugs, this portal system means that once absorbed, they can go to the organ that can metabolize them before reaching systemic circulation
19
Q
Most drugs are metabolized by ____ enzymes in the Liver
A
- cytochrome P450
20
Q
What is one of the most common causes of drug interactions
A
CYPs
21
Q
Most drugs are secreted by …
A
the kidney, in the urine
22
Q
Enterohepatic recycling
A
- Drug metabolite formed in the liver, much travels via bile, transported to the small intestine, drug can be reabsorbed back through the portal vein
- Slows the elimination of a drug!!
23
Q
Almost all drug targets are …
A
- proteins
- 1/2 of which are receptors
24
Q
Largest class of protein drug targets are
A
- G protein-coupled receptors
25
What are Ion channels?
* multi-subunit complexes that form a central pore that allows a specific ion or group of ions to pass in or out of the cell
26
Voltage-gated Ion Channels
* largely on nerves
* Sitting on an axon & they're inactive, as depolarization wave travels down the cell membrane, signal to open up the Na channel
27
Ligand-gated Ion Channels
* Ligand binds, channel opens
28
What are Intracellular Receptors?
* inside cells either in the cytoplasm bound to "chaperone" proteins or in the nucleus
* act on "gene response elements" (GREs) to increase/decrease the transcription of genes
* classically hormone (and vitamin) receptors
29
How are Intracellular Receptors Activated?
1. Bind ligands
2. Dimerize or heterodimerize
3. Enter the nucleus bind specific segments of DNA (gene response elements)
4. Promote or inhibit gene transcription
30
Kinases phosphorylate which groups?
* tyrosine, threonine or serine residue of a protein using ATP
31
How does a Serotonin reuptake inhibitor work?
* When pre-synaptic neuron fires, releases NT to bind post-synaptic cell
* To turn off signal serotonin goes through transporter back into the pre-synaptic neuron
* Block serotonin reuptake - stays in synapse longer
32
What are some Non-protein drug targets?
* DNA
* Hydrogen Ions or cholesterol-base bile acids
33
What are the subunits in a G protein
* alpha
* beta
* gamma
34
Signal transduction
* a chemical signal from the outside of the cell is "transduced" to a signal inside the cell & the G proteins will now carry the signal forward
35
What is Gs
* stimulatory
36
What is Gi
Inhibitory
37
What is GQ
* calcium
38
Efficacy
* description of the effect or maximal effect of a drug
* same ED50 values
* Ex. DrugA lowers BP by 5mm & DrugB lowers by 25mm -> drug B has greater efficacy
39
Potency
* measure of how much drug you need to achieve a particular effect
* Usually measure by the dose/[ ] at which 50% of max effect is observed
* different ED50 values
* Ex. DrugA needed to lower BP by 5mm was 1mg, DrugB was 750mg -> drug A more potent
40
Antagonists
* bind GPCRs at the orthostatic site
* occupy the ligand-binding site to prevent agonists from activating the receptor
41
Partial Agonist
* Every partial agonist is also a partial antagonist
* Partial agonist binds a GPCR at orthosteric binding site & activates it
* produce lower response at full receptor occupancy than do full agonists
42
Inverse Agonist
* type of antagonist
* Bind receptor, but stabilize it in a conformation that reduces the basal activation of the receptor
* activity goes below baseline
43
Allosteric Modulators
* bind GPCRs at site adjacent to orthosteric binding site
* can make the GPCR more/less responsibe to binding orthosteric ligands
44
Parasympathetic Division
* rest & digest
* D Division: digestion, defecation, diuresis
* pre-ganglion neuron releases Ach , post-ganglion Ach releases Ach
* PSNS long pre-synaptic ganglia & shorter post-synaptic ganglia
45
Sympathetic Division
* Fight or flight
* E Division: exercise, excitement, emergency, embarrassment
* pre-ganglion neuron releases Ach, post-ganglionic neuron releases NE
* SNS short pre-synaptic ganglia & longer post-synaptic ganglia
46
Sympathetic tone
* aka Vasomotor tone
* Keeps blood vessels in continual state of partial constriction
47
Cholinergic
described the actions of Ach and its receptor systems
48
2 Ways to increase cholinergic signaling
1. Direct activation of cholinergic receptors
2. Inhibition of acetylcholinesterase, increase in endogenous Ach, & subsequent increase in cholinergic receptor activation
49
What are the 2 Types of Ach receptors
* Nicotinic
* Muscarinic
50
What are the 5 types of Muscarinic receptors
* M1-5
* M1, 3 & - Gaq-coupled receptors
* M2 & 4 - Gai/o-coupled receptors
* M2 - major cardiac receptor
51
SAR for muscarinic agonist activity
1. posess nitrogen atom capable of bearing positive charge (preferrably quaternary ammonium salt)
2. size of alkyl substituted on nitrogen should not exceed size of methyl group
3. should have oxygen atom, preferrably ester-like oxygen, capable of hydrogen bonding
4. should be 2 carbon unit b/w the oxygen atom & the nitrogen atom
51
Physiological effects of Muscarinic agonist
* decreased heart rate (M2 receptors)
* bronchoconstriction
* increased GI activity
* increased genitourinary tract activity
52
What do Cholinesterase Inhibitors do?
* indirectly increase cholinergic signaling by inhibiting acetylcholinesterase
53
Acetylcholine metabolism
* Enzyme temporarily takes the acetyl group from Ach and then is de-esterified itself in order to become ready to catalyze another rxn
54
Irreversible Inhibitors
* Instead of acylating an enzyme (reversible covalent bond), phosphate esters are formed that are extremely stable to subsequent hydrolysis
* Organophosphate derivatives
55
Cholinesterase Regenerator Compounds
* Can regenerate active cholinesterase from the organophosphate-cholinesterase complex
* As long as they are administered before that phsopho group "ages"
* contain an oxime group (=N-OH)
* Ex. Pralidoxime & Atropine - administered after organophosphate poisoning
56
Nicotinic Receptors
* Pentameric, ligand-gated, sodium channels
* 5 subunits (a, B, y, S, E) arranged to form a pore
* Open in response to binding of Ach on the a subunit
* allow sodium & potassium to pass through
57
Varenicline
* Nicotinic acetylcholine receptor partial agonist
* Partial agonist - in presence of nicotine, acts as partial antagonist
* results in dopamine release, decrease craving & withdrawal
58
Non-depolarizing neuromuscular blocker
* a nicotinic receptor antagonist
* Blocks nicotinic receptors & prevents Ach from binding & prevents AP in muscle fiber
* Ex. Tubocurarine
59
Depolarizing Neuromuscular Blocker
* activate nicotinic receptors, but do it really well
* Receptors become constitutively activated - always turned on
* muscle cannot contract in a synchronized fashion & flaccid paralysis occurs
* Ex. Succinylcholine
60
Myethenia Gravis
* an autoimmune disorder in which body mounts an immune system attack on nicotinic acetylcholine receptors
* Results in muscle weakness & fatigue
* Treatment: cholinesterase inhibitors to boost Ach signaling in NMJ to improve functioning, & immunosuppressants to reduce autoimmune attack
61
Anticholinergics would ________ PSNS
decrease
62
Atropine is a...
* muscarinic receptor antagonists
* neutral competitive antagonists
63
Physiological Effects of Anticholinergics
* Increased Heart Rate
* Pupil dilation & impaired accommodation
* Bronchodilation
* Block GI secretions
* Reduce genitourinary motility
* Cause sedation
* Reduce Nausea & vomiting
64
Anticholinergic Toxidrome
* A - open airway
* B - normal resp rate
* C - tachycardia, hypotension in sever cases
* D - dilated pupils but not reactive to light, confusion, hallucinating
* E - decreased or absent bowel movements, dryness
65
Catechol Ring
* six membered benzene ring with hydroxyl groups
66
What are Amino Acid are NE & E derived from
Tyrosine
67
NE & E are produced in what ratio
4:1
68
Catecholamine Production Pathway
* L-Tyrosine -> L-Dopa -> Dopamine -> NE -> E
69
How do we Breakdown Catecholamines
* MAOs
* COMTs
* additional enzymes: aldehyde reductase & aldehyde dehydrogenase
70
Monoamine Oxidase (MAO)
* converts amine group to aldehyde
* MAO inhibitor -> treatment of depression & Parkinson's
71
Cathechol-O-methyltransferase (COMT)
* methylates one of the hydroxyl groups on the catechol ring
* COMT inhibitor -> treatment of Parkinson's
72
What are the 5 Types of Adrenergic Receptors
* a1
* a2
* B1
* B2
* B3
73
a1 adrenergic receptors
* coupled to Gaq
* phospholipase C cleaves membrane phospholipids into IP3 & DAG & results in release of intracellular calcium & get activation of protein kinase C
* Ca2+ results in muscle contraction
74
a2 adrenergic receptors
* primarily presynaptic
* AKA Autoreceptors
* Gai coupled
* A2 receptor agonists inhibit sympathetic nervous system activity by reducing SNS activation in the CNS
* Activate the a2 receptor -> inhibit adenylate cyclase -> decrease cAMP levels -> neuron becomes less sensitive to AP & release less NT
75
B1 adrenergic receptors
* primarily in heart
* increases rate & force of contraction
* Gas-coupled
76
B2 adrenergic receptors
* primarily in smooth muscles, skeletal vascular smooth muscle & bronchioles & internal organs
* causes muscle relaxation
* Gas coupled
77
B3 adrenergic receptors
* primarily in adipose tissue
* breakdown of fats for energy
* Gas coupled
78
Direct Acting Adrenergic Agonists
* Selective - for one receptor type
- ex. phenylephrine
* Non-selective - agonists that activate multiple receptors
- Ex. E activates all adrenergic receptors
79
Mixed-Acting Adrenergic Agonists
* Ex. Ephedrine binds adrenergic receptors but also causes release catecholamines
80
Indirect-Acting Adrenergic Agonists
* analogous to cholinesterase inhibitors
* Increase the levels or release of catecholamines
* releasing agents - ex. Amphetamines
* uptake inhibitor - ex. Cocaine
* MOA inhibitors
* COMT inhibitors
81
Sympathomimetic
* Any drug that results in increase in SNS activity
82
Relative Receptor Affinity of Phenylephrine
* classic alpha agonist
* a1>a2
83
Relative Receptor Affinity of Isoproterenol
* classic beta agonist
* B1=B2 >a
84
Relative Receptor Affinity of Epinephrine
* great B2 agonist (NE is not)
* a1=a2, B1=B2
85
Relative Receptor Affinity of Norepinephrine
* a1=a2, B1>>B2
86
Physiological Effects of Adrenergic Agonists
* increase heart rate & force of contraction
* bronchodilation - treat asthma
* increase breakdown of glycogen
* pupil dilation & increase aqueous humour - treat glaucoma
87
Effect of Phenylephrine
* a1 receptor agonist
* Blood vessels constricted
* BP goes up (spikes) -> baroreceptors adapt (increase PSNS activity)
* reflex bradycardia -> HR decreases
88
Effect of Histamine
* vasodilation
* BP goes down
* SNS goes up, PSNS goes down
* reflex tachycardia -> HR increases
89
If you Inject someone with NE
* Activate a1 & B1
* A1 - constrict smooth muscles (vasoconstriction), increase peripheral resistance
* B1 - should increase heart rate but we see the opposite
* Reflex bradycardia - significant increase in BP & resistance activates PSNS to release Ach
* Increases PR, Increased BP (spike), Decreased HR
90
If you Inject someone with E
* Activate B1 in heart, a1 in systemic vasculature and B2 in skeletal muscle
* Decrease of peripheral resistance & BP (not a big spike in BP) -> don't get reflex PSNS activation
* Decreases PR, decreases BP, increases heart rate
91
If you Inject someone with ISO
* Activate B1 in heart and B2 receptors in skeletal muscle (vasodilation)
* No a1 effects!!!
* Decreases peripheral resistance slightly & increases heart rate
* Triggers further reflex SNS activation -> increases HR
* Decreases PR, Decreases BP, Increases HR
92
Alpha Recptor Antagonists
* can block a1 & a2 together or separately
93
Beta Receptor Antagonists
* non-selective (block all beta receptors) or B1 selective
94
a1 Receptor Antagonists
* -azosin or -osin suffix
* Used to treat hypertension
* The blockage of a1 receptors inhibits the ability of the vascular system to constrict if pressure suddenly needs to be increased (ex. From sitting to standing position)
* **orthostatic hypotension**
* BP drops, activates SNS, release NE, reflex tachycardia
95
B-blocker therapeutic uses
* hypertension
* angina
* cardiac arrhythmias
* migraine headache prophylaxis
* various CNS disorders
96
B1 Receptor Antagonsits
* reduce chances that HCN channels will open & decreases heart rate
97
Non-selective B-blocker physiological effects
* inhibit renin release from kidney
* bronchoconstriction of bronchioles
* inhibit glycogenolysis (glycogen -> glucose)
* prevent migraines
* AEs in CNS: sedation, sleep disturbances, nightmares & causing/worsening depression
98
Reserpine
* Causes a release of catecholamines
* increases SNS activity briefly, over time catecholamine stores are depletes & decreases SNS activity
* treat HTN, but many ADRs
99
a-Methyldopa
* Metabolic pathways same way as they act on L-DOPA
* methyldopamine & methylnorepinephrine are produced
* The "real" NT levels are reduced
* Methylnorepinephrine is an agonist at a2 adrenergic receptors that further reduced SNS activity
* used in HTN in pregnant mothers
100
Toxicology
* study of adverse effects of chemicals & other substances on living organisms
101
Toxicologist
* researcher that examines the nature of the adverse effects at many levels
* How toxins & toxicants are ADME -> toxicokinetics
* Molecular mechanisms of whole body, system/organ, cellular or macromolecule damage
* Short & long term harms
* Probability of occurrence of toxic effects
102
Toxin
is from a biological source - plant, bacteria, animal
103
Toxicant
is anthropogenic (human-made)
104
Ways to Classify Toxins & Toxicants
* By source - animal, plant toxins, anthropogenic toxicants
* By where they are occurring - in patients, in animals, in the workplace, in the environment
* By how they are used - pesticides, drugs, industrial solvents, etc.
* By subject - humans, animals, insects, etc.
* By target organ - liver, brain, etc.
* By type of adverse effects - irritant, carcinogen, teratogen, etc.
* By duration and frequency
105
Acute Exposure
typically from minutes to around 48 hours
106
Sub-acute exposure
repeated exposures lasting less than around 1 month
107
Sub-chronic exposure
typically 1-3 months
108
Chronic Exposure
3 months+
109
EMAX
* Maximal effect
* 100% of whatever effect you are measuring
110
EC50
concentration at which 50% of the maximal effect is observed
111
TC50
concentration at which 50% of a toxic maximal effect is observed in cells
112
ED50
dose at which 50% of the maximal therapeutic effect is observed, or 50% of subjects (humans, research animals) experience a particular therapeutic effect
113
TD50
dose at which 50% of the maximal toxic effect is observed, or 50% of subjects (humans, research animals) experience a particular toxic effect
114
LD50
dose at which 50% of subjects (typically research animals) experience mortality due to the drug or toxin
115
Therapeutic Window or Therapeutic Index (TI)
* ratio of the TD50 to the ED50
* Gives an idea of where you would expect effective dose vs. starting to observe toxicities
116
Margin of Safety
* ratio of the lethal dose in 1% of a population vs. effective dose in 99% of pop
117
Essential Nutrient Dose-response Curve
* In the absence of nutrients you have adverse effects
* As you increase consumption of nutrient you enter homeostasis
* Increase too high levels, you start to see toxicity
118
NOAEL
* no observed adverse effect level - "threshold dose"
* Highest dose where you don't see any effects
119
LOAEL
* lowest observed adverse effect level
* Lowest dose where you just start to see some toxic responses
120
Ways to Classify Adverse drug Reactions
* mechanism of action
* off-target effects
* reversibility
* exposure time
* non-specific or organ-specific
* relative risk
121
Acetaminophen Toxicity
* CYP2E1 & CYP3A4, produce toxic metabolite that is very chemically reactive
* At low doses able to neutralize the reactive metabolite w/ glutathione
* At higher doses (greater than 10g/dose or 4g over multiple doses), the toxic metabolites can react w/ proteins & cause dysfunction & cell death
122
Ethanol Toxicity
* 1st step - convert ethanol into acetaldehyde by alcohol dehydrogenase
* 2nd step - acetaldehyde to acetic acid by aldehyde dehydrogenase
* Acetaldehyde causes most of the adverse effects of alcohol headache, nausea, vomiting and facial flushing
* steps in detoxification of alcohol require NAD+ -> alcohol metabolism is saturated at relatively low [ ]s
* over time, fat accumulation & fibrosis
123
Methanol Toxicity
* Methanol is similar to alcohol
* But the metabolism is much more toxic!!
* toxic intermediates including formaldehyde and formic acid that can cause blindness, metabolic acidosis, respiratory depression & death
124
MPTP Toxicity
* MPTP is a protoxin that is converted by monoamine oxidase B (MAO-B) into N-methyl-4-phenyl-pyridiniym (MPP+)
* MPP+ results in cell death of dopaminergic neurons of the substantia nigra
125
Magic Bullet
* to describe the ideal antibiotic
* Key features Kill the infectious organism quickly but leave the host alone
126
What are Viruses
* obligate intracellular parasites
* not technically living
* They require activity of the infects host cell in order to replicate
127
Processes that Antivirals Block
* Block viral attachment & entry into cells
* Interfere w/ penetration
* Interfere with uncoating
* Interfere w/ nucleic acid synthesis
* Interfere w/ protein processing - protein inhibitors
* Prevent viral particle release
128
Oseltamavir
* Antiviral
* Oseltamivir (& zanamivir) interact w/ neuraminidase & causes a conformational change -> inhibits enzyme's activity
* Virus aggregates at cell surface, attracting immune system
* Viral spread is reduced in the respiratory tract
129
Remedesivir
* Antiviral
* Used to treat COVID-19
* Inhibitor of viral replication, specifically a class of nucleotide analogues that mimic natural nucleosides & disrupt the replication of viral DNA & RNA
* affinity for the viral RNA polymerase (an enzyme required for viral RNA replication)
130
Processes that Antibacterials Target
* Cell wall synthesis inhibitors
* cell membrane inhibitors
* Folate synthesis inhibitors
* DNA gyrase inhibitors
* RNA polymerase inhibitors
* Protein synthesis inhibitors
131
Mechanisms of Antibiotic Resistance
* production of drug-inactivating enzymes
* modification of an existing target
* acquisition of a target bypass system
* reduced cell permeability
* drug removal from cell
132
Penicillin
* 1st beta-lactam antibiotic discovered
* interfere w/ bacterial cell wall synthesis
* Bind a transpeptidase called the penicillin-binding protein
* interferes w/ the joining/cross-linking of 2 cell wall building blocks
* bacterial cells will explode due to osmotic pressure
133
Fluconazole
* Antifungal
* Target a unique component of the fungal cell membrane
* Antifungal inhibit ergosterol synthesis, resulting in both reduction of total ergosterol & production of toxic sterols that accumulate in membrane & cause disruption
* NOTE: inhibit CYP450 enzymes -> numerous drug interactions
134
Permethrin
* Antiparasitic drug
* interferes w/ Na+ transport, resulting in neuronal depolarization & respiratory paralysis of arthropods
* Typically treats lice/scabies
135
Vincristine
* Vincristine & vinblastine -> make up the vinca alkaloid group of chemotherapy agents
* Bind tubulin to inhibit polymerization
* disrupts the assembly of microtubules required for creation of the mitotic spindle -> daughter cells can't pull apart & divide in two
* Cell division if halted & cell death occurs
* **Cell-cycle-specific, acting during the M phase of the cycle**
136
Methotrexate
* Cytotoxic immunosuppressant that possess anticancer activity
* dihyrofolate reductase inhibitor
* Inhibitor of folic acid synthesis that disrupts the production of purine DNA & RNA bases
* Also... Inhibiting LTB4 synthesis in macrophage, reducing TNFa concentrations
137
Infliximab
* Immunosuppressant
* One cytokine involved in several autoimmune disorders is tumour necrosis factor a (TNFa)
* antibody against TNFa
* inhibits immune system signalling & causes apoptosis in TNFa-expressing cells
* used in combo w/ methotrexate to reduce production of anti-infliximab Abs
PHARM 141
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