Lecture 5 Flashcards
What protein do acidic drugs bind to?
albumin
What protein do basic drugs bind to?
Alpha1-acid
Only what type of drug can act on targets and elicit a biologic response?
Unbound
What is involved in the 2nd phase of drug metabolism?
Conjugation with a 2nd endogenous substrate
How is valproic acid metabolized?
Hepatic via glucuronidation (conjugation)
What drug is the only P450 inhibitor in the antiepileptic class?
Valproic acid
Is the relationship b/w dose and total valproate concentration linear or non-linear?
Non-linear
Concentration doesn’t increase proportionally with the dose but increases to a lesser extent due to plasma binding
When you use carbamazepine with what other drug will you have a higher free fraction of carbamazepine?
Valproate sodium
What is the one active metabolite that eliminates carbamazepine?
carbamazepine 10,11 epoxide
What is carbamazepine primarily metabolized by?
CYP3A4
Carbamazepine has _____ induction; it induces it’s own metabolism.
auto
What happens to the half-life of carbamazepine after about 3-5 weeks?
Drops because it is inducing its own metabolism
What is warfarin’s onset of action?
24-72 hours
When is Warfarin’s peak effect?
5-7 days (INR increases in 36-72 hours)
What is Warfarin metabolized by?
CYP2C9
If you are heterozygous for reduced function of CYP2C9 what happens with warfarin metabolism?
Warfarin doesn’t metabolize well
Where is digoxin absorbed?
Small intestine (via passive non-saturable diffusion)
Digoxin distributes very nicely to where?
The heart (serum concentration of 70:1)
How long does the distribution phase of digoxin last?
6-8 hours
Digoxin has a very _____ therapeutic index.
Narrow (0.5-0.8 ng/mL)
When is digoxin toxic?
> 2ng/ mL
Patients with variation in ________ have a decreased rate of metabolism of succinylcholine resulting in prolonged paralysis after drug exposure (anesthesia).
BChE (butyrlcholinesterase)
A slow acetylator phenotype of N-acetyltransferase 2 (NAT2) is associated with drug ______.
toxicities
What drugs does NAT2 catlyze the acetylation of?
Isoniazid, Hydroalazine, Procainamide
What are some meds that are metabolized by CYP2D6?
Metoprolol
Haloperidol
Codeine
Fluoxetine
What are the three types of metabolizers for CYP2D6?
Poor (caucasians)
Extensive
Ultra-rapid (Ethiopians, Spaniards)
If a ultra-rapid CYP2D6 metabolizer gets codeine what will it be metabolized quickly into?
morphine –> Heroin
Normal codeine can result in OD
Codeine is relatively ineffective in ______ CYP2D6 metabolizers.
Poor
Thiopurine S-Methyltransferase (TPMT) catalyzes the S-Methylation of thiopurine drugs such as __________ and ___________
mercaptopurine
Azathioprine immunosuppressant agents
What does TPMT*3A result in?
Decrease in tissue level of TPMT
Patient’s homozygous for TPMT*3A are at a greatly increased risk for ______________ when treated with a standard dose of thiopurine drugs.
life threatening myelosuppression
What is a drug target for the asthma drug Zileuton?
5-lipoxygenase
What does ZIleuton do?
Decreases airway inflammation by inhibiting 5-lipoxygenase
5-lipoxygenase is encoded by what gene? What is the most common ALOX5 repeat variations?
ALOX5; 5 repeats is most common
Only people with at lest ???? copy(ies) of the five-repeat allele respond to zileuton therapy?
one copy
What is warfarin’s target?
Vitamin K epoxide reductase
What gene encodes Vitamin K epoxide reductase?
VKORC1 (vitamin K epoxide reductase complex 1)
What type of warfarin is metabolized predominately by CYP2C9?
S-Warfarin
What seems to result from interactions between the medication and a unique aspect of the physiology of the individual patient?
Idiosyncratic rxns
HLA-B*5701 is associated with ________ induced hypersensitivity.
Abacavir (reverse-transcriptase inhibitor)
these are cardiovascular afferents. Respond to changes in BP. Found in aortic arch and carotid sinus.
Cardiovascular afferents
Nociceptive nerusons follow _______ nerves.
Sympathetic
In the ANS, which is myelinated- preganglionic neuron or postganglion neuron?
Preganglionic neuron
This innervates the GI tract, pancreas and gallbaldder.
Enteric portion of the autonomic nervous system
The preganglionic neuron neuron to where doesn’t have a postgnaglionic neuron.
To adrenal medulla
What is released when the preganglionic neuron stimulates the adrenal medulla.
Epi
This type of chemical signaling is rapidly destroyed and doesn’t enter the blood.
Local mediators
This type of chemical signaling is by endocrine cells into the blood. It exerts effects on targets throughout the body.
Hormones
What are the 5 key steps of neurotransmission?
Synthesis of neurotransmitter Storage of neurotransmitter Release of neurotransmitter Recognition of neurotransmitter Metabolism of neurotransmitter
The parasympathetic system synthesizes and uses what NT?
Acetylcholine (ach)- is call cholinergic
What receptors does Ach interact with?
Muscarinic
Nicotinic
What NT does the sympathetic system use?
Norepinephrine (NE) is called adrenergic
What receptors does norepienprhine interact with?
alpha andrenergic and beta adrenergic receptors
Arterioles, veins, and sweat glands have a predominant what tone (ANS)?
Sympathetic
Sweat glands have a sympathetic tone but are mediated by what?
Muscarinic mechanism (type of cholinergic receptor)
Cholinergic Pharmacology is centered on what NT?
Ach
WHat does cholinergic pharmacology involve?
NMJ
ANS
CNS
What is the precursor of Ach?
choline
What transports choline from the plasma into the nerve cell?
Na+ dependent carrier
What inhibits choline transport?
Hemicholinium
Choline + Acetyl CoA in the presence of what leads to the production of Ach?
Choline acetyltransferase (CAT)
Ach is trasnported into synaptic vesicles via what?
Proton antiporter (protected from degradation)
What causes the release of Ach?
Action potentials of Calcium influx –> release of vesicles through exocytosis
What blocks the release of Ach?
Botulinum toxin
What exogenous substance causes the release of Ach?
Spider venom
What enzyme is present in cholinergic synapses and rapidly converts Ach.
Acetylcholinesterase (AChE)
What does AchE convert Ach into?
choline and acetic acid
What is an enzyme that is less specific for Ach and is found throughout the body.
BuChE (butylcholinesterase)
M1 receptors are found where?
Neural: CNS, PNS, gastric parietal cells
M2 receptors are found where?
Cardiac, bladder, lung
M3 receptors are found where?
Glandular: exocrine glands, smooth muscles, bladder, and also eye
What M receptors are coupled to G-proteins and responsible for Stimulation of phospholipase C
M1, M3, and M5
What receptors are coupled to G-proteins responsible for adenyl cyclase inhibition and K+ channel activation?
M2 and M4
What nicotinic receptors are at autonomic ganglia?
N2 or Nn
What nicotinic receptors are at NMJ- somatic motor end plates?
N1 and Nm
Where are binding sites for Ach?
Preganglionic synpases of both sympathetic and parasympathetic ganglia (Nm, M1, M2, M3)
parasympathetic postganglonic neuroeffector junctions
All somatic end-plates of skeletal muscle (nM)
What muscarinic receptor decreases heart rate?
M2
What muscarinic receptor does all the other function except decrease HR ?
M3
Activation of muscarinic receptor of the eye leads to what?
Contraction of spinchter muscle of iris and ciliary muscle.
What does activation of the muscarinic receptors of the GI lead to?
Increased tone, motility and secretion.
What response does activation of muscarinic receptors of the secretory glands lead to?
Increased secretion
What does activation of muscarinic receptors of the urinary bladder lead to?
Relaxation of the sphincter
What are two direct-acting receptor agonists of cholinomimetic drugs?
Choline esters
Alkaloids
What cholinergic agonists are hydrolyzed by AchE?
Ach
Methacholine
What cholinergic agonists aren’t hydrolyzed by AchE?
Carbachol
Bethanechol
Muscarine
Pilocarpine
What cholinergic agonists are specific only for muscarinic recpetors?
Bethanechol
Muscarine
Pilocarpine
What cholinergic agonists have specificity for both muscarinic and nicotinic receptors?
Ach
Carbachol
Methacholine
Is methacholine more specific for mAChR or nAChR?
mAChR
Does carbachol have more receptor specificity for mAChR or nAChR?
nAChR
Which choline ester has the largest pharmacological action on the CV system?
Metacholine
The stimulation of ____ receptor on endothelial cells releases endothelium-derived relaxing factor _______ to produce dilation of all vascular bed?
Stimulation of M3 receptor
Relaxing factor- nitric oxide
Coronary vasodilation may be elicited by direct electric stimulation of what nerve?
Vagus
Cholinergic stimulation affect cardiac function directly by inhibiting effects of what?
Adrenergic activation
cholinergic stimulation leads to a decrease in the force of what?
Cardiac contraction (negative inotropic effect)
Cholinergic stimulation leads to a decrease in the rate of conduction in specialized tissues where?
SA and AV nodes (negative chronotropic effect)
What receptors does bethanechol act at?
M1, M2, M3
What sites does bethanechol work at?
smooth musculature of the bladder, and GI
Increases intestinal motility and tone and stimulates detrusor muscles of the bladder
What are some therapeutic applications of bethanechol?
Stimulate the atonic bladder postpartum or postoperative urinary retention
Treat Postoperative abdominal distension and gastric atony and retention
What are some ADR of bethanechol?
sweating, salvation, flushing, HPOTN, N/D, abdominal pain, bronchospasm
What drug is used as an alteranative to pilocarpine to promote salivaiton in Sjogren syndrome?
Bethanechol
How long is the DOA of carbachol (carbamylcholine)?
As long as 1 hour
What receptors does carbachol activate?
M1, M2, M3, weak nicotinic agonist
Since carbachol is a weak nicotinic agonist what will it don on the CV and GI systems?
May 1st stimulate then depress
Carbachol may also cause the release of ______ from the ________ by its nicotinic actions.
Epinephrine from the adrenal medulla
What is the therapeutic applications of carbachol?
Rarely used
Sometimes used as miotic for glaucoma
What are the ADRs of carbachol ?
Little or no side effects when used in the eye.
What receptors does Methacholine activate?
M1, M2, M3
What is methacholine used for?
Diagnostic for bronchial hyperreactivity and asthmatic conditions
_______ acts almost eclusively at muscarinic receptor sites
Muscarine
Arecoline acts at what type of receptor?
Nicotine receptors
_________ has a dominant muscarinic action, but causes anomalous CV responses, and sweat glands particularly sensitive to drug
Pilocarpine
What receptors does pilocarpine act at?
M1, M2, M3
This drug is an alkaloid and a tertiary amine. It is less potente than other cholinomemtic drugs and is hydrolyzed by AchE?
Pilocarpine
What is the therapeutic use of pilocarpine?
Emergency lowering of intraocular pressure in both wide and narrow angle glaucoma.
What are some ADRs of pilocarpine?
CNS effects
Profuse sweating and salivation
What is the antidote of Ach and its agonists analogs?
Atropine
What are the only ways Ach and its agonists should be administered?
Oral of subcutaneous routes
Why is asthma contraindicated with Ach and its agonists?
Bronchoconstrictor action coudl precipitate asthmatic attack
Why is hyperthyroidism contraindicated for Ach and its agonists?
May develop a-fib
Why is coronary insufficiency contraindicated for Ach and its agonists?
hypotension induced by these agents can severely reduce coronary blood flow
Why is peptic ulcer disease contraindicated for Ach and its agonists?
Gastric acid secretion producted by choline esters can aggravate symptoms
What are some undesirable effects of Ach and its agonsits analogs?
Flushing Sweating Abdominal cramps Sensation of tightness in urinary bladder Difficulty in visual accomodation headache salivation
