Drug Mechanisms

Local anesthetic - target molecules

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

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

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

flunixin meglumine - mechanism

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

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

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

mepivacaine - mechanism

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

-lasts longer than lidocaine

tetracaine - mechanism

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

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

ketamine - mechanism

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

Gabapentin - mechanism

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

Atipamezole - mechanism

Dexmeditomidine reversal

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

Acetylcholine - mechanism

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

Directly acting cholinergic agonist

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

Edrophonium - mechanism

Indirectly acting cholinergic agonist - short acting, reversible

Competitively binds to AchE → more Ach available

Used to diagnose myasthenia gravis

Pyridostigmine - mechanism

Indirectly acting cholinergic agonist - carbamylating ester

Competitively binds to AchE → more Ach available

AchE-pyridostigmine complex degrades slowly, so effects las longer

Atropine - mechanism

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

Used to treat organophosphate (OP) poisoning

Phosphorylates OP and pulls it off AchE

Atracurium - mechanism

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

Pancuronium - mechanism

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

Succinylcholine - mechanism

Depolarizing -

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

Dantrolene - mechanism

Treatment for malignant hyperthermia -

Decreases Ca2+ release from sarcolemma → reduces muscle contractions

Phenobarbital - mechanism

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

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

vit K mechanism

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

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

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

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

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

Clopidogrel - mechanism

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

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,

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

Aminocarproic acid

Fibrinolysis inhibitor

Inhibits plasminogen activator substances

vitamin K

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

Aluminum hydroxide

Used to reduce hyperphosphatemia

Aluminum salts bind to dietary phosphorus and prevent GI absorption

Maropitant

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)

Less acid also means less pepsin secretion

Telmisartan

Decreases vasocontriction

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

Epoetin alpha

Replacement for erythropoietin (EPO)

EPO stimulates erythropoiesis

Tumil K

Dietary potassium supplement

Albuterol

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

Anti-inflammatory

Prevent transcription genes for inflammatory proteins (including cytokines)

Stimulate production of anti-inflammatory proteins

Epinephrine

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

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

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

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

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

Beta agonist

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

Metoprolol

Beta-1 blocker

Decreased sinus HR, slowed AV conduction, decreased CO

Norepinephrine

Alpha and beta agonist, not as potent as epi

Increase in BP, HR may decrease do to barorecpetor reflex

Phenylephrine

Alpha-1 agonist

Peripheral vasoconstriction → increased BP

Small decrease in CO

Pimobendan

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

Beta blocker - used to treat arrhythmias

Decreases sinus HR, depressed AV conduction

Spironolactone

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

Lactulose

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

Stimulate absorption of fluids and electrolytes

Metoclopramide

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

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

PEG 3350

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

Bismouth subsalicylate

aka pepto bismol

Bismuth  absorbs entertoxins and endotoxins

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