Drug mechanisms Flashcards
Mydriatics (eye)
Parasympatholytics/anticholinergic/muscarinic antagonist: antagonize M3 receptors on constrictor pupillae
Sympathomimetic: alpha 1 adrenergic agonist: agonize alpha 1 receptor on dilator pupillae
To decrease aqueous production (gluacoma) with no effect on pupil
Sympatholytics:
- non-specific beta antagonist possibly via beta-2 receptors
- B1 adrenoceptor antagonist: decrease aqueous production
Sympathomimetics:
epinephrine: non-specifc adrenoceptor agonist- decreases aqueous production via alpha 1 vasoconstriction of ciliary blood vessels
apraclonidine: alpha 2 adrenoceptor agonist (also weak alpha 1 agonist- capitalizing on this action)
Miosis (pupillary constriction) to open drainage angle (glaucoma)
Direct parasympathomimetic: non-specific muscarinic agonists (local application)
Indirect parasympathomimetic: acetylcholinesterase inhibitors–> increase [ACh] (targets NT rather than receptor)
To treat detrusor hypercontractility/spasticity (urinary incontinence)
Aim: decrease detrusor activity (M3 receptors)
Antimuscarinic: non-specific muscarinic antagonists
To treat detrusor atony (urinary retention)
Aim: increase activity–> cholinergic agonists
Bethanechol: Non-specific muscarinic agonist, but higher affinity for M3
Urethral sphincter incompetence (incontinence)
Aim: increase sphinctor tone
Alpha 1 agonists ideally
Oral phenylpropanolamine: non-specific alpha adrenergic agonists
Ephedrine: stimulates NA release, binds to alpha and beta receptors
Urethral spasticity (retention)
Aim: decrease urethral activity
Non-selective alpha antagonist: phenoxybenzamine- preferential binding to alpha 1
Prazosin and terazosin: selective alpha 1 antagonist
Aluminum salts and magnesium salts
alkaline chemicals that neutralize acid in stomach
neutralize gastric HCl, inhibit pepsin secretion
Histamine receptor antagonists (antacid)
i.e. cimetidine and ranitidine
competitive antagonism of H2 receptors in parietal cells; decreases production of HCl
[nb:Histamine receptor is couple to G-protein–> increase AC–>increase cAMP–>stimulate proton pump to secrete acid]
Sucralfate
sucrose sulfate-aluminum hydroxide complex
polymerizes to viscous gel at pH <4
forms long chains under acidic conditions–> exposted sulfate groups bind to protein in ulcerated area to create a bandage
Proton pump inhibitor
i.e. omeprazole
inhibits H+/K+ ATPase pump on luminal membrane of parietal cells
binding is irreversible; body has to synthesize new enzyme to create pump again
PGE2 analogues
e.g. misoprostol (methyl ester of prostaglandin)
PG analogue decreases acid secretion, increases blood flow and increases mucus production
Agonist at PG receptor
3% hydrogen peroxide
stimulates visceral afferents as a mild gastric irritant
Ipecac (huana)
local irriation (similar to hydrogen peroxide); direct central activation of receptors in CTZ
Xylazine
alpha 2 adrenoceptor agonist
direct central activation of receptors in CTZ (most species CTZ has alpha 2 adrenoceptors (cats have high amount))
Apomorphine
dopamine agonist; binds to receptors in CTZ
Phenothiazines (ACP)
block dopamine receptors in CTZ; weak anticholinergic and antihistamine also
Metoclopramide
dopamine antagonist; also some antimuscarinic effects
Diphenhydramine
antihistamine, antimuscarinic
effective for antiemesis (motion pathway)
Neurokinin antagonist
e.g. maropitant (cerenia)
NK-1 receptor antagonist
shuts down emetic pathway
Serotonin antagonist- Odansetron
blockade of serotonin receptors in CTZ
Adsorbents (diarrhea)
Kaolin (Al3+ salt) suspension
absorbs toxins; provides prtective coating on inflamed mucosa (changes consistency of feces)
Opioids (antidiarrheal)
diphenoxylate and loperamide won’t cross BBB- no typical CNS effects of opioid
inhibits ACh release in myenteric plexus–> slows gut, allows for reabsorption of water
Anticholinergics (antidiarrheals)
muscarinic antagonism (buscopan, atropine)
Aminosalicylates
cleaved by bacteria in bowel to sulfapyridine and 5-amniosalicylic acid (related to aspirin)
have anti-inflammatory effect–> inhibit PG synthesis?
Lubricant (laxative/ cathartic)
lubricate tract and soften feces
mineral oil, liquid paraffin
Bulk (cathartic)
add dietary fiber to absorb H2O
hydrophilic colloids absorb water, increase bulk–> stimulate persistalsis
Osmotic cathartic
magenesium sulphate, lactulose
non-absorbale salts/polymers
retain water in intestinal lumen, decrease consistency, soften stools
Stimulant cathartics
bisacodyl, phenophthalein
stimulate intestinal motility via irritant effect–> promote organized peristaltic action
Beta-adrenergic agonists (respiratory)
adrenaline
used for life threatning bronchoconstriction
Beta-2 specific agonists (respiratory)
bind to b2 receptors–> increase cAMP –> relaxation of bronchial smooth muscle
also inhibit histamine release from mast cells–> benefit in allergic reaction
Anticholinergics
antimuscarinics
M3–>increase IP3–>increase cytosolic concentration of calcium–> constriction of bronchial SM
Methylxanthines
PDE inhibitors
PDE breaks down cAMP to 5’AMP
PDE inhibitiors increase cAMP–> bronchial smooth muscle relaxation
also decreases inflammatory mediators
inhibit adenosine: circulating substance that causes bronchoconstriction
Antihistamine (respiratory)
H1-receptor antagonists
histamine–> bronchoconstriction, local edema, vagal nerve stimulation
Sodium cromoglycate
inhibit release of inflammatory mediators (histamine, leukotrienes) from mast cells
NO bronchodilator action, just prevents bronchoconstriction
Corticosteroids
decrease inflammation associated with inflammatory pulmonary diseases by inhibiting transcription of certain genes involved in producing inflammatory mediators
also enhance action of beta-2 agonists: slow down down-regulation process–> enhance length of efficacy
NSAIDs (respiratory)
useful with inflammatory process i.e. PG mediated respiratory disease
Leukotriene inhibitors
1) lipoxygenase inhibitors
2) luekotriene receptor blocks
Opiates (antitussives)
directly depress cough center via mu and kappa receptors
Mucolytics
acetylcysteine: anti-oxidant compound that chemically interfereswith mucus
Saline expectorants
make a greater volume of mucus and stimulates coughing
decongestants
alpha agonists: vasoconstriction of BVs in upper respiratory tract–> decreased producton of mucus
antihistamines: decrease inflammation
Local anaesthetics
block Na+ channels to prevent initation/conduction of action potentials
Opioid analgesics
bind to opioid receptors in brain, spinal cord, periphery
GCPR: inhibit adenylate cyclase and decrease cAMP
promote opening of K+ channels (hyperpolarization, decreased neuronal excitability)
inhibit opening of voltage-gated calcium channels (decrease NT release)
NSAIDs
inhibit cyclooxygenase to decrease production of PGs and thromboxanes
act peripherally: decrease PG production at site of inflammation and reduce sensitization of nociceptive nerve endings to inflammatory mediators
act centrally: block PG release and neuronal excitation; decreased central sensitization
Phenothiazines (tranquilizer)
non-selective dopamine antagonist (in basal ganglia, limbic system); also antagonist action at alpha 1, serotonin, histamine, muscarinic receptors
Butyrophenones
chemically unrelated to phenothiazines
dopamine antagonist (some alpha 1 antagonism)
Alpha 2 agonists (sedative)
Alpha 2 agonism–> inhibit adenylate cyclase, decrease cAMP–> inhibit voltage gated Ca2+ channels and activate Ca2+ dependent K+ channels.
Pre-synaptically: alpha 2s inhibit NT release via inhibiting cAMP production
Post-synaptically: alpha 2 agonism–> vasoconstriction
Benzodiazepines
BZPs potentiate GABA (not actually agonists)
In the presence of GABA, BZPs facilitate opening of GABA activated Cl- channels
BZP binding site is distinct from GABAa site
BZP increases affinity of GABA for its receptor–> enhanced agonist effect.
Propfol (induction, TIVA)
enhanced GABA transmission (increased flux of Cl-), similar to BZP but at a different site
Alfaxalone (induction, TIVA)
enhances inhibitory action of GABA; it also possibly inhibits nicotinic ACh receptors and noradrenaline uptake
Barbiturates
reversibly depress activity of all excitable tissue; reticular activating system is particularly susceptible
enhances inhibitory action of GABA at an allosteric site; promote binding of GABA to GABAa receptor; enlarge GABA-induced chloride currents
Etomidate
imidazole derivative
non-barbiturate, but similar to thiopentone
enhance inhibitory action of GABA
Ketamine
dissociative agents
interrupts association between limbic and cortical regions by acting on NMDA receptor (excitatory) ion changes which receptor is an intergral part of
Inhibits NMDA receptors
can also physically block the open ion channel, but it also decreases frequency of opening by binding modulatory sites
Nitrous oxide
provides specific analgesia: NMDA receptor antagonist
Non-depolarizing NMBs
competitive antagonist at the nicotinic ACh receptor. bind to receptor as antagonists, leaving fewer receptors for ACh to bind (need to block at least 80% of receptors)
reversed by anticholinesterases (i.e. increase ACh overcomes block)
Depolarizing NMBs
agonist at nicotinic ACh receptor but metabolized slowly.
ACh is normally rapidly cleared from the synapse
depolarizing NMB has persistence of action, leading to a rapid loss of muscle control and eventual muscle relaxation
has effect of initial fasciculations
Guaifenesin
blocks impulse transmission at internucial neurones within spinal cord and brain stem
relaxes limbs more than respiratory muscles
AEDs
target: GABA, glutamate, voltage-gated channels (sodium, calcium, choloride)
Act to hyperpolarize INSIDE of cell
Phenobarbital
enhances activity of GABA and thereby increases nueronal inhibition
reduces neuronal excitability through interaction with glutamate receptors
inhibits voltage-gated calcium channels
competitive binding of chloride channel picrotoxin site
Potassium bromide
not fully understood but involves bromide interaction with chloride channels
Cl- channels modulated by GABA and function to hyperpolarize cell membrane, making it more stable
Bromide cross the chloride channels in preference of Cl- has it has a smaller hydrated diameter. Bromide facilitates the neurotransmitters acting on GABA channel by hyperpolarizing cell membrane.
Imepitoin
partial agonist at BZP recognition site of GABA receptor
potentiates GABA receptor-mediated inhibitory effects on neurons
weak calcium channel blocking effect
Beta 1 adrenergic agonists (positive inotropes for HF)
Dobutamine
in cardiac muscle: beta-1 agonists stimulate AC via GCPR to form cAMP–> increases Ca2+–> contraction
PDE III inhibitor (positive innotrope/vasodilator)
Vasodilator: In VSM: cAMP causes relaxation due to inhibitory effect on myosin kinase. if you increase amount of cAMP using PDE III inhibitor–> relaxation
In cardiac muscle: cAMP causes contraction to do effect of activating Ca2+ channels. increase PDE III inhibitor–> increase cAMP
Pimobendan (calcium sensitizer)
Calcium sensitizer: enhances Ca2+/troponin interaction by increasing the affinity of Ca2+ for binding site; increased force of contraction without an increase in Ca2+ concentration
Inodilator: PDE III inhibitor effects
Decrease pulmonary hypertension: PDE V inhibitor in pulmonary blood vessels
positive lusitropic effects: diastolic relaxation of ventricles for better filling and CO
Calcium channel blockers (pure vasodilators)
Amplodipine: works vascularly
blocks voltage operated Ca2+ channels that allow Ca2+ during depolarization–> triggers Ca2+ release from SR to cause contraction
Hydralazine (vasodilator)
potent, but not sure how it works–> suggestion that it has direct relaxant action on VSM
Prazosin (vasodilator)
alpha 1 adrenoceptor antagonist
relaxation of VSM
Nitrates (vasodilators)
Nitrates act like endogenous system of vasodilation.
Primary stimulus for production of NO is shearing force generated by blood flow–stimulates endothelium nitric oxide synthase to convert L-arg to NO
NO stimulates guanylate cyclase to convert to cGMP–> relaxation of smooth muscle
Nitrates spontaneously donate NO which diffuses and causes relaxation
PDE V inhibitor (vasodilator)
selectively prevents pulmonary hypertension
ACE inhibitors (neuroendocrine modulating vasodilators)
ACE inhibitor blocks formation of angiotensin II. Angiotensin II stimulates aldosterone secretion, increase BP, increase ADH, increase sympathetic activity
ACE breaks down bradykinin which is a vasodilator. ACE inhibitors result in increased amounts of bradykinin, thereby increasing vasodilation.
Angiontensin II receptor antagonists
directed action against ATII receptors; blocks ATII formed by other routes; doesn’t prevent breakdown of bradykinin
aldosterone antagonists
spirolactone (diurectic)
used to block aldosterone escape
negative inotropes
Beta blockers (class 2); calcium channel blockers (class 4)
Class 1 AARDs
block sodium channels
reduce rate of depolarization by blocking fast inward Na+ current
Class 2 AARDs
Beta-blockers: reduce sympathetic drive; slow AV node conduction; negative inotrops (decrease force of contraction, decrease O2 consumption, offset any hypoxia that may be contributing)
B1 in heart; B2 in bronchial and VSM, also in nodal tissue
Class 3 AARDs
Block outward K+ channels (responsible for repolarization)
markedly increases AP duration and refractory period
also have effects on other classes
Amiodarone is a sodium channel blocker, alpha and beta block and calcium channel blocker
Sotalol has beta blocking actions also
Class 4 AARDs
block L-type calcium channels (voltage operated Ca2+ channels that allows Ca2+ during depolarization–> triggers Ca2+ release from SR to cause contraction)
reduce AP height, prolong AP at node
shorten AP at cardiacmyocytes
negative inotropes: decrease force of contraction
positive lusitropes: diastolic relaxation of ventricles
Cardiac glycosides
inhibit Na+/K+ pump so that sodium can’t be extruded, intracellular sodium concentraions increase, and calcium levels also build up inside the cell.
Increased cytoplasmic concentrations of calcium cause increased calcium uptake into SR–> more powerful contraction
Refratory period of AV node is increased
Increased parasympathetic activity results in a decreased sinus rate, decreased speed of AV node conduction, prolonged refractory period; slow ventricular response to atrial flutter.
Treatment of bradyarrhythmias
muscarinic antagonists; methylxanthines, beta agonists
Muscarinic antagonists (bradyarrhythmia tx)
antagonism of muscarinic ACh receptors–> positive chronotropes
Methylxanthines
mild pde inhibition- not specifc to III or V
enhanced sympathetic drive–> mild positive inotropic and chronotropic effects
beta agonists
stimulation of beta adrenergic receptors
