Pharm 1 Flashcards
_ stimulates salivation by the submaxillary gland. _ blocks it
Pilocarpine
Atropine
Pilocarpine and atropine produce their effects by acting on _ proteins of _
Muscarinic acetylcholine receptor proteins of salivary glands
Which antagaonists can produce xerostomia?
Muscarinic
Like pilocarpine and atropine, _ and _ have the same relationship but with a chicken gastrocnemius muscle
Nicotine and curare
A and B with respect to Y compete based on what two things
How much of each is present
How well each can bind to receptor
Dissociation constant =
[R] [L] / [RL]
Interaction of a drug with a receptor is based on the law of _
Mass action
Kd happens at _ binding to the receptor
1/2
What is EC50?
The dose of the drug that produces 1/2 maximal effect
What is a dose response curve?
Dose on x, change on Y
Shows pharmacological effect
What are partial agonists?
Agonists that activate a low % of receptors and produce a partial effect
What is drug efficacy and what is drug potency?
Efficacy: ability to confer the response after binding
Potency: ability of a drug to confer an effect
Potency = affinity and efficacy
What are receptor gene families and why are they important in understanding pharmacology?
Receptors that differ in responsiveness to similar structures
One drug can elicit different effects in different contexts.
Explain why we need receptor specific agonists and antagonists and explains complexity of drug action
EC50 vs. Keq
EC50 produces 1/2 maximal EFFECT
Keq produces 1/2 maximal BINDING
Drugs with insufficient efficacy will be _ no matter how high their affinity
Partial agonists
Antagonists efficacy
0
4 types of signaling receptors
Ligand activated ion channels
G protein coupled
Ligand activated transcription factors
Tyrosine kinase receptors
40% of all drugs are agonists or antagonists of _
A G protein coupled receptor
The basis of transmission of nerve impulses is _
Activating and inhibiting ligand activated plasma membrane ion channels
Ca release from the ER is mediated by
IP3
4 steps in the G protein cycle
- Ligand binds to GPCR, GDP-GTP exchange
- complex falls apart into Galpha and GBetagamma
- Galpha hydrolyzes GTP to GDP and Pi
- Complex reassembles
Which parts of the GPCR are the major and minor parts
Major is Galpha
Minor is GBetagamma
What does adenylate Cyclase do
ATP -> cAMP + PPi
cAMP -> protein kinase A -> phosphorylation of many proteins causing many effects
Activation of glycogenolysis is mediated by _
PKA
How do GPCR liberate signaling molecules from within phospholipids
Activate phospholipases which free them up
_ is the source of eicosinoid signaling molecules and prostaglandins
Arachidonic acid
Cleavage of _ by phospholipase C yields DAG and _
PIP2
IP3
What turns off GPCR
Desensitization
Two fates of endocytosed receptor
Recycling
Degradation
How does signaling by receptor tyrosine kinase work? (Steps)
Binding of ligand -> dimerization of receptor (homo/hetero) -> transphosphorylation of receptors -> docking of signaling molecules -> different cascades of signaling -> Change in gene expression in cells
STAT proteins mediate _
Biological response to cytokines
Class 1 vs class 2 nuclear receptors
Class 1: binds to ligand on complex, complex falls apart, forms homodimer, binds to DNA
Class 2: binds to target DNA or corepressors, switches from corepressor to coactivator
Patient factors influencing drug effects
Body weight/composition Age Sex Pregnancy Environmental Diet Physiologic differences Pathologic conditions Genetic factors
Pharmacokinetic vs. pharmacodynamic tolerance
Kinetic: effective drug conc is diminished
Dynamic: response is diminished
Acute pharmacodynamic tolerance is called _
Tachyphylaxis
How does warfarin work?
Inhibits synthesis of vit. K dependent clotting factors (II, VII, IX, X)
Can lead to hemorrhaging
5 categories of drugs during pregnancy
A - no risks in humans
B - no risks in humans BUT animal studies bad OR no human studies, animal studies clear
C - no human and either no animal studies, or bad news animal studies
D - human fetal risk
X - human or animals BAD BAD. Risks outweigh benefit
Pharmacokinetic vs pharmacodynamic variations
Kinetic: response changes with drug concentration
Dynamic: diff response to drug
Most important oxidation polymorphic enzyme
CYP2D6
Why is CYP2D6 important
Poor metabolizers have higher incidence of bad effects (cevimeline isn’t metabolized as fast as it should be)
Need it to convert tamoxifen to endoxifen. W/o it, tamoxifen is less effective for breast cancer tx
Converts codeine to morphine
What do ryanodine receptors do?
Defect causes what
Mediate Ca mediated Ca release from SR in muscle
Malignant hyperthermia
% of americans that:
Take 1 prescription drug
At least 2
5+
70%
50%
20%
How does drug potentiation occur
One drug: -Enhances absorption -Alters distribution -Inhibits elimination Of another drug.
Types of pharmaceutical interactions
Antagonism Potentiation Unexpectation Summation Synergism
Pharmacokinetic interactions
Absorption
Distribution
Metabolism
Excretion
Most drugs metabolized in liver by _
Microsomal P450 enzymes
When does net efflux of K end
When the chemical force leading K outside is balanced by the electrical force bringing it back
Nernst equation
Vk = -60 mV log ([K]in/[K]out)
_ and _ are primarily responsible for maintaining homeostasis
Autonomic nervous sys
And
Endocrine
Synthesis of catecholamine NTMs
Tyrosine
DOPA
Dopamine -> norepinephrine -> epinephrine
I
V
NoradrenalinAdrenergic vs cholinergic transmission at synapse. What happens to NTM
A: NE transported back into presynaptic terminal
C: Ach hydrolyzed in synapse
Rate limiting step of catecholamine synthesis
Tyrosine hydroxylase (tyrosine -> L-DOPA)
Alpha 1 receptors do what
Where are they
Increase Ca
Increase activity of myosin light chain kinase
Increase myosin light chain phosphorylation
Increase muscle contractility
Smooth muscle cells
Increasing Ca in the smooth muscle cell will do what to the cell
Constrict
Alpha 2 receptors are where and do what
Presynaptic termini
Inhibit epinephrine and NE release
Beta 2 receptors on smooth muscle do what
Increase PKA Phosphorylation and inhibit MLCK Lower Ca levels Inhibit MLCK Diminish phosphorylation of MLC Decrease muscle contractility
Beta 1 receptors on cardiac muscle cells do what
Activate PKA
Activate L type Ca channels
Increase Ca levels
Increase muscle contractility
Drugs that activate B1 in heart are used to do what
Improve contractility of failing heart
NE doesn’t activate _ receptors, but epinephrine does
B2
Epi activates a, B1 and B2
Why use NE or epi with local anesthetic
Keep anesthetic around longer due to vasoconstriction
Alpha1 receptor agonists do what
Produce contraction of vascular smooth muscle
-increase BP
_ is sometimes used as a vasoconstrictor in conjunction with a local anesthetic
Levonordefrin
3 reasons to use a vasoconstrictor with a local anesthetic?
Which is the most common and second most common
- Prolong duration of nerve block, increase success
- Diminish systemic toxicity of anesthetic
- Minimize blood loss during surgical procedure
What do alpha2 receptor agonists do
Inhibit epi and NE release from presynaptic termini in CNS
Beta1 agonists do what
Tx of heart failure and cardiogenic shock
Beta2 receptor agonists do what
Produce smooth muscle relaxation. Treat asthma, relax uterine wall
Adverse effects come from what 4 things
Too large a dose
Accidental intravascular injection
Heightened sensitivity
Patient with cardiovascular disease
Alpha 1 antagonists are used to treat what
Hypertension
Hemodynamics shock
Raynaud’s disease
3 alpha1 antagonists
Prazosin
Alfuzosin
Tamulosin
_ is used to reverse soft tissue numbness after local anesthetic
It is a _
Phentolamine
Non-selective alpha adrenergic receptor antagonist
Beta blockers are mostly used to block out _
What do they do
Beta1
Decrease heart rate and force of contraction
Beta blockers diminish _ release from the kidney
Renin
What is ISA and how does it affect beta blockers
Intrinsic sympathomimetic activity
(Partial agonists)
Low beta stimulation when using blockers. Don’t depress cardiac function as well but still attenuate agonist driven increases.
Therapeutic uses of beta blockers
Hypertension Ischemic heart disease (reduce oxygen consumption by reducing CO) Post MI Congestive heart failure Treat arrhythmias
A patient taking a beta blocker could have what kind of conditions
Moderate, well controlled
Serious disease
Anything in between
What can treat glaucoma
Beta blockers
Two drugs are alpha and beta receptor antagonists
Labetalol
Carvedilol
Adverse effects of Beta blockers Heart Smooth muscle Metabolic CNS
Heart: bradycardia, AV block
Smooth muscle: reduce vasodilator responses, increase bronchospasms
Metabolic: hypoglycemia
CNS: depression, fatigue, sleep disturbances, hallucinations, dizziness
Alpha blockers can cause _ hypotension
Orthostatic
Who is at risk of a hypertensive episode after receiving local anesthetic with a vasoconstrictor?
Why?
Patient taking non-selective beta blocker
Doesn’t get B2 mediated vasodilation to counteract alpha mediated vasoconstriction
-zosin
Alpha1 adrenergic receptor blocker
-olol
Beta-adrenergic receptor blocker
-ilol, -alol
Beta-adrenergic receptor blocker with alpha1 activity
Two types of cholinergic receptors
Nicotinic and muscarinic
Nicotinic AcCHRs bind what?
What kind of receptor is it?
Structure of receptor?
Bind nicotine
Ligand activated ion channel
Receptors contain 5 subunits and bind two molecules of agonist
Difference in adult vs infant nicotinic receptors
Both have 2 alpha1, one Beta, one delta
Adult has one epsilon
Infant has one gamma
How many muscarinic receptors are there
They are _ receptors
5
G protein coupled receptors
M_, _, _ are linked to Galphaq
M_, _ are linked to Galphai
M1,3,5 G-alpha-q
M2,4 G-alpha-i
How can we figure out whether an Ach receptor is nicotinic or muscarinic?
Ask whether we want to depolarize across a membrane (nicotinic) or activate G protein coupled receptor (musc)
Two types of cholinergic agonists, how do they work
Direct: bind to nicotinic/muscarinic AcCh receptor or both
Indirect: cholinesterase inhibitor
Acetylcholinesterase breaks Ach into _ and _
Acetate
Choline
Which is hydrolyzed faster b/t ach and methacoline? What is the effect
Ach is hydrolyzed faster, shorter duration
4 steps in neuromuscular transmission
Nicotinic Ach receptors activated, post-synaptic membrane de polarized
Local depolarization leads to action potential
Post synaptic depolarization leads to release of Ca from SR
Ca leads to muscle contraction
How do troponin and tropomyosin work?
Ca binds to troponin complex
Troponin causes tropomyosin to shift exposing myosin binding sites
Myosin binds actin
Muscle cross bridge cycle stops when
Ca levels drop
Which muscarinic receptors are stimulatory, which are inhibitory
1,3,5 are stimulatory
2,4 are inhibitory
_ receptors on the sphincter muscle mediate pupil constriction
M3 muscarinic
Cardiac muscle contains _ receptors and parasympathetic innervation. Activation of these receptors _
M2
Reduce cardiac output
Most arteries and veins in the body are innervated by _ nerves
Sympathetic adrenergic
Vascular endothelial cells express _ receptors. When activated they produce vasodilation
M3
_ on the bronchial muscle mediate muscle constriction
M3 muscarinic receptors
Secretory glands are activated by _ receptors
M3
_ receptors mediate detrusor muscle contraction (voids bladder)
M3
3˚ vs 4˚ amine, which is better absorbed? Why?
3˚
Pass through biological membranes better
Muscarinic agonists have what effect
SLUD
Salivation, lacrimation, urination, defecation
Which anticholinesterases act in a completely irreversible manner
Malathion
Sarin
(Both organophosphate)
Anticholinesterases produce an effect that is similar to _
Direct acting cholinergic agonists
T/F anticholinesterases produce muscarinic mediated vasodilation
FALSE. They do not.
Not much parasymp innervation of vascular endothelium
What is physostigmine and what does it do
Tertiary amine
Produces vasodilator effects through action in the CNS
_ and _ (drugs) are frequently used to treat dry mouth
Pilocarpine
Cevimeline
5 therapeutic used of cholinergic agonists and anticholinesterases
- Glaucoma
- Xerostomia
- Reversal of neuromuscular block
- ACE for treatment of Myasthenia Gravis
- ACE cross BBB to improve cognitive function in Alzheimer’s
_ have the potential to cause significant CNS impairment
Antimuscarinics
Antimuscarinics usually place the target under control by _
Except _
Symp NS
Sweat glands (both S and PS act on muscarinic)
Anti-muscarinics cause _ in the eye
Pupil dilation
Anti-muscarinics are used to produce _ in the lungs
Bronchodilation
Heart and urinary respond how to antimuscarinics
Mild bradycardia
Urinary retention
Quaternary amine anti-cholinergics are _ absorbed, have a _ therapeutic margin, and are _ tolerated
Poorly absorbed
Wide therapeutic margin
Well tolerated
Anti-cholinergic toxidrome
Hot, blind, dry, mad
_ receptors are important mediators in the CNS
Nicotinic Ach
Desensitization especially happens at _ receptors
Ach
Non-depolarizing blockers are competitive antagonists of _
Ach
Non-polarizing vs polarizing blockers onset of action and duration
Depolarizing has rapid onset and shorter duration
Intravenous infusion of neuromuscular blocking agents induces _
Flaccid paralysis
Neuromuscular blockers are used how in dentistry
Muscle relaxation for surgery
Adverse effects of neuromuscular blockers
Respiratory failure
