Drug Mechanisms

Local anesthetic - target molecules

voltage gated Na channels

Local anesthetic - action on target

inhibition

Local anesthetic - downstream events on target cells

Blockage of action potentials

Local anesthetic - physiologic consequences

Blocking nociceptive pain transmission

What are the the local anesthetics used in vet med

procaine (amino-ester)

lidocaine (AA)

ropivacaine (AA)

bupivacaine (AA)

mepivacaine (AA)

tetracaine

Opioids - target molecules

Opioid receptors (GPCR)

Opioid - direct action on target

Activation

Opioid - Downstream event in the target cell

Inhibits Ca channels, facilitates K channels

Opioids - physiological consequences

suppress pain

What are the opioids used in vet med

Morphine

Methadone

Hydrocodone

Fentanyl

Butorphanol

Buprenorphine

NSAIDs - target molecules

COXs (EP4 for grapiprant)

NSAIDs - direct action on target

inhibition

NSAIDs - downstream events on target cells

Reduced production of prostanoids, especially in PGE2

NSAIDs - physiological consequences of action

reduced peripheral/central pain

anti-inflammation

What are some NSAIDs used in vet med

Flunixin

Ketoprofen

Firocoxib

Meloxicam

Caroprofen

Aspirin (is an NSAID but not used for that--used as an anticoagulant)

alpha2 adrenoceptor agonist - target

alpha2 adrenoceptor (GPCR)

alpha2 adrenoceptor agonist - action on target

Activates

alpha2 adrenoceptor agonist - downstream events

Inhibits Ca channels, promotes K channels

alpha2 adrenoceptor agonist - physiologic consequences

Membrane hyperpolarization -→ inhibits neural firing in the brain and SC -→ decreases pain

What are some alpha2 adrenoceptor agonists used in vet med

Xylazine

Dexmedetomidine

Gabapentin - target

Subunit of voltage gated Ca channels

Gabapentin - action on target

Inhibition

Gabapentin - downstream events

Fewer neurotransmitters released

Gabapentin - physiologic consequences

Fewer AP transmitted → less nociceptive information → less pain

What class of drug is gabapentin and what is the other example we learned in lecture

Anticonvulsant

pregabalin

aspirin - mechanism

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Covalently binds to COX → prevents production of prostanoids → decreases inflammation and pain 

\*in low doses blocks COX on platelets → preventing production of TXA2 which is involved in platelet aggregation 

carprofen - mechanism

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Binds to COX enzymes → inhibition → prevents arachidonic acid from being converted into prostaglandins (especially PGE2) → anti-inflammation, reduced pain sensitivity 

flunixin meglumine - mechanism

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Binds to COX enzymes → inhibition → prevents arachidonic acid from being converted into prostaglandins (especially PGE2) → anti-inflammation, reduced pain sensitivity 

deracoxib - mechanism

Binds to **COX-2** enzyme → inhibition → prevents arachidonic acid from being converted into prostaglandins (especially PGE2) → anti-inflammation, reduced pain sensitivity 

\-has fewer side effects because COX-1 (renal perfusion, gastro-protectants) isn’t blocked

grapiprant - mechanism

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Binds competitively to EP4 (PGE2 receptor on nerve ending) → reduces pain and inflammation 

\-fewer side effects because PGs are still made, inflammatory ones just can’t dock 

lidocaine - mechanism

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Inhibit voltage-gated Na channels → no AP → nociceptive pain transmission blocked

mepivacaine - mechanism

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Inhibit voltage-gated Na channels → no AP → nociceptive pain transmission blocked

\-lasts longer than lidocaine

tetracaine - mechanism

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Inhibit voltage-gated Na channels → no AP → nociceptive pain transmission blocked

Morphine - mechanism

Bind to opioid receptors (GPCR) → activate → inhibit Ca2+ channels and facilitate K+ channels → pain suppression

Butorphanol - mechanism

Bind to opioid receptors (GPCR) → activate → inhibit Ca2+ channels and facilitate K+ channels → pain suppression

Dexmedetomidine - mechanism

Bind to alpha-2 adrenoceptors (GPCR) → activate → inhibit Ca2+ channels, facilitate K+ channels → reduce release of norepinephrine →  inhibit neuronal firing in brain and spinal cord → sedation and analgesia

Xylazine - mechanism

Bind to alpha-2 adrenoceptors (GPCR) → activate → inhibit Ca2+ channels, facilitate K+ channels → reduce release of norepinephrine →  inhibit neuronal firing in brain and spinal cord → sedation and analgesia

Amantadine - mechanism

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Target post-synaptic NMDA receptors (antagonist) → inhibits neurotransmitter binding → fewer APs & reduced pain sensitization

ketamine - mechanism

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Target post-synaptic NMDA receptors → inhibit neurotransmitter binding → fewers APs & reduced pain sensitization 

Gabapentin - mechanism

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Targets subunit of voltage-gated Ca2+ channels on pre-synaptic terminals in DRG → reduces neurotransmitter release → reduces pain transmission 

Atipamezole - mechanism

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Dexmeditomidine reversal 

Knocks agonist off the alpha-2 adrenoceptor → Ca2+ channels activated, K+ channels inhibited → increased neuronal firing 

Acetylcholine - mechanism

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Bad drug because it isn’t specific and is degraded quickly 

Binds to ganglia, NEJ, and NMJ. Increases muscarinic and nicotinic effects depending on receptors 

Bethanechol - mechanism

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Directly acting cholinergic agonist 

Choline ester → binds to muscarinic receptors → increased tone and paristalsis in GI/urinary 

Edrophonium - mechanism

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Indirectly acting cholinergic agonist - short acting, reversible 

Competitively binds to AchE → more Ach available 

Used to diagnose myasthenia gravis 

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Pyridostigmine - mechanism

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Indirectly acting cholinergic agonist - carbamylating ester 

Competitively binds to AchE → more Ach available 

AchE-pyridostigmine complex degrades slowly, so effects las longer 

Atropine - mechanism

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Muscarinic antagonist 

Prevents Ach from binding to muscarinic effectors → increases HR, decreases tone & motility in GI and urinary systems, dilates eyes, can cause restlessness, delirium, coma, death 

Pralidoxime - mechanism

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Used to treat organophosphate (OP) poisoning 

Phosphorylates OP and pulls it off AchE 

Atracurium - mechanism

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Non-depolarizing - competitively binds to Ach receptors on motor end plate → no Ach binding → muscle relaxation 

Pancuronium - mechanism

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Non-depolarizing - competitively binds to Ach receptors on motor end plate → no Ach binding → muscle relaxation 

Succinylcholine - mechanism

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Depolarizing - 

Binds to Ach receptors → depolarization → muscle twitches → rapid repolarization → flaccid paralysis 

Dantrolene - mechanism

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Treatment for malignant hyperthermia - 

Decreases Ca2+ release from sarcolemma → reduces muscle contractions 

Phenobarbital - mechanism

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Binds to GABA-A recepeptors at allosteric site (beta subunits) and enhances GABA’s effects → channels open longer → more Cl- enters cell → hyperpolarization lasts longer 

Anticonvulsant 

Thiobarbital - mechanism & class

Barbiturate

Binds to GABA-A receptors at GABA AND barbiturate sites (allosteric and direct agonist) → no APs generated 

Injectiable anesthetic 

Diazepam - mechanism and class

Benzodiazepine

Allosteric agonist - binds to GABA-A receptors between alpa and gamma2 subunits → channels open for longer → more Cl- enters cell → fewer APs generated 

Anti-anxiety 

Muscle relaxants 

IV to stop active seizures 

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\*only about ⅔ of GABA-A receptors have gamma2 subunits\* 

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vit K mechanism

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Redox rxn of vit K epoxide → vit K quinone → vit K hydroquinone coupled to arboxylation of Fs II, VII, IX, X 

We need II, VII, IX, & X carboxylated so they can bind to Ca2+ → PS → platelet aggregation 

Used to treat anticoag rodenticide activity 

Warfarin

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Inhibits vit. K epoxide reductase → needed because the carboxylation of Fs II, VII, IX, X is coupled to the redox reaction that recycles vit K 

We need II, VII, IX, & X carboxylated so they can bind to Ca2+ → PS → platelet aggregation 

t1/2 - 6 days 

Diphacanone - mechanism

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Inhibits vit. K epoxide reductase → needed because the carboxylation of Fs II, VII, IX, X is coupled to the redox reaction thst recycles vit K 

We need II, VII, IX, & X carboxylated so they can bind to Ca2+ → PS → platelet aggregation 

t1/2 - 4-5 days 

Brodifacoum - mechanism

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Inhibits vit. K epoxide reductase → needed because the carboxylation of Fs II, VII, IX, X is coupled to the redox reaction thst recycles vit K 

We need II, VII, IX, & X carboxylated so they can bind to Ca2+ → PS → platelet aggregation 

Much lower LD50 

t1/2 - 6 days 

Citrate - mechanism

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Reversibly chelates Ca2+ → not available to bind coag factors and PS until added back in for coag testing 

Clopidogrel - mechanism

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This is an anti-platelet drug that blocks the platelet ADP receptor (P2Y12),

ADP is a platelet agonist released from the dense granules of activated platelets → inhibits activation of GP Ib/IIIa → no fibrinogen binding 

EDTA - mechanism

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Irreversibly chelates Ca2+ → not available to bind coag factors and PS 

In PTT

Heparin - mechanism

This inhibits secondary hemostasis by promoting the action of antithrombin,

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which is an inhibitor of many coagulation factors, particularly FXa and thrombin.

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Aminocarproic acid 

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Fibrinolysis inhibitor 

Inhibits plasminogen activator substances 

vitamin K

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Redox rxn of vit K epoxide → vit K quinone → vit K hydroquinone coupled to carboxylation of Fs II, VII, IX, X

We need II, VII, IX, & X carboxylated so they can bind to Ca2+ → PS → platelet aggregation

Used to treat anticoag rodenticide activity

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Aluminum hydroxide 

Used to reduce hyperphosphatemia 

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Aluminum salts bind to dietary phosphorus and prevent GI absorption

Maropitant

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Anti-emetic/nausea

Neurokinin-1 (NK1) receptor antagonist ---> blocks substance P (neurotransmitter involved in vomiting)

Suppresses both central and peripherally mediated nausea

Famotidine

H2 receptor antagonist

Competitively inhibits histamine in parietal cells ---> inhibits acid production (both during basal conditions and when stimulated by food, insulin, etc)

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Less acid also means less pepsin secretion

Telmisartan

Decreases vasocontriction 

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Angiotensin II receptor antagonist (binds to AT1 receptor) ---> prevents vasocontriction, water and Na retention

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Epoetin alpha 

Replacement for erythropoietin (EPO) 

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EPO stimulates erythropoiesis

Tumil K

Dietary potassium supplement

Albuterol

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Bronchodilator 

Beta-2 adrenergic agonist 

Interact with receptors on smooth muscle ---> 

\-activates Gs protein ---> 

\-activates adenylyl cyclase ---> 

\-cAMP produced ---> 

\-target proteins phosphorylated ---> 

\-smooth muscle relaxed ---> 

\-bronchodilation 

Dexamethasone

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Anti-inflammatory 

Prevent transcription genes for inflammatory proteins (including cytokines) 

Stimulate production of anti-inflammatory proteins 

Epinephrine

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Used for anaphylaxis (IM, SQ, or IV) 

Stimulates α & β receptors 

\-α1 ---> vasoconstriction 

\-β1 ---> increases HR and force of contraction to restore BP   

\-β2 ---> counteracts bronchoconstriction 

Theophylline

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Bronchodilator 

Mechanism is not well understood. Classic. 

3 Theories: 

\-PDE inhibitor ---> more cAMP available, potentiates beta-2 agonists 

\-adenosine receptor antagonists 

-adenosine causes bronchoconstriction via histamine and leukotriene release 

\-anti-inflammatory effects 

Found in tea 

Atropine

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Muscarinic antagonist - inhibits vagally-mediated smooth muscle tone ---> prevents bronchoconstruction 

Furosemide

Blocks Na-K-2Cl cotransporters in loop of Henle → reduces electrolyte absorption and increase K excretion → less fluid → reduced preload → increased SV & CO

Diltiazem

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Ca channel blocker → less Ca → inhibits cardiac & smooth muscle contractility → dilates vessels, decreases total peripheral resistance, slows AV node conduction and prolongs refractory period 

Enalapril

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Competitively inhibits angiotensin I by binding to ACE → reduced angiotensin II → vasodilation → decreased peripheral resistance → increased SV & CO 

Epinephrine

Alpha and beta agonist 

Increase HR and contractility, increases BP, relaxes smooth muscle in bronchi, decreases total peripheral resistance

Isoproterenol

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Beta agonist 

Stimulates cAMP production, increased HR and contractility, relaxation of bronchial smooth muscle, peripheral vasodilation 

Metoprolol

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Beta-1 blocker 

Decreased sinus HR, slowed AV conduction, decreased CO 

Norepinephrine

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Alpha and beta agonist, not as potent as epi 

Increase in BP, HR may decrease do to barorecpetor reflex

Phenylephrine

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Alpha-1 agonist 

Peripheral vasoconstriction → increased BP 

Small decrease in CO 

Pimobendan

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Inhibits phosphodiesterase III (PDE3) → cAMP not metabolized → increased contractility and heart rate 

Vasodilation 

Prazosin

Alpha-1 antagonist - competitively inhibits adrenrgic receptors 

Reduces BP and peripheral vascular resistance

Proplanolol

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Beta blocker - used to treat arrhythmias 

Decreases sinus HR, depressed AV conduction 

Spironolactone

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Competitively inhibits aldosterone → increased electrolyte excretion, aldosterone promotes myocardial fibrosis and remodeling 

Lactulose

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Hyperosmotic cathrtic 

Synthetic disaccharide 

Metabolized by intestina bacteria ---> acetic, lactic, formic acids ---> osmotic effects 

Converts ammonia to ammonium ions 

Loperamide

Motility modifier 

OTC synthetic opiate that targets the GI tract (no other systemic effects) 

Decreases propulsive contractions and increase sphincter tone 

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Stimulate absorption of fluids and electrolytes

Metoclopramide

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Antiemetic 

Acts in the CTZ as central dopaminergic antagonist in low doses and as a peripheral 5-HT (talks to emetic center) receptor antagonist in high doses 

Also stimulates GI motility, so don't use if obstruction is suspected 

Omeprazole

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Covalently binds cysteines in H-K-ATPase → irreversibly inactivated → no H or Cl pumped into lumen → no HCl 

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PEG 3350 

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Hyperosmotic cathartic 

Large molecylar weight polymer - H bonds to 100 molecules of water ---> high osmotic pressure ---> keeps water in lumen 

Not metabolized by gut bacteria 

Minimal side effects 

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Bismouth subsalicylate 

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aka pepto bismol 

Bismuth  absorbs entertoxins and endotoxins 

Salicylate (=aspirin, thank you chloe)  has anti-prostaglandin and anti-secretory effects (reduces inflammation)