Day 1.1 Pharm Flashcards
What is Km?
Substrate conc at 1/2 Vmax
Shows affinity of enz for substrate
If Km is decreased, what does this say abt affinity?
Affinity is increased if Km is decreased.
What is Vmax directly proportional to?
Enz conc
Lineweaver-Burke: What is the y-int?
1 / Vmax
Lineweaver-Burke: What is the x-int?
1 / -Km
Lineweaver-Burke: As the y-int increases, what happens to the Vmax?
Vmax decreases.
Y-int is 1 / Vmax. A bigger Y-int means a smaller number in the denominator.
Lineweaver-Burke: What happens as the x-int moves to the right?
Km increases.
X-int is 1 / -Km. As it moves to the right, it gets less negative. (So Km increases)
Lineweaver- Burke: If Vmax decreases, what happens to the y-int?
It increases.
Y-int = 1 / Vmax
Lineweaver-Burke: As Km increases, what happens to the X-int?
It increases.
X int = 1 / -Km
Lineweaver-Burke: What happens to the slope of the line when an uninhibited rxn gets a competitive inhibitor?
It increases.
Competitive inhibitors Cross Competitively. The Y-int stays the same (bc the Vmax stays the same), but the X-int increases (bc the Km increases)
Lineweaver-Burke: What happens to the slope of the line when an uninhibited rxn gets an non-competitive inhibitor?
It increases
The X-int stays the same (bc the Km stays the same) but the Y-int increases (bc the Vmax decreases)
What happens to Km with a competitive inhibitor?
It increases. (You need more substrate to get to 1/2 Vmax)
What happens to Vmax with a competitive inhibitor
It stays the same. The reaction can still go at the same max rate, you will just need more substrate (a higher Km) to get there.
With a competitive inhibitor, how does affinity change?
Affinity decreases. When Km goes up (as with competitive inhibition), affinity goes down.
With a competitive inhibitor, how does potency change?
Decreased potency.
T/F Competitive inhibitors can be overcome by increased substrate.
True
What effect do non-competitive inhibitors have on Vmax?
Vmax is decreased. The rxn can’t get to the same max rate, no matter how much substrate there is (bc the non-comp inhibitor doesn’t bind to the active site)
What effect does a non-comp inhibitor have on Km?
No change in Km. The amount of substrate needed to get to 1/2 Vmax is the same, it’s only that the Vmax itself is smaller.
How is non-competitive inhibition related to efficacy?
Non-competitive inhibitors decrease efficacy.
T/F Km is a measure of affinity
True.
Note: As Km is decreased, there is MORE affinity. (You don’t need as much substrate to get to Vmax)
What is the slope of the Lineweaver-Burke plot?
Km / Vmax
Slope = y / x Y = 1 / Vmax X = 1 / -Km
Equation for Vol of Distribution
Vd = amt of drug given IV / plasma conc of drug
Equation for Clearance
CL = 0.7 x Vd / t1/2
or CL = K x Vd where elim constant K = 0.7 / t1/2
Equation for loading dose
LD = Cp x Vd
Cp, or Css - it’s the plasma conc, or the desired conc at steady state
Equation for maintenance dose
MD = Cp x CL
How does renal dz affect LD and MD?
Renal dz = decreased CL.
LD (Cp x Vd) is unchanged, bc not affected by CL.
MD (Cp x CL) will decrease with decreased clearance.
What units are used to measure Vd
Liters (or any unit of volume)
If given L/kg, determine Vd by factoring in the weight of the pt in kg.
Half life
The amt of time needed for a drug conc to reach 50% when infused at a constant rate. Conversely, the time needed for 50% of a drug to be eliminated.
How long does it take a drug to reach 94% of steady state if constantly infused?
4 half lives
concentrations and # of half lives needed to get there
50% one half life
75% two
87.5% three
94% four
It takes between four and five half lives for a drug to reach steady state (or to be eliminated completely)
Bioavailability
Amt of drug that actually reaches blood after metabolism (1st pass in liver, etc). If given IV, F = 1 (100%). If given orally, usu not. If given F other than 100%, just divide the equations by F. (e.g. LD = Cp x Vd / F)
Zero-order elimination
Rate of elim is CONSTANT, regardless of amount. Conc decreases linearly with time. A constant amount is eliminated.
Drugs w/ Zero-order elim
PEA:
Phenytoin (anti-epileptic)
Ethanol
Aspirin
First-order elimination
Rate of elim is PROPORTIONAL to the drug conc- a constant fraction is eliminated. Cp decreases exponentially with time.
If a constant amount of drug is eliminated, what order elim is this?
Zero-order
If a constant fraction of drug is eliminated, what order elim is this?
First-order
Urine pH: why do ionized species get trapped in urine?
Bc ions can’t easily cross the plasma mbr. (Uncharged molecules do cross)
Are weak acids charged or uncharged?
Uncharged. Weak acid = HA
For acids, bases:
Is the protonated form charged?
Acids: No. Protonated form = HA
Bases: Yes. Protonated form = BH+
For acids, bases:
Is the unprotenated form charged?
Acids: Yes. Unprotonated = H+ and A-
Bases: No. Unprotonated = H+ and B
Are weak bases charged or uncharged?
Charged. Weak base = BH+
Uncharged molecules can cross the plasma membrane. Which form of acid and which form of base will cross the membrane?
Uncharged acid: Protenated form HA
Uncharged base: Dissociated form H+ and B
What is pKa
Acid dissociation constant. The pH at which protenated = unprotenated
If the pH is decreased below the pKa, what happens?
Low pH = acidic. So EVERYTHING will be in protenated form. For acids, this means they will be HA (uncharged), and for bases, it means they will be BH+ (charged). So bases will be trapped since they are charged.
If the pH is increased above the pKa, what happens?
High pH = basic. So EVERYTHING will be dissociated. For acids, this means they will be H+ and A- (charged), and for bases, it means they will be H+ and B (uncharged). Thus, acids will be trapped since they are charged.
Rx for aspirin overdose
Aspirin is a weak acid, so give NaHCO3 to make the urine basic and trap the acidic drug in basic urine.
Rx for amphetamine overdose
Amphetamines are basic, so give NHCl4 to make the urine acidic- trap the basic drug in acidic urine.
Drug metabolism: by what processes do Phase I rxns usually occur?
Reduction
Oxidation
Hydrolysis
Usually uses a Cytochrome P450 enz.
What kind of metabolites are produced in Phase I metabolism?
Slightly polar, water-soluble metabolites; they are often still active.
T/F Phase I and Phase II drug metabolism occur in a specific order.
False. They are non-sequential. You can have Phs II before Phs I or Phs I before Phs II.
T/F Phase I and II metabolism can both activate or inactivate drugs.
True.
Drug metabolism: by what processes do Phase II rxns generally occur?
GAS: Glucuronidation Acetylation Sulfation Usually occurs using conjugation.
What kind of metabolites are produced in Phase II rxns?
Very polar, inactive metabolites. Often, these metabolites are renally excreted.
Which phase of drug metabolism do eldery pts usually lose first?
Phase I.
Elderly pts have GAS (GAS = Phase II processes, Glucuronidation, Acetylation, Sulfation) They have GAS, so they don’t have Phase I.
Where does Phase I and II drug metabolism take place?
Mostly in the liver
Also in the kidney
What is efficacy?
The maximum effect a drug can produce.
Vmax
What is potency?
The amount of drug needed.
Km
What determines efficacy?
The Vmax
What determines potency?
The Km
Note: Higher Km = LESS potency
What happens to efficacy if the Vmax is lowered?
The efficacy is lowered.
In the case of a non-competitive inhibitor, Vmax would be lowered, so the efficacy would also be lowered.
What happens to potency is the Km is increased?
The potency is reduced.
In the case of a competitive inhibitor, Km is increased, which means potency is lowered.
What is the difference b/t a competitive and non-competitive inhibitor?
Competitive competes for the same active site. Non-comp binds elsewhere and changes the confirmation of the active site so that the enz can’t bind.
Non-comp = Irreversible inhibitor. (same thing)
What effect does a competitive inhibitor have on potency?
Competitive inhibitors increase Km. An increase in Km means that potency is lowered.
What effect do irreversible inhibitors have on efficacy?
An irreversible inhibitor (aka a non-competitive inhibitor) decreases the Vmax. Decreased Vmax means decreased efficacy.
What effect does a partial agonist have on Vmax?
It always lowers Vmax (and thus always lowers efficacy.)
What effect does a partial agonist have on Km?
It depends on the agonist. It can either increase Km (so decrease potency), or it can decrease Km (so increase potency). Potency is an independent variable.
What is the therapeutic index?
TI = LD50 / ED50
The dose that kills 50% / the dose that is effective (treats) 50%
Is it better to have a high or low therapeutic index?
Higher = safer drug
How can you get a high TI?
High TI when LD50 is high (so the dose it takes to kill 50% is really big), or when ED50 is low (so the amount needed to treat is small)
Which drugs have a low TI (meaning they are unsafe and need to be monitored)?
Phenobarbital (for seizures)
Lithium (bipolar)
Digoxin
Coumedin/Warfarin
What drugs inhibit Cytochrome P450?
PICK EGS: Protease inhibitors Isoniazid Cimetidine Ketoconazole
Erythromycin
Grapefruit juice
Sulfonamides
What are the characteristics of a good clinical trial?
Randomized
Controlled
Double-blinded
What is a Phase I clinical trial?
“Is it safe?”
Testing healthy volunteers
Test for safety, toxicity, pharmacokinetics
What is a Phase II clinical trial?
“Does it work?”
Testing pts with dz
Efficacy, dosage, side effects
What is a Phase III clinical trial?
“Does it work better?”
Testing pts w dz
Compare to existing Rx/Standard of Care
What is a Phase IV clinical trail?
Post-market surveillance
How long does the process of Phase I to III take for clinical trials?
5-10 years
What systems are affected by autonomic drugs?
The SNS and PNS systems. The drugs can: Activate PNS Inactivate PNS (NOT the same as SNS) Activate specific receptors of SNS Inactivate specific receptors of SNS
What is a cholinomimetic?
Stimulates the PNS Ach Muscarinic (?M) receptor
Cholinomemetics: How do direct cholinergic agonists work?
They bind to the PNS Muscarinic Ach receptor and stimulate it.
Cholinomimetics: How do indirect agonists work?
They inhibit the AChE, which means that the ACh is degraded at a slower rate.
Aka anti-acetylchoinesterases
What does AChE do?
Breaks down ACh into choline and acetate (thus inactivating it)
-chol is what drugs?
Cholinergic agonists (at the PNS muscarinic receptor) eg Bethanechol, Carbachol
Bethanechol
Cholinomimetic - Direct Agonist of M ACh receptor.
Used for post-op ileus, neurogenic ileus, urinary retention
(makes you more leaky)
Carbachol
Cholinomimetic - Direct Agonist of M ACh receptor.
Used for glaucoma, pupillary contraction, and rls of interocular prs (so basically, glaucoma)
What is glaucoma?
Elevated interocular pressure
Pilocarpine
Cholinomimetic - Direct Agonist of M ACh receptor.
Used for glaucomic emergencies. Also stim’s sweat, tears, saliva (makes you more leaky)
Contracts ciliary musc of eye for open angle glauc, contracts pupillary spincter for narrow angle glauc.
Resistant to AChE
Methacholine
Cholinomimetic - Direct Agonist of M ACh receptor.
Used as a challenge test for asthma- causes bronchoconstriction. (so get asthma symptoms when you take it)
Neostigmine
Cholinomimetic - Indirect Agonist of M ACh receptor. (Anti-AChE)
Used for post-op ileus, neurogenic ileus, urinary retention, MysGrav, reversal of NMJ blockade post-op.
NEO = NO CNS penetration
-stigmine
AChE inhibitor (Indirect agonist)
What is Myasthenia Gravis?
Ab to the ACh receptor. Px with ptosis (droopy eyelid) or diplopia (dbl vision) which worsens throughout day.
What are the paralyzing agents (anesthesia)?
Succanylcholine
Rocuronium
Vecuronium
These cause NMJ blockade. Use neostigmine to reverse their effect.
Pyridostigmine
Cholinomimetic - Indirect Agonist of M ACh receptor. (Anti-AChE)
Used for MysGrav (long-term)
No CNS penetration.
Gets “rid” of MysGrav
Edrophonium aka Tensilon
Cholinomimetic - Indirect Agonist of M ACh receptor. (Anti-AChE)
Dx MysGrav, v short acting- if sympt of MysGrav go away when you give it, pt has MysGrav
Myasthenia Gravis is related to problems with which organ?
Thymus
50% of MG pts have thymic hyperplasia
20% have thymic atrophy
15% have thymoma
What is a myasthenic crisis?
rapidly progressing weakness, esp in respi muscles (diaphragm)
Rx for Myasthenia Gravis?
AChE inhibitors
Corticosteroids
Thymectomy
Plasmapheresis (wash out Ab)
Physostigmine
Cholinomimetic - Indirect Agonist of M ACh receptor. (Anti-AChE)
Phys Phyxes (fixes) atropine OD.
Also used for Glaucoma
Crosses BBB
Echothiophate
Cholinomimetic - Indirect Agonist of M ACh receptor. (Anti-AChE)
For Glaucoma
Cholinesterase inhibitor poisoning (excess PNS)
DUMBBELSS: Diarrhea Urination Miosis Bronchospasm Bradycardia Excitiation of CNS and smth musc Lacrimation Sweating Salivation Abd cramping
What causes cholinesterase inhibitor poisoning (excess PNS)?
Organophoshates = Insecticides = Parathion
Usu in farmers/gardeners
What is Parathion?
Insecticide, causes DUMBBELSS symptoms
How do you treat excess PNS / cholinesterase inhibitor poisoning /organophosphates / parathion?
Pralidoxime (regenerates AChE) and atropine
What are the anti-AChE durgs used in Alzheimer’s? (Alz = decreased ACh)
Donepezil
Galantamine
Rivastigmine
“trop” drugs
Muscarinic antagonist aka anit-cholinergic
What happens if you inhibit PNS activity?
Hot as a hare Dry as a bone Red as a beet Blind as a bat Mad as a hatter Bloated as a toad Incrsd body temp, dry/flushed skin, cycloplegia, delirium/disorientation, constipation & urinary retention
What receptors do the anti-cholinergics inhibit?
Muscarinic receptors.
Aka muscarinic antagonists
What are the muscarinic antagonists? (list)
Atropine, homatropine, tropicamide Benztropine Scopolamine Ipratroprium Oxybutynin Glycopyrrolate Methscopolamine, propantheline
What anti cholinergics (muscarinic antagonists) are used to treat urge-type incontinence?
Oxybutynin
Tolterodine
Darifenacin and solifenacin
Trospium
What does atropine do?
Muscarinic antagonist (anti-cholinergic) Eye: increases pupil dilation, cycloplegia Airway: decreased secretions Stomach: decresased acid secretion Gut: Decreased motility Bladder: decreased urgency in cystitis
Side effects of atropine?
Increased body temp, rapid pulse, dry mouth, dry flushed skin, cycloplegia, constipation, urinary retention, delirium/disorientation.
What is cycloplegia?
Paralysis of the ciliary muscles of the eye, causing lack of accomodation and therefore blurry vision
Contraindications for atropine
Elderly pts Glaucoma BPH or any urinary retention GI obstruction/ileus Pts w dementia, delirium Infants w fever (can cause hypothermia)
Atropine, homatropine, tropicamide
Muscarinic antagonists, used to produce mydriasis (dilation) and cycloplegia in eyes
Benztropine
Muscarinic antagonist, used in CNS for Parkinson’s
Park my Benz
Scoploamine
Muscarinic antagonist, used for motion sickness (ear patch) or in end of life care
Ipratroprium
Muscarinic antagonist, used for Asthma, COPD
I Pray I can breathe soon!
Oxybutinin
Muscarinic antagonist used for Genitourinary sympt - reduces urgency in mild cystitis, reduces bladder spasm
Glycopyrrolate
Muscarinic antagonist, genitourinary and also used to decrease airway secretions
Methscopolamine, propantheline
Muscarinic antagonist- GI, used for peptic ulcer treatment
What happens to the level of ACh in:
Parkinson’s?
Alzheimer’s?
Huntington’s?
Parkinson’s = Increased ACh
Alz and Huntington’s = Decreased ACh
Categorize: Physostigmine
-stigmine = Cholinomimetic: Indirect agonist (Anti-AChE)
Categorize: Pilocarpine
Cholinomimetic: Direct muscarinic agonist
Categorize: Echothiophate
Cholinomimetic: Indirect agonist (Anti-AChE)
Categorize: Oxybutinin
Muscarinic antagonist (urge incontinence)
Categorize: Atropine
trop = Muscarinic antagonist
Categorize: Donepezil
Cholinomimetic: Indirect agonist (Anti-AChE) for Alzheimer’s
Categorize: Pralidoxime
AChE regenerator (So inhibits ACh) Use after organophosphate poisoning.
Categorize: Bethanechol
-chol = Cholinomimetic: Direct muscarinic agonist
Categorize: Neostigmine
-stigmine = Cholinomimetic: Indirect agonist (Anti-AchE) for Alz
Categorize: Darifenacin
Muscarinic antagonist (urge incontinence)
Categorize: Ipratroprium
trop = Muscarinic antagonist
Categorize: Tropicamide
trop = Muscarinic antagonist
Categorize: Benztropine
trop = Muscarinic antagonist
Categorize: Scopolamine
Muscarinic antagonist
Categorize: Edrophonium
Cholinomimetic: Indirect agonist (Anti-AchE). Tensilon test for MG.
Categorize: Tolterodine
Muscarinic antagonist (urge incontinence)
Categorize: Trospium
Muscarinic antagonist (urge incontinence)
Categorize: Rivastigmine
-stigmine = Cholinomimetic: Indirect agonist (Anti-AchE) for Alz
Categorize: Homatropine
trop = Muscarinic antagonist
Categorize: Pyridogstigmine
-stigmine = Cholinomimetic: Indirect agonist (Anti-AChE)
Categorize: Carbachol
-chol = Cholinomimetic: Direct muscarinic agonist
