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132 Cards in this Set
- Front
- Back
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signaling chemicals coming from a cell act on their own receptor
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Autocrine
ex: norepinephrine on presynaptic receptor cytokines acting on lymphocytes |
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signaling chemicals that influence the function of neighboring cells and cells present in the close vicinity
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Paracrine
ex: Histamine and Seratonin |
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signalingchemicals that are carreid to a distant site and act on discrete organs
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Endocrine
ex: insulin, estrogen, testosterone |
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signaling chemicals that are present in gap junctions and activate post-synaptic neurons or interacting cells
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Neurotranmission
ex: acetylcholine and norepinephrine |
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direct communication through interaction of signaling molecules anchored on the cell membranes
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Cell-Cell Communication
ex: Tcell-B cell interaction HIV-T cell interaction |
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degrades cAMP to cGMP
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PDE
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Extracellular Receptors
vs Intracellular Receptors vs Plasma membrane bound receptors |
E- TBG, ANP-C receptor
I- Estrogen, Testosterone, Thyroxine PB-Peripheral, Integral, Transmembrane |
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probability of a drug molecule binding to free drug receptors at any given instant; drugs tenacity or persistant ability with which the drug binds to the specific receptors
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Affintiy
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1. Define intrinsic activity
2. The intrinsic activity is normally a property of the ______ not the ______ |
1. inherent property of the drug to impart biological signals on the receptor molecules which result in biological response
2. The intrinsic activity is normally a property of the drug not the tissue |
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Agonist
Antagonist Partial Agonist |
Agonist- 100% affinity; 100% Intrinsic activity
Antagonist- 100% affinity; 0% Intrinsic activity Partial Agonist- 100% affinity; 50% Intrinsic activity |
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Phenylethylamine
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only binds alpha 1
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Phenylephrine
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only binds alpha 1, but with more affinity than Phenylethylamine
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Norepinephrine
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binds alpha 1, alpha 2, beta 1, beta 2
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Epinephrine
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binds alpha 1, alpha 2, beta 1, beta 2; but binds mostly to beta 1 and beta 2
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Isoproterenol
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binds only beta 1 and beta 2
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metaproterenol
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binds only beta 2
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Terbutaline
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binds only beta 2
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Room Keys
Submaster Keys Master Keys |
Room Keys: Terbutaline, Phenylethylamine, Phenylephrine, Metaprotenol
Submaster Keys: Isoproterenol Master Keys: Norepinephrine Epinephrine |
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alpha 1
alpha 2 beta 1 beta 2 |
alpha 1: activates PLC to produce IP3 and DAG from PIP2 forming Calcium for smooth muscle contraction
alpha 2: lowers cAMP beta 1: increases cAMP beta 2: increases cAMP |
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Affects of Epinephrine on:
Heart Skin/Hair Eyes Arteries Veins Lungs |
Affects of Epinephrine on:
Heart- beta 1 increase HR Skin/Hair: alpha 1goosebumps Eyes: alpha 1dilates pupil Arteries: beta 2 dilates/ aphla 1 constricts Veins: alpha 2 constricts raising BP Lungs: beta 2 dilate bronchioles |
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Alpha 1 Agonists and Antagonists
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Agonists:
NE EP Phenylephrine Antagonists: Phentolamine Tolazoline Prozosin* *Selective |
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Alpha 2 Agonists and Antagonists
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Agonists:
NE EP Clonidine* Antagonists: Phentolamine Tolazoline Yohimbine * |
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Beta 1 Agonists and Antagonists
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Agonists:
Isoproterenol EP NE Dobutamine Antagonists: Propanolol Timolol Metoprolol* Atenolol* |
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Beta 2 Agonists and Antagonists
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Agonists:
Isoproterenol EP NE Terbutaline Metaproterenol Antagonists: Propanolol Timolol Butoxamine |
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Reflex Bradycardia
vs Reflex Tachycardia |
RB- increased BP causes decrease in HR
RT-low BP causes increased HR |
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What are the uses of these Agonists and receptors involved?
Phenylephrine Clonidine Isoproterenol Terbutaline |
Phenylephrine- alpha 1- to produce mydriasis also as a nasal decongestant
Clonidine- alpha 2- acts centrally and decreases norephinephrine release Isoproterenol- Beta 1- produce tachycardia Terbutaline-Beta 2- produce acute relief to asthma |
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What are the uses of these Antagonists and receptors involved?
Prazosin Yohimbine Propranolo |
Prazosin- alpha 1- treatment of hypertension
Yohimbine- alpha 2- blocks norephinephrine uptake at the pre-synaptic site and increases the neurotransmitter level at the synaptic gap Propranolo- To slow down the heart in patients with tachycardia or angina and recude oxygen requirement that might lead to myocardial infarction |
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Location and Activating Factors for:
Auto receptors |
alpha 2 receptors on presynaptic neurons in the adrenergic pathway
inhibit the release of NE for feedback mechanism |
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Location and Activating Factors for:
Stimulatory Heteroceptors |
Postsynaptic neuron at the neuroeffector junction
Angiotensin II receptors would augment the effect mediated by NE through adrenergic receptor |
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Location and Activating Factors for:
Inhibitory Heteroreceptor |
Postsynaptic neurons at the neuroeffector junction
Nuero Peptide (NPY) receptor would reduce the effect mediated by NE through adrenergic receptors |
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Location and Activating Factors for:
Baroreceptors |
in the carotid sinuses and aortic arch
activated by vascular barometric pressure |
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Location and Activating Factors for:
Chemoreceptors |
Located in Chemoreceptor Trigger Zone (CTZ)
activated by a variety of anticancer and other drugs |
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Location and Activating Factors for:
Auditory receptor Visual receptor Heat Cold sensing receptors |
Auditory receptor- ear and sound
Visual receptor- eye and light Heat Cold sensing receptors- skin and temperature |
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Muscarinic actions of Acetylcholine
M1 M2 M3 |
M1- increases PLC -> IP3 and DAG
M2- decreases AC loweres cAMP M3- increases PLC-> IP3 and DAG |
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Nicotinic actions of Acetylcholine
Nn Nm |
Nn- opens Na and K channels
Nm- contracts muscles |
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Effects of Ach on:
Lungs Salivary Glands Penis Heart GI tract Bladder Lacrimal glands Skin Eyes Blood vessel |
Lungs- bronchiol constriction
Salivary Glands- drolling Penis-erection Heart- decrease HR GI tract- M1 myenteric plexus M3 for rest of intestine Bladder- constriction Lacrimal glands- tears Skin- goosebumps and sweating Eyes- constriction Blood vessel- dilation and constriction depending on exposure of endothelial layer |
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compounds that can produce pharmacological and physiological effects similar to acetylcholine by binding to appropriate receptors
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Cholinomimetics
two categories 1. Sympathetic 2. Parasympathetic |
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Diphenozylate
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Heteroreceptor that blocks Ach release
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How to fully dilate the eyes
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M3 antagonist- Atropine
alpha 1 agonist- Phenylephrine |
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Antimuscarinic effects:
Eye GI Tract Bronchiolar Smooth muscle Brain Urinary Bladder Heart Salivary Gland Sweat Gland |
Antimuscarinic effects:
Eye- mydriasis (dilation) for eye examinations GI Tract- decreases muscl actions and decreased secretions for spams, hypermotility, preoperative medication Bronchiolar Smooth muscle- decreased muscle actions and decreads secretions for asthma and surgeries Brain- Blockade of CNS receptors for Parkinson's disease and motion sickness Urinary Bladder- Relaxation of Detrusor muscle and constriction of sphincter for urinary incontinence Heart- Tachycardia (^HR) for carotid sinus syncope Salivary Gland- decreased saliva secretion for excessive salivary secretion Sweat Gland- decreased thermoregulatory sweating usually a side effect; dry skin |
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M1 Agonists
M1 Antagonist |
Agonist:
Acetelcholine Muscarine Carbachol Antagonist: Atropine Pirenzepine |
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M2 Agonist
M2 Antagonist |
M2 Agonist:
Acetylcholine Muscarine Carbachol M2 Antagonist: Atropine |
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M3 Agonist
M3 Antagonist |
M3 Agonist:
Acetylcholine Muscarine M3 Antagonist: Atropine |
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Nn agonists
Nn antagonist |
Nn agonists:
Acetylcholine Nicotine Nn antagonist: Xexamethonium Mecamylamine |
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Nm agonist
Nm antagonist |
Nm agonist:
Acetylchonline Nicotine Nm antagonist: Tubercurarine Succinyicholine |
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inhibitor can combine with the free enzyme in such a way that it competes with the normal substrate for binding at the same active site
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Competitive inhibition
reversible |
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enzyme-substrate inhibitor complex can not undergo further reaction to convert the bound substrate to normal product
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Uncompetitive Inhibition
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combines with either free enzymes or the enzyme-substrate complex, and consequently interfere with the action of both
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Noncompetitive inhibition
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the activity of the enzyme is regulated by reersible binding of an effector molecule to a site on the enzyme other than the actve site
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Allosteric Regulation
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regulation of the substrate binding on one subunit by binding of an effector molecule to a site on a different subunit
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Cooperativity
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Negative Cooperativity
Positive Cooperativity Give examples |
Neg- opposite actions
ex: B- Carboline closes Cl- ion channels Pos- same action ex: GABA and Benzodiazepines open the Cl- ion channels/ depolarization |
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Feedback inhibition
2 examples |
enzyme that catalyzes 1st reaction of biosynthetic pathway is inhibited by final product
1. Threonin inhibits Isoleucine 2. NE binds to alpha 2 receptor to stop NE production |
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Acetylcholinesterace (AChE)
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breaks down acetylcholine into acetic acid and choline
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Butyrylcholinesterase (BuChE)
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hydrolyzes AChE and is present in the intestine, plasma, skin, and various glial cells but only to a limited extent in neuronal cells of the CNS and PNS
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Ture or False
AChE hydrolyzes Ach at greater velocity than cholineesters with acyl groups larger than acetate |
True
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Reversible anticholinesterases
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Alcohols: Edrophonium (binds only anionic site)
Carbamate: Neostigmine and Physostigmine (bind anionic and esteractic site) |
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amino acids found in active site for Acytelcholinesterase
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Histamine
Glutamate Serine Alanine Tyrosine Threonine |
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Which Active Site?
COO- his with glu-ser-ala |
COO- anionic site
his- with glu-ser-ala- esteractic site |
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What is aging of bond
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Aging of bond is the strengthening of the oxygen and phosphorous bond of an organophosphate when water replaces one of the OR groups
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Drugs with Oxime groups
what are they good for? |
*Pralidoxine (PAM)
Diacetylmonoxine (DAM) Hydroxylamine (HAM) can activate AchE by breaking P-O bond of oranophosphate with esteractic site; reactivates AchE |
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Irreversibly inhibits AchE
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1. DIPF
2. Parathion 3. Malathion ex. nerve gas and organophosphates |
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Treatment after exposure to nerve gas (Ach build up- AchE blocked)
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1. Atropine (antagonist for Ach production)
2. Pyridostigmine or Neostigmine (reversibly inhibits AchE, but competes with irreversible organophosphates) |
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Anticholinesterases used to treat:
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Glaucoma
and Myesthenia Gravis |
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Causes for Gluacoma
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1. insufficient Ach
2. # of cholinergic receptors M3 below normal |
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Difference between acute and chronic Glaucoma
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Acute- fast onset, fast progressing, optic pressure increases fast and rapidly, closed angle (happens when muscle is relaxed)
Chronic- slow onset, slow progression, high optic pressure, slowly opening angle (due to contraction of muscle); beta receptors on ciliary epithelium releases too much aqueous humor |
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Acute vs Chronic
OP Eyes Pupil Vision Endvision |
OP- rapid vs fast
Eyes- red vs red Pupil- dilated vs normal Vision- near vision vs normal End- tunnel vision vs tunnel vision |
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Beta-adrenergic non-selective antagonist prevents release of aqueous humor
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Timolol (Chronic glaucoma)
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Solutions for Glaucoma
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1. Pilocarpine (Ach Agonist)
2. Physostigmine (inhibits AchE for few hours) 3. Echothiophate (inhibits AchE for 100 hours) |
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autoimmune disease in which the cholinergic receptors on the skeletal muscles are decreased due to the attack of autoantibodies
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Myesthenia Gravis
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Penta valent phosphorous coupounds
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contains fluoride as diisopropylfluorophosphate
irreversible anticholinesterases |
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short acting; used to diagnose; either helps or doesn't in 5-15 min
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Edrophonium (alcohol)
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inhibits AchE in NMJ, increases Ach, used to treat myasthenia gravis; need more than normal Ach because receptor number is low
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Neostigmine (carbamate)
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Gram positive
vs Gram negative |
pos- 10-15 peptidoglycan layer; 1 plasmamembrane
neg- 5-7 peptidoglycan layer; inner and outer plasma membrane |
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Peptidoglycans linked by:
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Pentaglycine
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Penicillin Binding Protein (PBP)
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Transpeptidase
removesD-ala allowing to pentaglycines to attach |
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inhibitors of cell wall synthesis by blocking the cross linking enzyme, tranpeptidase
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Penicillins
and Cephalosporins |
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Penicillin resembles the conformation of:
the antimicrobial activity of penicillin resides int he ___________ of penicillins |
acyl-D-Ala-D-Ala
beta-lactam ring |
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Naturally occuring penicillins
Penicillinase resistant penicillins broad spectrum penicillins |
Naturally occuring penicillins:
Penicillin G Penicillin V Penicillinase resistant penicillins: methicillin naficillin oxacillin cloxacillin dicloxacillin broad spectrum penicillins: ampicillin amoxicillin all gram pos except ampicillin and amoxicillin can go thru porins making them affective on gram neg and pos bacteria |
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Penicillins differ in their:
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oral absorption
binding to proteins metabolism excretion |
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structurally resemble substrate; pseudosubstrate
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suicide inhibitors
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Resistance to Penicillin due to
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beta-lactamase (aka Penicillinase) of bacteria that breaks open beta lactam ring of penicillin, this prevents its binding to transpeptidase
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Augmentin
Unasyn Timentin |
Augmentin= Amox + clavulanate
Unasyn= Ampicillin + Sulbactrum Timentin= Ticarcillin + Clavulanate Amox, unasyn, ticarcillin- attacks transpeptidase clavulate and sulbactrum- beta-lactamase inhibitor |
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Suicide inhibition of thymidylate synthesis (TS)
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Fluorouracil (fluorodeoxyuridine) clinically used as anti cancer drug is converted into F-dUMP which irreversibly inhibits TS preventing dTMP formation from dUMP
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Suicide inhibition of Xanthine Oxidase (XO)
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Allopurinol, analog of hypoxanthine, used to treat gout where there is excessive accumulation of uric acid produced by action of xanthine oxidase
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beta-lactamase specific, irreversible inhibitors
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suicide inactivators
bind to active site of the beta lactamase very poorly, but eventually form covalent bonds leading to irreversible inhibition of the beta-lactamase |
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Occupation Theory
vs Rate Theory |
Occupation- response is a function of the occupation of receptor molecules by an agonist
Rate-response is a function of the rate of occupation of receptors by agonist molecules |
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Clark's Occupation Theory
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a linear relationship exists between occupation (binding) of a receptor molecule and the cellular response produced as a result of that receptor occupation
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Define KD
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concentration of drug that produces half maximal binding
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PD2
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-log [KD]
larger the PD2 the better the agonist smaller the KD, the better the agonist |
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Ariens Modified Occupancy theory
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includes a proportionality facter called intrinsic activity
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Paton Rate Theory
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based on the rates of association and dissociation of drugs from the receptors
antagonists act much more slowly than agonists |
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Emax
EC50 |
Emax- maximal response that can be produced by the drug
ED50- concentration of drug that produces 50% of maximal effect |
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Gaddum's Equation
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equation for competitive antagonism
E/Emax= [D]/ ([D] + KD (1+[A]/KA)) |
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Schild's Equation
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log (x-1)= pA2-pAx
log 9= 0.95= pA2-pA10 |
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Upregulation do to what?
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1. synthesis of new receptors
2. transport of receptors from intracellular storage sites |
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What happens to KD with an irreversible antagonist
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KD does not change
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Tolerance
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gradual decrease in effectiveness
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Tachyphylaxis
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if giving two doses close together, second does will not have as much response dur to down regulation; to prevent use lower dose and decrease the 2nd dose
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Different types of receptors
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Intracellular receptor (DNA)
Receptors linked to enzymes Receptors linked to ion channel Receptors linked to G-Proteins |
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Noncompetitive antagonism
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the noncompetitive acts competitively in low concentrations and similar to irreversible inhibitors in higher concentrations
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Name the receptors/channels that match with their speed
msecond seconds minutes hours |
msecond-ion channel linked
seconds- second messengers Minutes- protein kinases Hours- DNA-linked |
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hsp90
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Heat Shock Protein
masks protein; leaves receptor when steroid ligand binds; protein is active when hsp90 is not bound |
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Various factors that can regulate a drug's effect
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1. affinity between the drug and the tissue receptors
2. intrinsic activity of the drug to cause confirmation changes 3. responsiveness of the target tissue to the changes that occur at cellular levels 4. effectiveness of cellular and systemic reflexes in resisting or modifying the changes induced by the drug |
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Potency
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measure of how strongly drug can produce 50% of max effect with smallest concentration
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Efficacy
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the agonist with the maximal efficacy is defined as the one with the ability to produce the greatest of maximum effects
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graded curves
vs quantal curves |
graded- curves that relate the dose of a drug to any size of response that can be detected in a single biologic unit
quantal- all or none type curve in which the relationship is between the dose of the drug and the total f biological objectsthat are displaying a predetermined level of pharmacological response |
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Celing dose
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drug dose that can produce the ceiling effect (Emax)
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What channels do these open:
Ach GABA Glutamate NMDA |
Ach- open Na channel
GABA- opens Cl channels Glutamate- Ca channels NMDA- Ca channels |
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Activators for Gs
Activators for Gi |
Gs- beta-Adrenergic, histamine, seratonin; increases AC
Gi- alpha adrenergic, muscarinic, opiods; decreases AC |
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ED50
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effective dose in 50 % of the population
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L-type
T-type N-type |
L-type: high voltage operated, long lasting
T-type: low voltage activated, transient N-type: neither T nor L T opens first, then N, then L |
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What only blocks L-type
What blocks both L-type and T-type |
Dihydropyridine
Conotoxin |
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Therapeutic Index
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LD50/ED50
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Standard safety margin
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the percentage increase of a dose above the therapeutic dose that is lethal to a given proportion of the subjects
(LD/ED99-1) x 100= |
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Relationship among:
GABA Benzodiazepine Barbituates |
GABA- binds beta subunit
Benzodiazepine-binds alpha subunit and increases requency of opening Barbituates-binds to alpha/antagonist |
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GABA antagonists
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blocks Cl-
Bicuculine Picrotoxin |
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Benzodiapines
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Diazepam
Oxazepam Flurazepam Nitrazepam Triazolam Chlordiazepoxide |
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Inverse agonist
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blocks effect of benzodiazepine
B-cce |
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Barbituates
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slows closing of Cl- channel
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DHPs affect what?
Conotoxin affects what? |
DHP-L type
Conotoxin- N type and L type |
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These receptor types affect with cell/tissue type?
ATP Vasopressin Mitogens PTH NMDA Glutamate |
ATP- smooth muscle
Vasopressin- smooth muscle Mitogens- lumphocytes PTH-osteoclasts NMDA-Neurons Glutamate- Neurons |
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Time-Action Curves
Phase 1 Phase 2 Phase 3 Phase 4 |
Phase 1: time for onset action
Phase 2: time to peak effect Phase 3: duration of action Phase 4: residual effects |
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What is residual effects/carryover?
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over lap effect from one dose with the next
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used to control hypertension and phechromocytoma by irreversibly blocking alpha 1 receptors
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Phenoxybenzamine
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Drugs used for complete midriases
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Atropine (M agonist)
Phenylephrine (alpha agonist) |
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Drugs used for closing pupil
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Ach (M3 agonist)
Prazosin (alpha agonist) |
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Drugs used to treat diarrhea
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Atropine (M3 agonist)
Diphenoxylate |
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Drugs used to treat someone exposed to soman or serine (nerve gas)
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Atropine
if taken to hospital, give physostigmine, then it will be deactivated wiht PAM, DAM, hydroxylamine |
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Sides effects of atropine
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Dry mouth
Tachycardia (increase HR) dry skin (no sweating) |
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What is used to detect and to treat Myesthenia gravis
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Detect: Edrophonium (alcohol) only binds anionic site
Treat: Neostigmine (carbamate) binds to anionic and esteractic site |
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target enzyme for penicillin
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transpeptidase
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result of penicillin amidase
result of penicillinases (beta-lactamases) |
penicillin amidase- 6- aminopenicillanic
penicillinases (beta-lactamases)- penicilloic acid |
