LIST OF DRUGS FOR 1st TEST

I. Autonomic nervous system

GLAUCOMA Drugs: B-blockers, M agonists, PGF2a agonist;

M3 receptors on endothelial cells (Gq > IP3 and DAG > Ca2+ - activates NO synthase
Gastric secretion: M3/M1
- M3 receptors on parietal cells – gastric acid secretion ; on glands – secretions
- M1 recepotrs mainly on parasympathetic ganglia in stomach – trigger release of moclules like histamine
which then cause gastric acid secretion (H2 receptors on parietal cells)
Cholinomimetics (M2,M4 – Gi, M1,M3, M5 – Gq; ***M3 dilates healthy vessels)
a. direct
Acetylcholine – nAchR and mAchR agonist – short duration of action (5-30 s); intravenously
- should not be used in patients with asthma, bradycardia, or hypotension.
Methacholine – **Challenge test for asthma diagnosis (degree of bronchoconstriction)
> Patient is Coughing and Wheezing but spirometry results fairly normal – do methacholine challenge.
> If patient has an “obstruction” but you do not know if its COPD and asthma – give B2 agonist – asthma
will improve, COPD will not
Muscarine – natural mAchR agonist (alkaloid found in certain mushrooms – toxic at high doses)
Bethanechol – Activates bladder smooth muscle = voiding of urine (used to help with urine retenetion);
-- no nAchR activity (selectively stimulates mAchR)
- Only for non-obstructive causes of urine retention (e..g neurogenic bladder)
- should not be used in patients with a history of asthma (due to bronchoconstriction), peptic ulcer disease
(Ach stimulates acid secretion), or bladder obstruction (you would be trying to increase urination when there
is an obstruction = pain and damage)
- oral administration
Carbachol – both mAchR and nAchR agonist
- constricts pupil and relieves intra-ocular pressure in open-angle glaucoma
--- resistant to degradation by AchE
Pilocarpine
- drug of choice for both narrow-angle glaucoma (constricts sphincter = more access to canal of Schlemm)
and open-angle glaucoma (constricts ciliary muscle – allows aqueous humour to go form posterior to
anterior chamber (applied topically to eye)
- treatment of dry mouth and dry eyes in patients with Sjögren syndrome (oral administration)

Cevimeline – treat dry mouth in Sjorgen syndrome

B) indirect agonists = cholinesterase inhibitors
Edrophonium – short acting (5–15 min); used to diagnose MG; (IV administration)
- Tensilon challenge test – see if MG symptoms improve
Pyridostigmine – long-acting (4-8h) – treatment for MG ; oral
- Used with glycopyrrolate, hyoscyamine, or propantheline to control pyridostigmine side effects
Neostigmine - Treatment of MG (30 min – 2h)
- Used to stimulate the GI tract and bladder in cases of postoperative intestinal and bladder atony.
- Used by anesthesiologists to overcome non-depolarizing neuromuscular blockade (e.g., as caused by
pancuronium or vecuronium).
- „Neo = NO CNS penetration” (a quaternary (charged)
substance with poor lipid solubility)
Physostygmine – „Phreely crosses BBB” – tertiary amine
with good lipid solubility
> Antidote for anti-cholinergic toxicity (e.g. excess
atropine); 30 min-2h
- IV administration

Ambenonium – MG; 4-8 hours –

Demacarium – glaucoma – 4-6 hours

AchE inhibitors Penetrating CNS – Alzheimer’s disease –

Rivastigmine, Donepezil, Galantamine
Echothiophate – organophosphate; irreversibly inhibits AchE; long acting - 2-7 days
- treatment of chronic glaucoma

parathion, malathion – irreverible AchE inhbitor (active forms = paroxon and maloxon)
- palaxon = more toxic; (malaxon can be degraded in mammals and birds)
- increased stimulation of both nAchR and mAchR
- almost never used clinically – usually insecticide poisoning when systemic
--- seizures, bradycardia, GI upset (vomiting, diarrhea), salivation;
- flaccid paralysis from NMJ stimulation (depolarizing block)
****main cause of death = respiratory failure (strong bronchospasm and mucous secretion!)

*Atropine (mAchR antognist) used to treat mAchR symptoms (every 5-15 min until pupils start to dilate)
*Pralidoxime – if given early enough – can unbind the organophosphate from AchE
Dyflos, Parathion, Marathion, Sarin (nerve gas) *Sarin is strongest
> The “-thion” organophosphates (those containing the P=S bond) are activated by conversion to “-oxon”
(P:O) derivatives. They are less stable than halogenated hydrocarbon insecticides of the DDT type;
therefore, they are less persistent in the environment. Parathion is more toxic than malathion. It is very
lipid-soluble and rapidly absorbed through the lungs and skin
b. cholinesterase reactivators = Pralidoxime, Obidoxime – should be given for few hours
***ANTICHOLINESTERASE POISONING (too much Ach!)
> Muscarinic effects: Low HR, bronchoconstriction, Diarrhea, Urination, Salivating, Lacrimation, Sweating,
Vomiting, Pupillary constriction
> Nicotinic effects: Neuromuscular blockade (similar to succinylcholine which binds nAchR – lasts way
longer – muscle initially depolarizing but then more signals can; t be transmitted becasue succinylcholine is
still occupying nAchR receptors = muscle relaxation)
> CNS: Respiratory depression (***main cause of death), lethargy, seizures, coma
Cholinolytics – MUSCURINIC ANTAGONISTS
> EYE – prevent sphincter contraction = pupil dilation and prevent accommodation (cyclopegia)
> HEART – atria – slight increase HR
> LUNGS – decrease mucous secretion and cause bronchodilation
> GI tract – decrease motility and secretions (decreased salivation and lacrimation) – dry eyes and mouth
> URINARY – decrease urination (relax bladder)
> CNS – agitation, hallucinations, delirium – „mad as a hatter”
> Hyperthermia via sweat inhibition (especially in children) – heat retention – hot as a pistol
„Blind as a bat, dry as a bone, hot as a hare, mad as a hatter, full as a flask
Atropine – for treatment of bradycardia and ophthalmic applications
- antidote for severe AchEi poisoning, rapid-onset mushroom poisoning, reversal of lethal
bradyarrhythmias during advanced cardiac life support, motion sickness, helps asthma/COPD, reverses
depressed SA or AV nodal depression (that can accompany an MI or shock), treats AV block
- do not use if effect of something will be potentiated (e.g. Hypertension or high HR)
SCOPOLAMINE – CNS – treat motion sickness (SMS) via transdermal patch; CNS depression
- easily crosses BBB and blocks M1 receptors on vestibular apparatus
- interferes with neuronal communication between the vestibular area and the vomiting center of the brain,
thereby preventing motion sickness
- CNS effects – also used for sedation and amnesia
***Unusual side effect = blocking short term memory
Pirenzepine, Telenzepine – M1 antagonists – for peptic ulcer disease (not available in USA)
- block M1 on vagal ganglion cells that innervate stomach – fewer side effects
Glycopyrrolate - for peptic ulcer disease in adults; severe underarm sweating, excess salivation
Ipratropium – treat reactive airway disease - COPD and asthma (give up to 4 times daily
> Tiotropium, Aclidinium, Umeclidinium (LAMA = long acting mAchR Antagonist)
> Tiotropium = longer -acting (given only once daily***)
> Aclidinium = available in combo with long-acting β2-adrenoceptor agonist for COPD
Tropicamide (short acting – diagnostic) – 15-60 minutes
Cyclopentolate (2-12 h), Homatropine (24 h) – EYE - topical ophthalmic use
- prevent sphincter contraction = pupil dilation = miadrasis
- prevent ciliary contraction – prevent accomodation (cyclopegia)
- eye-drops or ointments for refractive measurements and ophthalmoscopic examination
> atropine (>72 h), homatropine (24 h), cyclopentolate (2–12 h), and tropicamide (0.5–4 h = diagnostics)
Oxybutinin, Tolteridine, Solifenacin Darifenacin -- urinary urgency and hyperhidrosis
- mAchR antagonists = bladder relaxation and less sweating
***Darifenacin – slightly selective for M3 antagonism

Dicyclomine & hyoscyamine – mAchR antagonists – IBS treatment (reduce motility, less cramping)
***Dicylomine – M1 specific – hence no effect on gastric secretions (since that’s M3 mediated)
Propentheline bromide – for excessive sweating, IBS (GI cramps and spasms), enuresis
Benztropine, Procyclidine, Biperiden, trihexyphenidil -- Parkinson’s Park my Benz)
-- Parkinson's disease - loss of dopaminergic neurons in substantia nigra (M1 antagonism)
*Normally, dopamine inhibits excess GABA release, while Ach stimulates GABA release
- Less inhibition = more GABA due to unopposed Ach
- Use mAchR to decrease Ach stimulation in attempt to bring back proper balance
Nicotine (as addictive) (Overdose – initially stimulates Nm and Nn– then causes block!
Varenicline – partial agonist at α4β2 nicotinic receptors - in CNS – for smoking cessation
Cytisine – another partial agonist – smoking cessation
Antinicotinic ganglion blockers (basically never used anymore)
> Hexamethonium – selectively blocked ganglionic Nn receptors *including the ones at adrenal medulla
-- was used for HTN in the past; obsolete now - too many side effects
What would you observe?
***In most of the body – it is the parasympathetic tone that normally predominates
***In vessels – it is the sympathetic tone
You give a patient hexamethonium – blocks Nn at all autonomic ganglia
- in almost all areas, you see slight sympathetic effects (since normally parasymaptehtic tone keeps
everything in check) = pupil dilation, increase HR, decreased gut motility, urine retention, less sweat
- but at vessels, you see vasodilation – since normally sympathetic tone keeps them fairly constricted
***Finally, realize that in the presence of an autonomic ganglionic blocking drug no autonomic reflexes
(e.g., baroreceptor reflexes; pupillary constriction in response to bright light) can occur.

> Trimethaphan : IV only, short-acting; was used for hypertensive emergencies and controlled hypotension
> Mecamylamine (non-selective nAchR blocker); oral, enters CNS; only for research now
Drugs affecting neuromuscular junction – Anti-nicotinic NMJ blockers (non-depo and depo)

NMJ blockers are medications used to relax the muscles during surgical procedures (e.g. tracheal
intubation) and mechanical ventilation. They work by inhibiting the actions of Ach on nicotinic receptors at
NMJ – muscles become relaxed and unable to move.
.
> Non-depolarizing blockers – competitive antagonists
- used in mechanical ventilation and to aid in surgery.
- all have „-CUR- within the name atracurium, vecuronium, rocuronium, pancuronium, and tubocurarine
- typically injected IV, and in less than a couple of minutes, they begin paralyzing small muscles of the face
and fingers; then larger muscles in the neck, torso, and limbs; then finally, the diaphragm.
- Gradually, in about 40 to 90 minutes, these muscles start recovering in the reverse order, so first the
diaphragm, then the limbs, torso, neck, and then fingers and the face.
> SIDE EFFECTS: depends on drug
- Atracurium can cause some histamine release = some hypotension and bronchospasm
---- breakdown product Laudanosine can cross BBB and cause seizures ****
- Pancuronium – can also increase HR (reflex tachycardia due to hypotension)
> Depolarizing agents cause prolonged stimulation and subsequent desensitization of the receptors.
--- They can facilitate tracheal intubation or SHORT surgical procedures.
Non-depolarizing agents (-CUR-)

Isoquinolones – side effect of some histamine release (and bronchospasm)

- tubocurarine – side effect of mast cell degranulation and histamine release – not used in practice
- atracurium – prototype – histamine release side effects; laudanosine > BBB > seizures
- Cis-atrcurium – has basically replaced atracurium – less side effects and stronger acting
*** spontaneously degrades in plasma – dose not affected by ppl with renal or liver failure
- doxacurium
- mivacurium – shortest acting (15 min)

Steroid structure – no side effects („ Robin Van PPersie”) – ONIUM

Pancuronium – can cause slight tachycardia (minor M2 antagonist activity)
Vecuronium
Rocuronium
Pipecuronium
Gantacurium – ultra fast onset & short acting (spontaneous degradation in reaction with cysteine)
Sugammadex – (brand name = Bridion)
- used for the reversal of neuromuscular blockade induced by rocuronium and vecuronium only in
general anaesthesia (*non-depolarizing blockade via competitive antagonism with Ach)
*** Sugammadex selectively binds (encapuslated or chelates) rocuronium or vecuronium, thereby
reversing their neuromuscular blocking action. Due to its 1:1 binding of rocuronium or vecuronium, it is
able to reverse any depth of neuromuscular block.
> Can give AchE inibitors (Neostigmine) to reverse non-depolarizing muscle block

***Halogenated hydrocarbon anesthetics such as desflurane enhance the effects of nondepolarizing

NMBs by exerting a stabilization effect at the neuromuscular junction (NMJ)
*** Aminoglycoside antibiotics increase the effects of nondepolarizing NMBs by reducing the release of
ACh from the cholinergic neurons (inhibition of VG Ca2+ channels)
Depolarizing blockers = Suxamethonium, Decamethonium (10 carbons b/w the N)
Succinylcholine – Nm agonist at NMJ – produces persistent stimulation and depolarization of the muscle
> RAPID ACTING - Initial muscle contractions (fasciculations) occur quickly (within 1st minute)
> short duration of action (max 10 minutes) due to rapid hydrolysis of liver and plasma cholinesterase
- induces brief paralysis in short surgical procedures
> Phase I block – agonist remains bound – muscle cannot repolarize – fasciculations can occur
> Phase II block – desensitization – even if Ach binds – muscle does not depolarize = full paralysis
**People with rare mutation in RyR receptor – excess Ca2+ release and muscle contractions = malignant
hyperthermia ---- treat with dantroline – inhibits RyR receptor
**Could also cause hyperkalemia – if muscles get damaged and release K+
* Note: 1:3000 patients have low levels of plasma cholinesterase = effects might last couple hours

Drugs affecting cholinergic transmission:

Botulinum – prevents Ach release from all cholinergic nerves in autonomic and somatic nervous system
= inability to activate all post-ganglionic neurons (sympathetic and parasympathetic), no physiologic release
of epinephrine from the adrenal/suprarenal medulla, and flaccid skeletal muscle paralysis due to failure of
ACh release from motor nerves.
> The cause of death is ventilatory failure because the intercostals muscles and diaphragm are paralyzed—
but of course that’s not the only problem [LETHAL DOSE = 1 pg]
> Symptoms of toxicity = Diplopia (double-vison), Dysarthria (trouble speaking), Dysphagia (trouble
swallowing), Dyspena (trouble breathing)

 Therapuetic uses of Botulinum:

- treat local muscle spasm
- urinary incontinence (intra-bladder injection)
- sialorrhea (hypersalivation; can cause drooling)
Hemicholium - inhibits choline transport in nerve endings
Vesamicol – inhibts VAT – transport of Ach into vesicles (inhibts storage)
Magnesium and aminoglycosides – block VG Ca2+ channels = no NT release from vesicles – RESEARCH

Amifampridine & 4 aminopyridine = block K+ channels on pre-synaptic neurons = more Ach RELEASE
- used to treat Lambert Eaton syndrome (Abs against presynaptic VG Ca2+) - small cell lung carcinoma
Adrenomimetics

Norepinephrine (a1 > a2 > B1) – for hypotension and septic shock
- increased TPR = increased BP + reflex bradycardia; B1 = increased contractility
- IV for rapid onset of action; 1 to 2 minutes, following the end of the infusion.
- It is rapidly metabolized by MAO and COMT, and inactive metabolites are excreted in the urine.
Epinephrine (B2 > a1, B1) – has much stronger effect on B2 receptors than NE
- B1 = increase HR and CO
- a1 = some vasoconstriction
- B2 = more vasodilation + reflex tachycardia *Pulse pressure will increase*
*At low does – B > a (increase HR and contractility) B2 – bronchodilation and vasodilation (low BP)
*At high doses – alpha constrictor effect predominates (see increase in diastolic)

***Treatment of choice following allergic reaction (Epi Pen injection 0.5 mg IM)
- Treatment of cardiac arrest and severe hypotension.
- Treatment of wide-angle glaucoma when administered as an ophthalmic solution.
*Low-dose subcutaneous injections can also be given when local anesthetics are administered as
epinephrine produces localized vasoconstriction, decreasing the ability of the local anesthetic to become
absorbed into the systemic circulation and increasing [local anesthetic] at desired site
Dopamine (D1=D2 > B > a) – septic shock (renal dilation helps save kidneys from ischemic injury)
*D1 receptors: Gs  cAMP = vasodilation of renal arterioles; activates direct pathway in striatum
* D2 recpetors: Gi = less CAMP; modulates/decreases NT release ; inhibits indirect pathway in striatum

LOW doses = renal vasodilation through D1 dopamine receptors; promotes natriuresis (via increased GFR
and Na+ excretion; in PCT, decreases Na+/K+ ATPase – more Na+ remains in tubules)
Medium doses = β1 stimulation and increases CO;
High doses, it causes α1 activation and vasoconstriction.
---- This is also used in treating the low blood pressure in septic shock
Dobutamine (B1 agonist > B2, a) – heart failure & cardiogenic shock (increase CO)
- used clinically as a β1-selective agonist.
- useful in CHF because of its ability to increase CO while causing a decrease in ventricular filling pressure.
- It may not benefit patients with ischemic heart disease because it tends to increase HR and O2-demand
To be precise, the dobutamine is a racemic mixture:
> the (+) isomer, which is a potent β1 agonist that also has some α1-antagonist effects;
> the (−) isomer is an efficacious and potent α1 agonist.
--- thus, on occasion, drug may cause significant increase of blood pressure via a1, however this is a dose-
dependent effect; the B1 cardiac effects persist for a while even after dose is dropped.
Xamoterol – 3rd gen B1 partial agonist
> It provides cardiac stimulation at rest but it acts as a blocker during exercise
Isoproterenol (B1 & B2 agonist; negligible a1) – for evaluation of tachyarrhythmias
- B1 = increase HR and CO - B2 = vasodilation = decreased BP + reflex tachycardia
> Used to treat torsade de pointes in conjunction with magnesium; and for HEART BLOCK
> can also be used as aerosoal in acute asthma (nebulizer)
Phenylephrine - pure α1 agonist = potent vasoconstrictor (reflex bradycardia)
- used in various forms to decrease nasal congestion (nasal spray),
- increase blood pressure (IV)
- dilate pupils (eye drops) for eye examinations by activating the pupillary dilator muscle (10-30 min)

OxymetaZOLINE and tetrahydrolozine – selective a1- agonist – vasoconstriction

- topically used for facial erythema associated with rosacea;
- intranasal form for nasal decongestion

NaphaZOLINE – a1 agonist
a) nasal decongestant
b) vasoconstrictor added to eye drops to relieve red eye; decrease congestion
------- rapid action in reducing swelling when applied to mucous membranes

Xylometazoline – nasal decongestant – used for rhinitis and sinusitis

- a1 agonist – stimulates receptors lamina propria of blood vessels in the nose.
- The decongestant effect is due to constriction of large veins in the nose which swell up during the
inflammation of any infection or allergy of the nose.
- The smaller arteries are also constricted and this causes the colour of the nasal epithelium to be visibly
paler after dosage.

A1 agonist side effects and contra-indications:

Due to a1 activity = vasocontriction; should not be used by people with HTN , or other heart problems.
Midodrine (α1-agonist = systemic vasoconstriction) – used to increase BP in orthostatic hypotension
- often used in patients with advanced liver disease
- Side efects: supine HTN, urinary retention
Tetrahydrolozine
Methoxamine – a1 agonist – no longer marketed
Metaraminol = catecholamine analog that is resistant to metabolic degradation by MAO and COMT
- used in the prevention and treatment of hypotension, particularly as a complication of anesthesia.
- displaces NE from nerve terminals; can also directly stimulate a1 at higher doses

Fenoldopam- D1-receptor agonist that is used to produce splanchnic and renal vasodilation for the
treatment of severe HTN (emergency) (promotes natriuresis);
> can cause hypotension and tachycardia
Droxidopa - synthetic amino acid precursor which acts as a prodrug to the NE
> Unlike NE, droxidopa can cross BBB (lipohillic)
> Neurogenic orthostatic hypotension (NOH) dopamine beta hydrolase deficiency (not enough NE)
-- NOH associated with multiple system atrophy (MSA), familial amyloid polyneuropathy (FAP), pure
autonomic failure (PAF) --- Droxidopa works to increase NE levels in periphery and brain

Mirab3gron – B3 – reduce urinary urgency (relax detrusor, constrict sphincter)

- may increase blood pressure and should not be used in patients with uncontrolled hypertension.
- It increases levels of digoxin and also inhibits the CYP2D6 isozyme, which may enhance the effects of
other medications metabolized by this pathway (for example, metoprolol).
Indirect sympathomimetics
Ephedrine – for urinary incontinence, hypotension; nasal decongestant; fix hypotension during anaesthesia
> stimulates release of NE and E from neurons (not Ca2+ dependent)
- also directly stimulate both α- and β-receptors.
- The overall net effect = increase systolic and diastolic blood pressure (through α1 - and β1 -stimulation), to
increase cardiac output (through β1 -stimulation), and to induce bronchodilation (through β2 -stimulation).
**can stimulate the CNS, causing insomnia, decreased appetite, and improved athletic performance.

Pseudoephedrine – nasal decongestant (constrict vessels in nose = less flow = less mucous production)
Amphetamine – enters the CNS and stimulates the release of NE, E and dopamine from neurons, thereby
leading to a hyper-aroused state; insomnia and decrease appetite
Methylphenidate = derivative of amphetamine > used to treat ADHD, obesity, narcolepsy

***Tyramine (found in wine, cheese, smoked meats) – also trigger release of NE form nerve terminals
***Monoamine oxidase inhibitors –de-aminates catecholamines, MAO-A – prefers NE and 5HT; MAO-B
prefers NE and DOP (Selegeline = selective MAO-B blocker – used for Parkinson’s)

Cocaine and TCA – blocks reuptake of norepinephrine, serotonin, and dopamine; drug of abuse
> increased [dopamine] in the brain’s limbic system = euphoria associated with cocaine use.
> Increase [NE] = vasoconstriction and can cause cardiac ischemia; nasal septum perforation

***Catecholamines – NE, E, dopamine, dobutamine, Iso

– rapid onset, brief duration, not administered orally, do not penetrate BBB
***Non-catecholamines – longer duration, orally or inhaled, can penetate BBB

> Postganglionic Sympathetic Nerve Terminal Blockers

> Drugs that deplete the adrenergic nerve terminal of its NE stores (eg, reserpine) or that deplete and block
release of the stores (eg, guanethidine, guanadrel) can lower blood pressure.
> The major compensatory response is salt and water retention.
> In high dosages, these drugs are very efficacious but produce severe adverse effects and are now
considered obsolete for hypertension
Guanethidine – inhibits NE release from sympathetic neurons via gradual depletion of NE stores
> in order for it to exert it effects, it has to be taken by the same NET re-uptake pumps; so imagine, if
someone is on TCAs for depression which blocks re-uptake and has side effects of HTN, prescribing
guanethidine will do nothing since it’s uptake is also being blocked
> It has been used to treat hypertension in the past
> rarely used due to significant side effects (e.g., orthostatic hypotension that may lead to shock)
Resperine – prevents dopamine movement into vesicles via VMAT (NE depletion)
- Side effect = mental depression = contra-indicated in people with depression
-- potential consequence of long term use = adrenergic receptor hypersensitivity (e.g. patient was on
reserpine for long time – showed up due to hypotension – doc gave a1 agonist and there was a HUGE
vasopressor effect compared to normal – due to hypersensitive receptors)

***Alpha-2 agonists - cause vasoconstriction when given as IV or topically (eg, as a nasal spray)
> when given orally they accumulate in the CNS and reduce sympathetic outflow and blood pressure
[act CENTRALLY = decrease symapethetic outlow to periphery]

CLONIDINE: high BP, ADHD (rarely), drug withdrawal (alcohol, opioids), Tourettes
> used by mouth, by injection, or as a skin patch.
> onset within an hour; effects on blood pressure lasting for up to 8 hours
Metabolism = Liver to inactive metabolites; 2/3 CYP2D6 – potential for drug intractions
Adverse effects: Those due to less sympatehtic outlfow – decreased HR and BP, miosis, CNS depression
***Rebound HTN upon abrupt cessation (taper down dose!)

GUANFECINE – high BP, ADHD (FDA approved monotherapy – can be combined with stimulants)
 Enhances the regulation of attention and behavior by the prefrontal cortex
> Frontal cortex has postsynaptic HCN and KCNQ K+ channels that are opened by higher [cAMP]
> Activation of post-synaptic a2 receptor = less cAMP = less K+ channel opening = depolarization
- enhances prefrontal cortical synaptic connectivity and neuronal firing
> metabolized by CYP3A4 (main one) = potential for numerous drug interactions
Adverse effects = sleepiness, tiredness, headache, and stomach ache
> Methyldopa is a prodrug; it is transported into the brain and then converted to methylnorepinephrine.
---- Direct Coombs hemolysis; drug-induced lupus; hyperprolactinemia
> Clonidine and methyldopa reduce blood pressure by reducing CO, vascular resistance, or both.
> The major compensatory response is salt retention

> TIZENIDINE - α2 agonist used to treat muscle spasticity due to spinal cord injury, multiple sclerosis,
and spastic cerebral palsy; - taken orally;
- mechanism of action : a2 agonism and muscle relaxation unknown.

*Newer a2-agonists for GLAUCOMA

> apraclonidine – glaucoma and diagnosis of Horner’s syndrome (via partial a1 agonist)
> brimonidine – glaucoma – decrease aqueous humour production
Dexmedetomidine (a2 agonist) – decreases sympathetic outfow
= sedative used in intensive care settings and surgery.
- unique - provide sedation without respiratory depression
• No respiratory depression • Blunts undesirable cardiovascualr reflexes

Potential side effects of a2 agonism = PLT aggregation and decrease insulin release !
LUNGS – B2-Selective agonists = drugs of choice for ACUTE asthmatic bronchoconstriction (-ROL)
- albuteROL, metaproteRENOL, – may be life-saving during emergencies (acute asthma attacks!)
- Long- acting = salmeteROL, formoteROL, indacaterol, olodaterol, and vilanterol are used in
combination with corticosteroids or antimuscarinic agents (iprotropium, tiptripoum) for prophylaxis in
asthma or for COPD – these are not intended for acute treatment
--- B2 agonists can cause skeletal muscle tremor and tachycardia, anxiety

Terbutaline & Ritodrine – short acting **β2 -agonist that relaxes smooth muscle in both the lungs (for
asthma and COPD) and in the uterus (reduces contractions)
> Used to delay preterm labor by reducing uterine contractions, but should only be used in cases where
preterm labor needs to be delayed by 48 hours or less (i.e., if corticosteroids need to be administered to assist
in fetal lung maturity).
Adrenolytics
Non-selective α-blockers (mainly for pre-surgical managemnt of pheochromocytoma)
Phenoxybenzamine – irreversible, long acting, non-competitive a1 antagonist; (slightly selective for a1)
- treatment of pheochromocytoma or given before removal of a pheochromocytoma to prevent
hypertensive crisis ; also some anti 5HT and anti H1 effects
Phentolamine – reversible; shorter-acting, (+ reflex tachycardia since a2 also blocked)
> diagnose pheochromocytomas (patients with pheochromocytomas will demonstrate a larger than
expected decrease in blood pressure when given phentolamine; ***also for SUDDEN BP increase
> Given to patients on MAO inhibitors who accidentally ate tyramine-containing foods (could cuase
hypertensive crisis) and for severe cocaine-induced hypertension (2nd line); also for pheochromocytoma
***Normally, Tyramine quickly metabolized by MAO = low bioavailability

Adverse effects: Orthostatic hypotension (vasodilation due to a1 block); reflex tachycardia

*** patient who comes in with HTN (200/140) due to pheochromocytoma (excess catecholamine release)
> Must give a-blocker first! Do not give B-blocker first. Why?
> a1 = massive vasoconstriction – which contributes to high BP – also causes high afterload
> Currently, LV is still capable of overcoming high afterload because heart is also being stimulated (B1
receptors) so contractility is also elevated (as well as HR)
> If you give B-blocker, cardiac HR and contractility will decrease, while vascular resistance (afterload
remains high – left ventricle will not be able to generate pressure necessary to pump blood out through aorta
– heart as a pump starts to fail > cardiogenic shock.
> Therefore, give a1-blocker first to vasodilate, then B1-blocker to decrease excessive cardiac stimulation

a1-selective blockers (-osin) - vasodilation + reflex tachycardia

Prazosin (2-3 hours), Alfuzosin (10 hours) , Doxazosin (t=18 h), Terazosin (t=12h)
> BPH (a1 block = sphincter relaxation) – Terazosin, Tamsulosin, Doxazosin
> HTN – all except selective alpha a1-A blockers (e.g. Tamsulosin)
> PTSD – only prazosin

General side effects:

> Decreased BP > dizziness, orthostatic hypotension, priapism
> Pupillary constriction (miosis)
> Good effect on lipoproteins – decreased LDL and TAG, raise HDL (a1 agonism normally increases
hepatic gluconeogenesis)
> All metabolized by liver – hence caution in people with heaptic impairment

PRAZOSIN – for HTN, PTSD and to manage Raynaud Phenomenon

* "first-dose effect" which is a sudden drop in BP and can occur within a few hours after the first dose.

DOXAZOSIN : HTN and BPH

TERAZOSIN : HTN and BPH
ALFUZOSIN – mainly for BPH

***TAMSULOSIN = newer medication specific for a1-A receptors in urinary system – used for BPH
(= no hypotension!!! – does not bind a1-b receptors on vessels - thus no reflex tachycardia)
Side effects: cause abnormal ejacualtion and back pain
SILDOSIN – weaker but longer acting than tamsulosin (also sleective a1-A)
a2-selective blocker:
- Mirtazipine – a2 antagonist, 5HT2 and 5HT3 antagonist, H1 antagonist
> used to treat DEPRESSION (especially if person also has eating disorder)
> Side effects: sedation, increased appetite, weight gain
*Why increase appetite? Lorcaserin = 5HT2-C agonist – used to decrease appetite (obesity treatment), so
blocks 5HT2-C can increase appetite

> Yohimbine – off-label treatment of erectile dysfunction (noramlly it is a vet drug for dogs)
---- may also reverse effects of A2 agonist like clonidine
> Idoxazan – scientific research
β-blockers (Uses: HTN, post-MI, chronic HF – decrease mortality, thyroid storm, performance anxiety)
B1 block = decrease cAMP = lower HR, conduction velocity, contractility, decrease CO
- effects most noticeable during exercise (when body naturally wants to increase HR)
B1 block in kidney = less renin release
B2 block – risk of bronchoconstriction in lungs
B2 block = decrease TAG breakdown in adipocytes, decrease glycogen breakdown; hypoglycemia
B2 block = less K+ uptake into cells = hyperkalemia (*Quick Tx of hyperK+ = AlbuteROL and insulin
B block in eye – decrease humour production *glaucoma – timolol
B-block – can be used for migraine prophylaxis; prodromal phase – triptans, ergotamines.
How do they mask symptoms of hypoglycemia ? Mask the rapid HR and tremor because they block the
effects of NE which is released when someone has low blood glucose levels.

B1 SELECTIVE (from A  M)
Acebutolol – has ISA = intrinsic sympathomimetic activity (patial agonist at low dose, but complete
blocker at higher doses; causes less bradycardia so may be useful in patients with low HR
Atenolol - is water-soluble, can enter the CNS and may cause nightmares
Betaxolol – glaucoma – decrease humou production
Bisoprolol
Esmolol – ultra short acting (half life = 10 min); for arrhythmias, HTN, aortic dissection
Metoprolol – all regular side effects of B-block + DYSLIPIDEMIA (metabolized by CYP2D6)
NON-SELECTIVE (B1 = B2) – mostly go from N  Z
Propranolol – treatment of HTN, migraines (cross BBB), anxiety, essential tremors, family tremors, control
of thyroid storm, akathesia = inability to remain still (on1ly effective in 30%)
Nadolol – excreted via kidneys – longest half-life
Sotalol (additional K+ - chanel blockade – prolongs repolarization phase – can be used for the treatment of
ventricular and supraventricular arrhythmias
-- may also cause QT prolongation, torsade de pointes, and electrolyte imbalances.
Pindolol – also partial agonist, and highly lipid soluble
Timolol – topical use for glaucoma (decreases humour production) -
NON-SELECTIVE α1 and β-antagonists (-ilol or -alol)
Carvedilol, Labetalol
- similar to normal B-blockers but more likely to cause orthostatic hypotension (a1) & sexual dysfunction
- may be useful for CHF
- Labetalol – HTN during pregnancy (Hydralazine, Methyldopa, Labetalol, Nifedipine)
Celiprolol – B1 antagonist; B2 partial agonist
Nebivolol –most selective B1 blocker!!!
- with some B3 stimulation = vasodilator – due to NO release from endothelium

PACPA – Pindolol, Acebutolol, Celiprolol, Penbutolol, Abetalol– have ISA = partial agonists
- At rest (no physical exertion) – demonstrate that agonist activity (light increase in HR and contractility)
- Upon exercise or stress – act like antagonists because they prevent stronger agonists (NE) from binding
******Do not give partial agonists to someone with ischemic heart disease

***IV β-blockers (e.g. labetalol, esmolol) are useful in the acute management of aortic dissection
(especially Stanford type B; follow with vasodilators) – aim for HR < 60 bpm - minimize shear

Propranolol and Pindolol – high lipid soluble – cross BBB – for anxiety, migraine, tremor

β-blocker toxicity is treated with glucagon, saline, or atropine (mAchR antoagnist)

**Glucagon has it’s own Gs receptors on heart – can bypass blockade of the others

Note: To quickly treat hyperkalemia (high K+, peaked T waves) – give B2 agonist like ALBUTEROL
- B2 agonists push K+ into cells

- Other B-blocker side effects – fatigue and exercise intolerance

Butoxamine = research drug – selective β2 antagonist – NO CLINICAL USE!

AUTACOIDS = endogenous molecules which don’t fall into autonomic groups

Autocoids – short-acting, near site of synthesis (paracrine)
- under thorough control in physiological conditions (responds to body’s needs or immune repsonse)
- can lead to tissue disease upon inapproariate activation or under-activation
Histamine
- major mediator of immune response (vasodilation, increased capillary permeability, pain sensitivity, itch)
- regulator of gastric secretion (H2 > Gs > cAMP)
- neurotransmitter in CNS (H1 – promotes wakefulness)
- synthesized in mast cells, basophils, ECL cells in gastric mucosa, neurons
- found in most tissues of the body; high [ ] in lung, skin, and GI
- Release from mast cells (degranulation) during allergic reactions (IgE cross-linked by antigen) or normal
inflammatory reactions (tissue injury)
***CERTAIN DRUGS can release histamine by non-receptor action (morphine, tubocurarine) –
therefore sometimes we will give patient anti-histamine before giving them their actual treatment drug.
Actions of histamine: *TRIPLE RESPONSE = redness, wheal, flare (pain + itch)*
> H2 – Gs – cAMP – gastric acid secretion from parietal cells
> Smooth muscle contraction (besides blood vessels) – H1 – Gq > IP3/DAG > Ca2+
- ***bronchi > bronchospasm (only strong in people with asthma or bronchial hyperreactivity
- bladder, bowel, uterus, iris
> Vasodilation (dilation of terminal arterioles and post-capillary venules) + capillary permeability
- constriction of veins*
> Increased CO and HR – H2 receptors on heart
> Pain and Itching
> CNS – mediaitor of some types of vomting (some H1 blockers good for motion sickness)
-- inhibitor of NT release in CNS and GI

H1 > Gq > IP3/DAG/Ca2+ - smooth muscles, vascular endothelium (= activation of NO synthase), brain,
GI smooth muscle, bronchial smooth muscle
H2 – Gs – cAMP – gastric mucosa, cardiac muscle (stimulation), mast cells (negative feedback)

Histamine
Mast cell stabilizers - used to prevent or control certain allergic disorders
> block mast cell degranulation, stabilizing the cell and thereby preventing the release of histamine and
related mediators. One suspected pharmacodynamic mechanism is the blocking of IgE-regulated calcium
channels. Without intracellular Ca, the histamine vesicles cannot fuse to the cell membrane and degranulate.
> inhalers they are used to treat asthma
> nasal sprays to treat hay fever (allergic rhinitis)
> eye drops for allergic conjunctivitis
> oral form used to treat the rare condition of mastocytosis (mast cell overproduction)
KETOTIFEN – H1 inverse agonist (also minor leukotriene antogonist and PDE inhibitor)
- relieves and prevents eye itchiness and/or irritation associated with most seasonal allergies.
- starts working within minutes; Half life = 12 hours
Azelastine - nasal spray to treat allergic rhinitis (hay fever) and as eye drops for allergic conjunctivitis
- The most common side effect is a bitter taste (about 20% of people).
--- Due to this, the manufacturer has produced another formulation of azelastine with sucralose
- Azelastine has a triple mode of action:
> Anti-histamine effect, Mast-cell stabilizing effect and Anti-inflammatory effect.

Nedocromil, Cromolyn (cromoglycans) – prevent mast cell degranulation

- given often to CHILDREN WITH ALLERGIES
Histamine H1 receptor antagonists 1st generation
a) Treatment of allergic rhinitis and conjunctivitis. .
- Many antihistamines are used to treat the common cold, based on their anticholinergic properties, but they
are only marginally effective for this use.
- Diphenhydramine also has an antitussive effect not mediated by H1-receptor antagonism.
b. Treatment of urticaria and atopic dermatitis, including hives.
c. Sedatives - Several (doxylamine, diphenhydramine) are marketed as over-the-counter sleep aids.
d. Prevention of motion sickness. e. Appetite suppressants

> Allergies, anxiety, insomnia, motion sickness

> were lipid soluble, crossed BBB = significant CNS actions, mainly due to anti-mAchR activity
--- anti H1 in brain – sedation
--- anti-mAchR side effects: sedation, dry mouth, blurred vision, urine retnetion, tachycardia
--- because of anti-mAchR – also quite effective to treat motion sickness or insomnia
--- also mild anti a1 = vasodilation and orthostatic hypotension
-- mild anti-5HT in CNS – stimulate appetite and weight gain
H1 1st-gen antagonist LIST:
 Ethanolamines:
o Dimenhydrinate
o Diphenhydramine – also has anti-cough effect (not H1 mediated)
 Ethylaminediamines: Tripelennamine
 Piperazines:
o Hydroxyzine – used now as anxiolytic drug and for insomnia (sedation desired)
o Cyclizine
o Meclizine – motion sickness + for vertigo associated with vestibular disorders (MENIERE)
 Phenothiazines = Promethazine – almost exclusively used as anti-emetic
 Miscellaneous:
o Cryoheptadine – also 5HT2-C antagonist – stimulates appetite
o Antazoline
o Doxylamine – mainly sleeping aid & *Only FDA approved drug for morning sicknes
- In combo with Vitamin B6  used to treat morning sickness in pregnant women.
- Doxylamine is available OTC - used in nighttime cold medicines, such as NyQuil, as well
as in pain medications containing acetaminophen and codeine, to help with sleep.
- taken orally
 Clemastine – approved for rhinorrhea
Histamine H1 receptor antagonists 2nd generation
FEXO-LORA-AZEL-CET – anti-allergic effects (hay fever)
- far less lipid soluble – developped to avoid sedation and anti-cholinergic effects of 1st gen
- much preferred to treat allergic rhinits, HAY FEVER

Azelastine – triple mode of action – anti H1, mast cell stabilizer, anti-inflammatory
Cetirizine – minimal metabolsim - still some sedative effects
Loratidine – often given with pseudoepehdrine (nasal decongest); metabolism CYP2D6- and 3A4-mediated
Fexofenadine (metabolite of 2nd gen drug – sometimes refereed to as 3rd gen) –
Acrivastine
Levocetirizine

*** H1 blocking agents are: • Largely ineffective in bronchial asthma

• Not effective in angioedema since it is precipitated by histamine but maintained by peptide kinins
H2 receptor antognists – „--TIDINE” (H2 receptor on parietal cells > cAMP > gastric acid secretion)
- competitive antognists ; 4 available („ CIME nizza ran fam)
> Used for: Peptic ulcers, GERD, ZE syndrome (decrease gastric acid secretion)
> Cimetidine (prototype) – rarely used anymore due to side effects
***anti-androgenic side effects – gynecomastia, galactorrhea and impotence
***CYP450 inhibitor = numeorus drug interactions (if person is taking couple other drugs, could
experience various effects if cimetidine is added to his regimen
> Ranitidine
> Famotidine
> Nizatidine
Adverse effects: drowsiness
- dizziness, diarrhea, muscle pain, cardiac effects (H2 on heart)
- rebound effect (=when patient taken off the drug, production of gastric juices might be higher than before)

Serotonergic Drugs
• Enteramine - a smooth muscle stimulant in intestinal mucosa (later a local! hormone in the gut)
• an important neurotransmitter (main popualtion in raphne nucleus of brianstem)
> PLT aggregation – 5HT2-A
• plays a role in migraine headache and several other clinical conditions including carcinoid syndrome
• unusual manifestation of carcinoid tumor~ a neoplasm of enterochromaffin cells
Serotoninergic neurons
• mood, sleep, appetite, and temperature regulation, the perception of pain, the regulation of blood
pressure, and vomiting
• depression, anxiety and migraine
• the enteric nervous system of the GI tract (peristalsis and fluid secretion – 5HT4)
• Enterochromaffin cells – 90% of serotonin in body
• paracrine regulator in the gut
• IMAO: 5-hydroxyindole acetaldehyde, further oxidized to 5-HIAA
• 24-hour excretion of 5-HIAA = diagnostic test for tumors that synthesize excessive quantities of serotonin

5HT-1 – Gi – decrease cAMP – brain and smooth muscle (CNS blood vessels) - migraine
5HT-2 – Gq = IP3, PLC – CNS (hallucinogenic effects) & smooth muscle and PLTs (aggregation)
5HT3 – ligand gated Na+/K+ channel – Area postrema (CNS bottom of 4th ventricle) – nausea, vomiting;
sensory and enteric nerves – pain
5HT4 – Gs – increase cAMP – GI tract – peristalsis and secretion (pro-gastro-kinetic)
Serotonin agonists

Buspirone - 5HT-1-A partial agonist – management of Generalized Anxiety Disorder (GAD)

- takes 1-2 weeks for effects to appear
- does not involve GABA – hence less sedation and addictions than benzos
- minimal effects on cognition or memory; not additive with ethanol in terms of CNS depression;
- tolerance is minimal; and it has no dependence liability
- metabolized by CYP3A4 – plasma levels affected by CYP inducers

Sumatriptan (- triptans) = 5HT-1B/D agonist – for acute migraine and cluster headaches
- vasoconstriction and reduce inflammation of intracranial blood vessels (Gi > less cAMP > constrict)
- 50-80% of patients report pain relief within 2 hours (also decrease CGRP release)
***SIDE EFFECT – can cause coronoary artery vasospams = don’t give to ppl with CAD or angina
- avoid in: pregnancy, CAD, angina (including Prinztmetal, Raynaud’s phenomenon)

*Almotriptan – contains a sulfa-group – watch for allergies!

*Eletriptan – metabolized by CYP3A4 – do not give within 3 days after potent CYP3A4 inhbitor (e.g.
ketoconazole, nefadozone, ritonavir)
> Frovatriptan – do not give to ppl with peripheral vascular disease
> Zolmitriptan – longer duration; do not give to ppl with Wolff- Parkinson-White syndrome
Lorcoserin – 5HT-2-C agonist - in the CNS --- moderately reduce appetite „Lord I’m full”
Tegaserod – 5HT-4 partial agonist – IBS-C - newer drug - agonist in the colon (promotes peristalsis)
-- was approved and briefly marketed for use in chronic constipation (IBS-C)
-- but because of cardiovascular toxicity, its use is now restricted.

Metoclopramide – 5HT4 agonist (Gs) / 5HT3 antagonist ; Dopamine D2 antagonist

- anti-emetic (D2-CMZ) and pro-gastro-kinetic drug (improve bowel movements)
- indicated for diabetic gastroparesis and GERD as it promotes gastric emptying
Flibanserin – 5HT-1A receptor – full agonist in frontal cortex; partial agonist in hippocampus
> treatment of pre-menopausal women with hypoactive sexual desire disorder (HSDD)
> improves sexual desire, increases the number of satisfying sexual events, and decreases the distress
associated with low sexual desire „Flibanserin – Flick my clit”
Serotonin antagonists
Clozapine – was the first atypical (2nd gen) antipsychotic - 5-HT2A antagonist
- improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia
***Do not give to ppl with neutropenia – risk of even more agranulocytosis!
Cyproheptadine - very potent antihistamine (anti-H1) = allergy treatment
***At higher concentrations, also potent 5HT2-antagonist (Gq)
= effective treatment of serotonin syndrome (facial flushing, diarrhea, wheezing)

Ketanserin – 5HT-2 antagonist & a1-blocker

- for HTN and serotonin syndrome (5HT2 block – Gq)
- used for HTN caused by overdose of protamine during cardiac surgery (not available in USA)
- Can get GEL formulation for treating wounds, bruns, ulcers, fissures– accelarates epithelialization
OndanseTRON (Zofran), Granisetron (higher affinity; longer), dolasetron = 5HT-3 antagonists
– block serotonin centrally in CTZ and peripherally on vagal nerve terminals
- prevention and nausea and vomiting due to chemo-therapy and radiation; and POST-OP vomiting
***Best anti-emetic drugs currently used in clinical practice !
- side effects: QT prolongation and possible arrythmias

**Alosetron – approved for IBS-D in women – blocks 5HT3 in enteric neurons

- May cause GI side effects – severe constipation, ischemic colitis – must be discontinued immediately if
patient gets rectal bleeding, bloody diarrhea or wrsening of abdminal pain

Pizotifen – 5HT2-A/C antagonist – anti-migraine

Trazodone and nefazodone (5HT2 antagonist) –for depression & insomnia

> but also highly sedating, particularly trazodone; - low dose in evening for insomnia
> These drugs cause GI disturbances and postural hypotension in the elderly.
> trazodone may cause a rare priapism (prolonged erection) in men.
> Nefazodone has been associated with a rare hepatotoxicity resulting in hepatic failure and death.
Methysergide – 5HT2-b, 5HT2-c antagonist – antimigraine drug + used in caricnoid syndrome
5-HT2A antagonist, and it inhibits initial vasoconstriction in the early stages of a migraine
- is effective in 60% of patients for the prophylaxis of migraine
- toxicity = retroperitoneal fibroplasia and coronary and endocardial fibrosis

Ergot alkaloids – produced by Claviceps purpurea, a fungus that infects grasses and grains (rye)
- various degree of agonist and antogonist activity at 5HT, dopaminergic and a-adreno-receptors
- pharmacoloigc use determined by relative affinity and efficacy of individual agent for receptors

Post-partum hemorrhage – the -VINES

Methyl ergonovine & ergonovine – uterine selective agent
- produces sustained contraction of uterine smooth muscle which
decreases bleeding (5HT2 and a1)
***Must not be given before delivery of placenta; once placenta has
been removed – then administer
*** contraindicated in patients with pre-eclampsia or eclampsia (+
seizures) [HELLP]

MIGRAINES - ergot – „amines”

- Ergotamine and Dihydroergotamine
- 5HT-1B/D agonists = Gi = less cAMP
= vasonctriction of intracranial blood vessels
- often taken with caffeine which increases absorption
*Side effect = GI distress and vasospasm = also contra-indicted in ppl with CAD
*Most serious side effect = Retroperitoneal fibrosis - can lead to hydronephrosis or varicocele
***Serious ischemia may occur when given with intense CYP 3A4 inhibitors (grapefruit juice)
***Triptan derivatives preferred nowadays – less toxic

HYPER-PROLACTINEMIA
- Bromocriptine, cabergoline, pergolide = dopamine agonists (D2 = Gi = less cAMP – less PRL)
- dopamine = PIH (prolactin inhibitory hormone)
*Recall: Excess PRL – decreases GnRH levels
- infertility and amenorrhea in women; galactorrhea and gynecomastia in men
***Bromocriptine – also appears to reduce size of pituitary tumours of PRL-secreting cells

CARCINOID SYNDROME
– use Methysergide (5HTb & 5HT-c block) or 5HT-2 Antagonists (e.g. Cryoheptadine, Ketanserin)

LSD – causes hallucinations at higher doses

Main side effects of ergots:
> Vasospasm or prolonged vasoconstriction – can lead to ischemia or gangrene
***Use nitroprusside as antidote in case of emergency
> When used for long periods – unusual hyperplasia of connective tissue (methysergide)
> GI upset – nausea, vomiting
> Avoid during pregnancy
Trouble with sleep? Use short acting drugs
Shallow sleep or early awakening? Use long acting drugs

MELATONIN (MT1 and MT2 receptor agonists)

- used as sleep aid in jet-lag
- oral dosees of 0.5-5 mg
- usually given before bed

Ramelteon = approved for insomnia

- strong first pass effect, but long acting metabolite
Toxicity = dizziness, fatigue, fall in testosterone, rise in PRL

Tasimelteon – for non-24 hour sleep-wake disorder

- used in totally blind people to maintain circadian rythym

AGOMELATINE – MT agonist + 5HT2-c antagonist –

- major depressive disorder due to few side effects (no sexual dysfuncton, withdrawal, weight gain)

Cisapride = 5HT4 agonist = pro gastro-kinetic drug

- that increases motility in the UPPER GI tract
- used to treat symptoms of nighttime heartburn in people who have not responded to other treatments
- Adverse effects = serious arrythmias
Bradykinin drugs
Hereditary angioedema (HAE) = inherited condition characterized by recurrent episodes of nonpruritic,
nonpitting, subcutaneous or submucosal swelling without redness
- mutation of the C1-inhibitor gene.
- Labs – LOW C4
- Defective or missing C1-inhibitor permits excess activation of kallikrein, a protease that is responsible for
liberating BK from its precursor kininogen
- Excess BK leads to fluid leakage from blood vessels, causing swelling of tissues.
- Bradykinin binds to B2 receptor (GPCR)
- leads to dissolution of the adherens junction, which plays a critical role in limiting vascular permeability
- more endothelial cell contraction = more fluid leakage
Treatments via replacement of C1-esterase inhibitor:
 HAEGARDA = plasma-derived concentrate of C1 Esterase Inhibitor (Human)
 Berinert & Cinryze – treat acute attacks and for prophylaxis of HAE

Ecallantide – treatment for HAE – reversible plasma kallikrein inhibitor

> selectively and reversibly inhibiting the activity of plasma kallikrein (a protease)
= less liberation of BK from its mother molecule – HMW-kininogen

Lanadelumab – human monoclonal Ab inhibitor of kallikrein

- prophylactic treatment of hereditary angioedema with C1 esterase deficiency

IcatiBant –– Bradykinin B2 receptor antagonist - treatment of acute attacks of HAE

- molecule made up of 10 amino acids

Bradyknin Physiology:
Bradykinin is one of the most potent vasodilators
-- can be further converted to an octapeptide (BK1-8 or des-Arg-BK) by Kininase I
--- normally degraded by ACE (also called kininase II) in the lungs
> It increases vessel permeability (endothelial cell contraction)
> dilates blood vessels and causes smooth muscle cells to contract (bronchospasm)
> mediator of pain (increases sensitivity)
> stimulates secretion of fluid in airways and GI
> coughing
> Surplus bradykinin > typical symptoms of inflammation = swelling, redness, overheating and pain.

B2 receptor – constitutive – responds to BK

and kallidin
B1 receptor – inflammation induced (IL-1) –
responds to Des-Arg-BK

INTEFERONS – cytokines released by

virally-infected cell to warn neighbouring cells
– prime them for defense – downregulating
transcription rates and expressing more anti-
viral proteins
IFNa (produced by WBCs) – hepatitis B and C
IFNb (produced by fibroblasts)– Multiple sclerosis - reduces exacerbations
IFNy – normally released by TH1 – stimulates macrophages --- used in chronic granulomatous diseases
-- osteopetrosis (thick bone due to decrease osteoclast activity (Carbonic anhydrase mutation)
Neuropeptides:
- released from sensory neurons  neurgenic inflammation

*Substance P
- major pain transmitter - released by nociceptive nerve endings at site of inflammation (can senstizie
surrounding nerves); also released in dorsal root ganglion – pain transmission
*Arteriolar vasodilation but venous constriction
*Vomiting – high [Substance P] and [NK-1 receptor] in CTZ (chemoreceptor trigger zone)

*Capsaicin – naturally found in chili peppers it triggers release of substacne P from nerve endings until it is
depleted = temporary pain releif
-- used as cream for joint pain; also for post-herpetic neuralgia (after herpes)

> Tachykinins: Substance P, neurokinin A – bind mainly to the NK-1 receptor (GPCR)
- smooth muscle contraction, mucous secretion
- stimulating degranulation of mast cells (inflammation)

*APREPITANT – NK-1 antagonist – anti-vomiting – often given with odansetron for best results
- ORAL drug used to prevent chemotherapy-induced and postoperative nausea and vomiting (PONV);
drug can cross BBB to antagonize NK-1 receptors in CTZ
*often given together with ondansetron (5HT3 antagonist)
***Substance P is found at high [ ] in the CTZ – when it binds to NK-1 – triggers vomiting reflex
*Fosaprepitant = prodrug for aprepitant; IV injection
> Others: Rolapitant, Netupitant, Fosnetupitant („- PITANT = NK1 block – anit -emesis)

Calcitonin gene-related peptide (CGRP) –*** most potent vasodilator ***

- can cause hypotension and reflex tachycardia
* high [ ] in most smooth muscle tissues, and thyroid
- some evidence suggests it’s implicated in migraine headache

ERENUMAB = monoclonal antibody that blocks CGRP receptor

– used to prevent migraines - given via subcutaneous injection

* Telcagepeant = CGRP antagonist

- found to be as effective as triptans (5HT3 antagonists) during Phase III clinical trials
- however they terminated its development due to signs of liver damage

Endothelins - peptide vasoconstrictors formed in and released by endothelial cells in blood vessel
- much more potent contrictors than NE with longer lasting effect;
- idiopathic PULMONARY HTN (imbalance b/w endothelin vs NO and PGI2
- also stimulate the heart, increase natriuretic peptide release, and activate smooth muscle proliferation.
- Two receptors, ETA and ETB – both GPCR – Gq; ET-1 (vascular), ET-2 (intestines); ET-3 (brain)
DAGLUTRIL – mixed (neutral endopeptidase/ET convertin enzyme inhibtor)
– under development for treatment of essetnial HTN and congestive HF
Dual antagonists: block both ETA ad ETB
Bosentan (Side effects: - Hepatotoxicity (increase in ALT, AST); anemia; teratogen; edema)
Macitentan

Selective ETA antagonist:

> Ambrisentan – metabolized by CYP3A4 = drug interactions
> Darusentan, Atresentan

SPARSANTAN - IgA Nephropathy – endothelin and AGII receptor antagonist

– used to reduce proteinuria in adults with primary IgA nephropathy;
> Riociguat = oral activator of soluble guanylyl cyclase (not an ET receptor antagonist) that is also
approved for use in pulmonary hypertension „RiociGUA”
Angiotensin Inhibitors
Angiotensin-converting enzyme (ACE) inhibitors
> Used in the treatment of HTN and congestive heart failure
> treat and prevent diabetic nephropathy *first line in HTN patients with DM if renal function normal
> decrease mortality in post-myocardial infarction patients (decrease AGII heart remodeling)
> Miraculous for treatment of kidney disease in systemic SCLERODERMA
***ACEi and diuretics do not cause reflex tachycardia !

Physiology: JGA cells sense decreased GFR – release renin (also stimulated via B1)
- converts angiotensinogen to AG1
- ACE converts AG1 to AGII
- AGII has 5 main functions:
---- binds to AT1 receptors – vasoconstriction
--- hypothalamus – triggers ADH release = H2O reabsorption
--- stimulates Na+/H+ exchanger on PCT = more Na+ and HCO3- and H2O reabsorption (this mechanism
contributes to contraction alkalosis if vomiting)
--- zone glomerusola – aldosterone release
--- constricts efferent arteriole = preserves GFR in conditions where RBF reduced

***Note: ACE also breaks down bradykinin (a vasodilator)

- Therefore, inhibition of ACE = less bradykinin breakdown = vasodilation and decreased blood pressure

Main side effects:

> Dry non-productive cough (likely due to increased bradykinin levels)--goes away once therapy stopped
*** People who experience this cough are often switched to AGII receptor antagonists.
> Could cause some angioedema (bradykinin > endothelial cell contraction and fluid leakage)
> Hyperkalemia (less aldosterone = less H+ and K+ secretion)
> Modest reductions in GFR and small increases in creatinine (acute kidney failure – proteinuria)
***Contra-indications:
> Bilateral renal artery stenosis (you need AGII to maintain decent enough GFR)
- normally, stenosis leads to lower kidney perfusion and RAAS activation
-- AGII works to constrict efferent arteriole to maintain an adequate GFR for kidney
- If you give ACE inhibitor = decrease AGII = fall of GFR and kidney failure – will see creatinine increase
> Teratogens – never give in pregnancy (if mom has HTN – stick with metyldopa (a2 agonist)
Captopril (first ACE inhbitor made – had metallic taste due to -SH group)
- **can be taken sublingually for fast-acting relief of a moderate BP spike**
Lisinopril – active drug (no conversion in the liver) – can be taken once daily
***All ACEi are prodrugs except for Captopril and Lisonopril (take into account if you have HTN patients
with mild liver failure as CYP enzymes needed to convert prodrugs to active metabolite)
ENALAPRIL – supposedly most effective ACEi + only one avaialble for IV ! 1st line for Heart Failure !
Fosinopril
Quinapril
Perindopril - LONG-acting
Ramipril
Trandolapril

Plasma ACE (10%) – peripheral vasoconstriction, negative feedback of renin release, aldosterone secretion
 Captopril, Enalapril
Tissue ACE (90%) – also growth stimulation, pro-atherogenic, thrombotic, oxidative stress
 Perindopril, Quinapril
Interactions:

Angiotensin receptor blockers – ARBs - (--SARTAN)

 HTN, portal HTN in patients with cirrhosis; also Mafan syndrome
 All orally active – given once daily – except Valsartan – given twice daily
*** unlike the ACEi, the ARBs have no effect on the metabolism of bradykinin = not associated with a
cough or angioedema (both of these side effects are believed to be related to elevated levels of bradykinin).
- also teratogens – should not be given to pregnant moms

Losartan - *only one that undergoes first pass metabolism to generate active metabolite
Valsartan – given twice daily
Irbesartan
Candesartan *small Vd in constrast to the rest which have large Vd
Telmisartan - *drug interaction with digoxin
*** Entresto = ARNIs (Angiotensin Receptor & Neprilysin Inhibitors).
- COMBO of Valsartan (an ARB) and Sacubitril (Neprilysin inhibtor)
> Sacubitril inhibits the action of neprilysin = enzyme that normally degrades ANP and BNP
= more ANP and BNP = enhanced natriuresis.
*Entresto has been shown to reduce CV mortality and heart failure re-hospitalization in patients with
chronic heart failure and reduced ejection fraction.
Direct renin inhibitor = Aliskiren („kills renin”) – management of HTN with elevated renin levels
- contra-indicated in pregnancy; metabolized via CYP3A4 = drug interactions
- may cause diarrhea at higher doses

Natrieretic peptides (ANP – from atria – fluid overload; BNP – from ventricles due to high stretch)
- promote natriuresis (kindeys); promote vasodilation (decrease sympaethetic tone); inhibit RAAS
- 2 receptors: NPR-A and NPR-B
*NESITIRIDE = BNP receptor agonist – used to treat acute heart failure
---- renal toxicity; hypotension
*CARPERITIDE – ANP analogue
* ULARITIDE – ularitide analogue

VOSORITIDE – CNP analogue – binds to NPR-B recpetor – vasodilation + chondrocyte stimulation

-- treatment of achondroplasia (over-active FGRF3 receptor = decreased encochondral ossification)
--- patients have short limbs; normal head, feritlity not affected; average height = 4 feet.
- Vosoritide binds to NPR-B which decreases FGRF3 activity allowing for more growth
- side effect = hypotension (since NPR-B receptor also promotes vasodilation)
ALL ENDING IN „—ITIDE”

Aldosterone antagonists: - decrease Na+ reabsorption (prevent K+ and H+ secretion)

Spironolactone – aldosterone receptor antagonist (HTN, Conn syndrome)
- anti-androgen effect – gynecomastia in males; disturbance in menstruation (binds some nuclear receptors)
Eplerenone – more selective for aldosterone receptor – less side effects
Overall side effects: hyperkalemia, hyperchloremic metabolic acidosis

***For hypertensive urgency: ACEi, ARB, diuretics – do not significantly increase HR

> On the other hand – direct vasodialtors (NO, K+ channel openers – Minoxidil, Diazoxide do increase HR)

Nitric oxide drugs (relax smooth muscle  cGMP  MLC-phosphatase = dilation = decreased blood
pressure); dilate all blood vessels (arteries = decreased afterload; veins = decreased preload)
Nitroglycerin (prodrug) > Mitochondrial ALDH2 converts it to NO
 Short acting = sublingual – acute angina pectoris – rapid onset (1 min) & short duration (15 min)
- reduces preload (veins) and afterload (arteries)
 Intermediate acting – ORAL – prophylaxis of angina; slow onset; duration 2-4 hours
 Long acting = transdermal patch – prophylaxis of angina; duration = 24 hours
Isosorbide mononitrate and dinitrate – have longer duration of action than nitroglycerin and more
effective for long-term management of CAD
Molsidomine >>> metabolized in liver to active linsidomine;
- unstable compound that releases nitric oxide (NO) upon decay (dilates arteries and veins)
> prevention & long-term treatment of stable/unstable angina pectoris, with or without left heart failure.
Nitroprusside, Diazoxide, Fenoldapam – parental (IV) –mainly used in HTN emergencies

Sodium nitroprusside – used in hypertensive emergencies due to rapid action (DIRECT NO DONOR)
- used by continuous injection into a vein.
- Onset is nearly immediate and effects last for up to 10 minutes
* Nitric oxide reduces both total peripheral resistance and venous return, thus decreasing both preload and
afterload. So, it can be used in severe congestive heart failure where this combination of effects can act to
increase cardiac output.
***ONLY molecule that spontaneously releases NO in the bloodstream; rest are intracellular

Common side effects:

- low blood pressure
- cyanide toxicity – can be converted to CN-
----- risk is minimized by co-administering thiosulfate (detox to thiocyanate) and hydroxocobamalin
---- CN- toxicity may cause acidosis, tachycardia, mental status changes
- methemoglobinemia – can cause conversion of Hb to Met-Hb – NITRITES
*** High doses are not recommended for more than 10 minutes

Diazoxide = thiazide derivative but lacks diuretic properties (open K+ channels and decreases insulin)
> given as IV boluses or as an infusion and has several hours’ duration of action.
> opens K+ channels = hyperpolarizing and relaxing smooth muscle cells – decrease BP
*** opens ATP K+ channels in B cells of pancreas = hyperpolarization = less insulin release
– can be used to treat hypoglycemia caused by INSULINOMAS

Fenoldapam – D1 agonist (GPCR) = renal dilation (promotes natriuresis) + reduction in blood pressure
- short term management of severe HTN (vasodilation of arterial beds + natriuresis)
- contraindicated if glaucoma (can raise IOP)
- do not give with B-blocker – since reflex tachycardia won’t be possible
ADVERSE EFFECTS OF NITRATES: (mainly due to vasodilation)
- throbbing headache (due to vasodilation of cranial vessels)
- low blood pressure with standing (orthostatic)
- blurry vision - skin flushing

DRUG INTERACTIONS: Nitrates contra-indicated with PDE-5 inhibitors (sildenafil, tadalifil) due to
potentiation of vasodilatory effects of cGMP

Hydralazine - used to treat severe HTN, but is not a first-line therapy for essential hypertension
***first-line for HTN in pregnancy „Hypertensive Moms Love Nifedipine”
***effects on arteries (not so much on veins) = arteriolar relaxation
- since it elicits reflex tachycardia, it is given with B-blockers and diuretics ***
-mechanism = inhibition of IP3-induced Ca2+ release from the SR in arterial smooth muscle cells
- found very useful in combination with isosorbide dinitrate for the treatment of congestive heart failure in
black populations; first race-based drug combo (side effect = headache, hypotension, increased HR)
> rarely used at high dosage because of its toxicity
> Hydralazine-induced lupus erythematosus is reversible upon stopping the drug, and lupus is less
common at dosages below 200 mg/d (ANA + anti-histone Abs)

Minoxidil (prodrug)  active metabolite = minoxidil sulfate

*** used for HTN and male-pattern hair loss
- Mechanism - opening of arteriolar ATP-sensitive K+ channels = hyperpolarization = decreased smooth
muscle contraction = vasodilation – decreased blood pressure
--- vasodilation also promotes more O2 and nutrient delivery to hair follicles = more growth
--- often causes severe reflex tachycardia that must be controlled with B-blockers
--- can produce hirsutism - excessive growth of dark/coarse hair in a male-like pattern -face, chest and back

***Both Hydralazine and Minoxidil exert effects moreso on arteries than veins
*** Because they are well-tolerated and produce fewer compensatory responses, the calcium channel
blockers are still much more commonly used than hydralazine or minoxil for HTN.
HTN therapies : STEPPED CARE (Polypharmacy)
> Therapy of HTN is complex because the disease is symptomless until far advanced and because the drugs
may cause major compensatory responses and significant toxicities.
> However, overall toxicity can be reduced and compensatory responses minimized by the use of multiple
drugs at lower dosages in patients with moderate or severe hypertension.
> Typically, drugs are added to a patient’s regimen in stepwise fashion; each additional agent is chosen from
a different subgroup until adequate blood pressure control has been achieved.
> The usual steps include:
(1) lifestyle measures such as salt restriction and weight reduction
(2) diuretics (THIAZIDE – if HTN is only problem)
(3) sympathoplegics (a β blocker)
(4) ACE inhibitors (if HTN + diabetes + normal renal function)
(5) vasodilators *** usually a calcium channel blocker is 1st dilator option
>> Ca2+ channel blockers [*Peripheral edema = one of most common side effects!]
- Dihydropyridines (e.g. Nifedipine) – greater effect on peripheral vessels
- Non-dihydropyridines (Verapamil, Diltiazem) – greater effect on heart vessels (*constipation side eff)
The ability of drugs in steps 2 and 3 to control the compensatory responses induced by the others should be
noted (eg, propranolol reduces the tachycardia induced by hydralazine).
> Good polypharmacy minimizes toxicities while producing additive or supra-additive therapeutic effects.
***Can start with 2-drug combo if current blood pressure is 20/10 above target levels ***
Monotherapy
> It has been found in large clinical studies that many patients do well on a single drug (eg, an ACE
inhibitor, calcium channel blocker, or combined α and β blocker).
> This approach to the treatment of mild and moderate HTN has become more popular than stepped care
because of its simplicity, better patient compliance, and a relatively low incidence of toxicity
***EXAPLE: A patient does not respond to first drug you prescribed for HTN – let’s say ACEi
- you can either increase the dose or add a second drug from a different class – so you would not give her
Aliskiren or an ARB – you could give a diuretic or Ca2+ channel blocker

Resistant HTN = BP remains high despite administration of a 3-drug regimen that includes a diuretic
 Causes = poor compliance, excessive ethanol intake, concomitant conditions (diabetes, obesity, sleep
apnea, hyperaldosteronism, high salt intake, and/or metabolic syndrome
PDE-5 INHIBITORS (prevent breakdown of cGMP) ; type 5 isoform mainly in repro-tissues & lungs
Sildenafil, Tadalafil (Vardenafil, Avanafil)
USE: Erectile dysfunction, Pulmonary hypertension,
---- BPH (tadalafil only)

ADVERSE EFFECTS: those due to vasodilation = headche, blurry vivion, flushing, hypotension
-- contra-indicated in ppl taking nitrates (might overdo effects = potentiation – major drop in BP)
***Sildenafil side effect = CYANOPIA (blue-tinted vision) due to inhibition of PDE-6 in retina

Milrinone = PDE-3 INHIBTOR = more CAMP available;

- Heart – more cAMP = increase CO and HR
- Vessels – more cAMP = vasodilation
> Pulmonary vasodilator used in patients who have heart failure (cAMP – inhibition of MLCK)
> Acute decompensated HF with cardiogenic shock
***but only for short term use due to risk of arrytmias !

Theophylline – non-specific PDE inhibitor – for asthma and COPD,

- more cAMP = smooth muscle relaxation
- limited use due to narrow therapeutic index (cardiotoxicity, neurotoxicity)
**also adenosine antagonist
PDE-4 INHIBITORS = "milast"
> Roflumilast and Cilomilast - for severe COPD (bronchial epithelium dilation)
> Neutrophils – increase cAMP = decreased inflammatory response

> APREMILAST - for PSORIASIS and PSORIATIC ARTHRTIS (seronegative)

***PDE-4 main isotype in inflammatory cells (neutrophils)
> increased cAMP = active PKA = decreased NFKB transcription = less cytokine production

Anti-PLT functions:
Cilostazol = PDE-3 inhibitor – decrease PLT aggregation + vasodilation
-used in peripheral artery disease (intermittent claudication – pain in muscles – since decreased blood flow

---- can give both cilostazol and aspirin (prevent thrombotic events, stroke, TIA)

Dipyridamole = non-specific PDE inhibitor

- thromboembolism prophylaxis and prevention of restenosis after valve replacement
*Cardiac stress testing – patient comes in with chest pain – shows you where it hurts – it’s diffuse pain –
not well localized – do EKG – MI ruled out (no troponins, or abnormal waves)
--- ask patient to exercise on treadmill; if he physically can’t – do stress test with dipyridamole (normally it
will dilate coronary vessels and a contrast agent will be taken up into heart circulation)
Prostaglandin Drugs (all have „prost”) - ALL Gq receptors, except
Alprostadil – PGE1 analogue – vasodilator and muscle relaxant
> can be used for erectile dysfunction – directly injected into corpus cavernosum
--- side effects: penile pain, priaprism (prolonged erection), hypotension, bradycardia
> maintain PDA prior to surgery

Misoprostol (Cytotec) – PGE1 analogue; 3 functions:

> Labor induction (uterine contractions and ripening (thinning) of the cervix);
> Medical abortion ***often given with the progesterone antagonist mifepristone (RU 486) as an
extremely effective and safe abortifacient combination
> Inhibition of gastric acid secretion and stimulate mucous protection (prevent NSAID-induced ulcers)

Gameprost – PGE1 analogue – also given with misoprostol to induce abortion (up to week 24)

Dinoprostone – PGE2 analogue –

- at [low] = uterine contractions – abortifacient
- [high] – can actually relax uterine and cervical muscle
Carboprost (Tromothamine) – PGF2a analogue (Gq  Ca2+ - myometrial contraction)
- increase uterine contractions (positive feedback loop with oxytocin);
- Dilate arteries and constrict superficial veins
- abortifacient - can be used to induce abortion in 2nd trimester
- post-partum hemorrhage
Latanoprost – PGF2a – for glaucoma – increase aquous humour drainage via canal of Schlemm
- bimatoprost, travaprost, unoprost, - do same thing
*Note: Bitmatoprost – ppl developed nice strong and dark eyelashes
*Side effects: blurry vision; foreign body sensation in eye
Protacyclin (PGI2) synthetic analogues: (E-T-I)
> Inhibit PLT aggregation (via increase in cAMP which antagonizes TXA2)
--- given during dialysis if heparin contra-indicated
> Vasodilation (cAMP in smooth muscle cells decreases contraction) - IP receptros (GPCR)

> General Side effects of vasodilation– headache (coronary vessels), hypotension, flushing (face)
Epoprostenol - (*jaw pain side effect) – for pulmonary HTN & portopulmonary HTN
Iloprost: half-life = 30 minutes; inhaled 6-9 times per day (2.5–5 mcg/dose)
Treprostinil: half-life = 4 hours; may be delivered by subcutaneous or IV infusion or by inhalation.

Degradation of prostaglandins:
 Spontaenous:
- TXA2  inactive TXB2 ( half life = 30 sec)
- PGI2  6-keto PGF1a (half life = 3 min)
 Enzymatic = remaining PGs
- In LUNGS by fatty-acid oxidizing enzymes (half-life = 1min)

Fever: pyrogens (IL-1, IL6) induce PGE2 produciton in hypothalamus > EP3 receptor mediated
Pain: PGE2 and PGI2 – sensitive nerve endings and facilialte pain transmission in spinal cord – EP1/4
PGD2 – mainly from MAST cells – vasodilation, inhibtion of PLT, relaxation of GI muscle and releaxation
of uterine muscle, ***induces natural sleep (DP receptors)
PGF2a – gluacoma – increase outflow; AND stimulates uterine contractions (labour or abortion)
TXA2 – vasocontriction and PLT aggregation vs PGI2 – dilation and inhibits PLTs
TXA2 related drugs:
TXA2 synthase inhibitors:
 Dazoxiben – used for Raynaud’s syndrome (vasospasm of small arteries reduces blood flow to end
arterioles – typically in fingers and less commonly toes „red, white, blue”)
--- Raynaud also treated with = Ca2+ channel blockers (dihydropiridines – more vessel effect)
 Primagrel (ozagrel, camonagrel)

Ridogrel = TXA2 receptor antagonist

- an adjunctive therapy to induce thrombolysis in patients suffering acute myocardial infarction

5-LOX inhibtor: Zileuton (trade name Zyflo)

= orally active inhibitor of 5-lipoxygenase, and thus inhibits leukotrienes (LTB4, LTC4, LTD4, and LTE4)
formation, used for the maintenance treatment of asthma
- used for prophylaxis and chronic treatment; ****not for reversal of acute attacks
***hepatotoxic – can see elevation of liver enzymes (ALT, AST) -- use with caution

MonteLUKAST, zafirLUKAST—block leukotriene receptors (CysLT1) „---LUKAST”

> Especially good for aspirin-induced and exercise-induced asthma
- not first choice in asthma – usually additional; has no use for acute asthma attacks
> ***Zafirlukast - inhibits CYP P450 = potentiation of drugs that are metabolized this way (warfarin)
> Contra-indicated in patients with liver disease

Respiratory tract – Cys-LT1 receptors – bronchoconstriction and mucous secretion

Cardiovascular system – Cys-LT2 receptors
---- in peripheral arteries – vasodilation – similar triple effect as histamine (redness, swelling,
--- coronary arteries – vasoconstriction
PAF = PLT activating factor [lysophophatidylcholine + AcCoA = PAF]
- released from PLTs and stimulated inflammatory cells
- vasodilation – erythema
- increased permeability
- PLT aggregation (e.g. forming clot at site of injury)
- bronchoconstriction
- GI smooth muscle contraction

PAF inhibitors: glucocorticoids

Lexipafant - selective inhibitor PAF
- developed in the 1990s by British Biotech with several potential applications, including HIV-associated
neurocognitive disorder and acute pancreatitis.
- progressed as far as Phase III clinical trials, but final results showed that it failed to improve survival
rates in pancreatitis despite some improvement --- was ultimately discontinued from development as a
medicine, though it continues to be used as a model PAF inhibitor for pharmacology research
GENERAL MECHANISM OF ACITONS OF NSAIDS
> Analgesic, anti-pyretic (decreased PGs in hypothalamus), anti-inflammatory
- Can reduce polyp formation in patients with FAP; Long-term use reduces the risk of colon cancer !

Analgesic– decrease pain – mainly due to decreased prostaglandin synthesis

> PGE2 and PGI2 are the most important prostaglandins involved in pain.
> Inhibition of their synthesis is a primary mechanism of NSAID-mediated analgesia
1) Prostaglandin primary hyperalgesia:
- PGs sensitize pain receptors; peripheral input via C and Aδ fibers and TRPV-1 Ca2+ channels
(2) Afferent input processed in dorsal horn (prostaglandins inhibit GABA and glycine inhibitory
interneurons) = prostaglandin secondary hyperalgesia
(3) Prostaglandins produce changes in central pain processing that leads to allodynia = painful sensation
caused by normally innocuous stimuli (e.g. you touch someone and they feel pain)
b. NSAIDs also prevent the potentiating action of prostaglandins on endogenous mediators of peripheral
nerve stimulation (e.g., bradykinin).

Antipyretic effect – via inhibition of production of PGs induced by (IL-1) and (IL-6) in the hypothalamus
and the “resetting” of the thermoregulatory system
- leads to vasodilatation and increased heat loss

Anti-inflammatory effect – decrease production of PGs and TXA2

- prostaglandins, leukotrienes, and other cytokines are released during local inflammatory responses
- chemotaxis of neutrophils (LTB4) and macrophages, vasodilation, increased cap-perm

Used to treat: rheumatoid arthritis, juvenile arthritis, osteoarthritis, psoriatic arthritis, ankylosing
spondylitis, Reiter syndrome, and dysmenorrhea.
- Pain and inflammation of bursitis and tendonitis also respond to NSAIDs
Note: osteoid osteoma (small nidus, cortex of bones) responds to NSAIDS while osteoblastoma (vertebrae,
larger nidus) does not respond to NSAIDS
Note: Minimal change disease (kidney – effacement of foot processes) – responds to NSAIDs and steroids
C) Nonsteroidal Antiinflammatory Drugs (NSAIDs)
Nonselective Cyclooxygenase Inhibitors
Aspirin (irreversible) – acetylates a serine residue in acive site of COX
> Low doses – inhibit PLT aggregation (irreversible COX-1 inhibtion in PLTS = less TXA2)
- indicated in every patient with ischemic heart disease or following MI
> Medium dose – anti-pyretic and analgesic
> High dose = anti-inflammatory

***Do not give aspirin to children under 18; risk of Reye syndrome
> Rare, often fatal childhood hepatic encephalopathy.
> Associated with viral infection (especially VZV and influenza) that has been treated with aspirin.
> Aspirin metabolites decrease β-oxidation by reversible inhibition of mitochondrial enzymes.
> Steatosis of liver/hepatocytes; Hypoglycemia/Hepatomegaly; coma, Encephalopathy – NH3

Unwanted effects:
- gastric ulcers / bleeding (less prostaglandin synthesis) ; renal problems – decreased GFR
- aspirin intolerant asthma – inhibit COX = more lipoxygenase and LTC4/D4 = bronchoconstriction
- High dose  salicylism – tinnitus, vertigo, decreased hearing
> Aspirin overdose (> 150 mg/ kg) : Hyperthermia, HAGMA, ETC uncoupling > lactic acidosis, coma
First 20 minutes – hyperventilation – respiratory alkalosis
After first 20 minutes – acid buildup – HCO3 consumed for neutralization = metabolic acidosis
= Eventually causes MIXED Respiratory alkalosis, metabolic acidosis
- No aspirin antidote: try to rid the body of it as quickly as possible – alkalize the urine !

Drug interactions
a. Aspirin can displace certain drugs from serum albumin
- The action of anticoagulants may be enhanced
- Aspirin also displaces tolbutamide, phenytoin, and other drugs from their plasma protein-binding sites.
b. The hypoglycemic action of sulfonylureas may be enhanced by displacement from their binding sites on
serum albumin or by inhibition of their renal tubular secretion by aspirin.
c. Usual analgesic doses of aspirin (2 g/day) decrease renal excretion of sodium urate and antagonize the
uricosuric effect of sulfinpyrazone and probenecid; aspirin is conraindicated in patients with gout who are
taking uricosuric agents (use same Oragnic acid transporter)
d. Antacids may alter the absorption of aspirin.
e. Aspirin competes for tubular secretion with penicillin G and prolongs its half-life.
f. Corticosteroids increase renal clearance of salicylates.
g. Alcohol may increase GI bleeding when taken with aspirin
h. Never give aspirin with warfarin (inhibits 1972 Vitamin K clotting factors) – bleeding risk
Sodium salicylate – salycilic acid often used
for supericial skin problems – plantar warts,
corns – kills keratinocytes
Diclofenac
Diflunisal – no anti-pyretic effect
Etodolac
Fenoprofen
Flurbiprofen
Indomethacin – can close PDA
- rarely used to day – side effects
Ibuprofen – one of most popular
- used to close PDA in kids
- contra-indicated in ppl with nasal polyps
- risk of aspirin-intolerant asthma

Ketoprofen - ***blocks COX + LOX

ACeclofenac – also stimulates cartilage

regeneration
= exception to rest of NSAIDS
Ketorolac – mainly used as systemic
analgesic; peranteral formulations

Mefenamic acid
Nabumetone * ketone prodrug > converted to active acid in liver
Meloxicam
Naproxen – considered one of safest NSAIDS – most non-selective
Piroxicam – long half-life – use once daily
Acetaminophen (Tylenol) – paracetamol
- Active in CNS; inactivated in periphery
- Anti-pyretic and analgesic;
*No anti-PLT activity or bad GI effects = can give to someone with ulcers !!!
*** overdose or taken with alcohol = build-up of toxic NAPQI metabolite (and depletes GSH levels);
- can see AST/ALT increase 1000 – 10 000 X
 give N-acetylcysteine!
***AVOID NSAIDs during pregnancy!!!
- avoid in 1st and 2nd trimester
- complete contra-indicated during 3rd
Selective Cyclooxygenase-2 Inhibitors „- COXIB”
- MAIN indication – chronic inflammatory diseases – RA
- much lower risk of gastric ulcers (since COX-1 still active)
- higher risk of CV events (inhibit COX-2 in endothelial cells which normally makes PGI2 = excess of
TXA2 being made by COX-1 in PLTs = risk of thrombosis! *imbalance*
Main side effects = edema, high blood pressure, dizziness, stomach upset.
Celecoxib (Celebrex) – used for RA & OA (spares COX1 = less damage to gastric mucosa)
-- sulfonamide structure = higher risk of skin rashes
Lumaricoxib
Valdecoxib and Etoricoxib – only in EU
Meloxicam – not as COX-2 selective
Seeing this table, what can cause bronchconstriction?
> mAchR agonists (acetylcholine), B2 antagonists (if they exist)
> Allergic reaction – leukotrienes – bronchospasm (LTC4, LTD4)
> Thromboxane (TXA2), PGF2a
> Note: In PAH – potential mecahnism is too little vessel dilators (NO, PGI2) and too much endothelin
Main risk of COX-2 inhibitors:
Normal vessel physiology – maintenance of normal
pressure:
 PLTs mainly have COX-1 – release TXA2;
 endothelium mainly has COX-2 – releases PGI2
= everything is in balance
 When you give COX-2 inhibitor = more unopposed
generation of TXA2 – vasoconstrictor and promotes PLT
aggregation = risk of MI or stroke (brain)

Overall side effects of COX inhibitors (non-selective):

> RENAL – decreased GFR = potential damge; Na+ and H2O retention  HTN
-- PGI2 and PGE2 normally dilate afferent arterioles = increase GFR and natriuresis – now this is decreased
- hemodynamic acute kidney injury
***Do not give NSAID to person with acute heart failure ! Goal is to deal with the edema via increased
urine output – prostaglandins help dilate afferent arteriole to increase GFR
*Nabumetone = ketone – non-acidic prodrug that is metabolized in liver to active acetic acid form
*LICOFELONE and Ketoprofen = COX and LOX inhibitors

Diffusinal – mainly used for analgesic and anti-inflammatory effect (NO anti-fever effect!)
- long plasma half life and long duration of action
- popular with dentists – one injection = patient feels no pain from end of surgery until they go to bed
- could have a potential use in transthyretin-related hereditary amyloidosis (clnincla trials)

GLUCOCORTICOIDS:
Prednisone, hydrocortisone, cortisone, prednisolone, methylprednisolone, betamethasone, and
dexamethasone.

*Glucocortiocids can stimulate lipocortin (annexin) production = inhbition of PLA2

Prednisone – most commonly used glucocorticoid due to high activity (gets converted to active form of
prednisolone in liver) – inhibits Phospholipase A2 + apoptosis of lymphocytes
= anti-inflammatory, decrease WBC migration, and decrease immune response

Beclomethasone = inhaled glucocorticoid that is used to treat chronic asthma.

> Because the drug is inhaled and not administered systemically, side effects are minimal

Cushing side effects: hyperglycemia, HTN, osteoporosis (increased RANK-L expression), fat re-ditribution
(from lipolysis) – buffalo hump, moon facies, thinning of skin and abdominal striae, peripheral muscle
wasting, impaired wound healing, peptic ulcer due to increased acid secretion

Selected Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

(DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in
rheumatoid arthritis to slow down disease progression.
> The term is often used in contrast to NSAIDS - which refers to agents that treat the inflammation, but not
the underlying cause and in contrast to steroids - which blunt the immune response but are insufficient to
slow down the progression of the disease)
Auranofin (Au = gold salts) – only gold salt left on US market
Aurothioglucose – formerly used to treat RA – recently withdrawn from markets
Penicillamine - Wilson disease & cystinuria, & severe RA that failed to respond to conventional therapies
- Wilson’s - can chelate heavy metals such as copper, lead, and mercury and form a soluble complex that
is renally excreted in the urine.
- Cystinuria - combines and forms disulfide bonds with cysteine resulting in a more soluble compound that
facilitates the excretion in urine
- RA - can depress T cell activity, although its precise MOA unknown
Chloroquine, Hydroxychloroquine – mainly for malaria; occasionally for RA and lupus
 Chloroquine is thought to work by interfering with the parasite's ability to break down and digest
hemoglobin in RBC  accumulation of toxic heme kills the parasite
- Against RA, it operates by inhibiting lymphocyte proliferation, phospholipase A2, antigen presentation in
dendritic cells, release of enzymes from lysosomes, release of ROS from macrophages, and IL-1 prod.
*Relatively safe in pregnancy**
Azathioprine  active metabolite = 6-thioguanine (6-MP = 6 mercaptopurine) ; given orally
- supresses T and B cells, Ig and IL production *PRPP amindotransferase inhibition
***Most important side effect = bone marrow supression (pancytopenia)
* Metabolized by XO -- Dose reduction needed when it is administered with allopurinol or febuxostat
Methotrexate - first line DMARD for RA – also anti-cancer drug
- inhibits AICAR transformylase – more AICAR – inhibits AMP deaminase – accumulation of AMP which
is eventually released and convered extracellulary to adenosine, an inhbitor of inflammation
- inhbits DHFR – less TH4 for conversion to N5-N10 methylene THF = less conversion of dUMP to dTMP
(less proliferation of T and B cells)
***Side effects: mucosal ulcers, nausea, blood and liver toxicity***, pulmonary fibrosis

Cyclophosphamide – active metabolite = phosphamide mustard – cross-links DNA

- suppression of T and B cells
- drug of choice in the treatment of WECENER granulomatosis (c-ANCA, throat, lungs, kidneys)
- Side effects: hemorrhagic cystitis (give MESNA) , cardiomyopathy [Think everything C]
Leflunomide – active metabolite = Teriflunomide
- Reversibly inhibits dihydroorotate dehydrogenase, preventing pyrimidine synthesis.
- Suppresses T-cell proliferation - used for RA and psoriatic arthritis
- Common side effects: Diarrhea, HTN, elevated liver enzymes
***Teriflunomide – also used for MS (with IFN-b); anti-viral properties (CMV, HSV1, BK)
Mycophenolic Acid – inhibits IMP dehydrogenase – no GMP formation = replication inhibited
- used in heart, liver, kidney trasnplants (espeically if cyclosprine was not effective)
- side effect – like all – increased susceptibility to infection – but CMV in particualar !
- GI side effects, hepatotoxicity
Sulfasalazine – used to treat IBD = Ulcerative colitis, and Crohn's disease
- prodrug  metabolized in the colon by bacteria to 5-aminosalicylic acid = 5-ASA
- Decrease Ig production and lymphocyte activity
*Poorly tolerated – N/V, hemolytic anemia, neutropenia

Anti-TNFa monoclonal antobodies: AIG = Adalimumab; Infliximab; Golimumab – bind TNFa

- Use: Inflammatory bowel disease, RA, ankylosing spondylitis (HLA-B27 - bamboo spine), psoriasis
Adverse effects:
> Predisposition to infection (bacterial and macrophage dependent)
--- including reactivation of latent TB, since TNF is important in granuloma formation and stabilization.
> Increased risk of skin cancer (including melanoma) – do skin examinations every so often
- Can also lead to drug-induced lupus (anti-histone Abs)
Etanercept - TNF-a antognist – „intercepts” by acting as decoy receptor for TNFa)
Anakinra (IL-1 receptor antagonist)
- 2nd line treatment for RA if DMARDS failed
- also: cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease
- short half life = mutiple daily subcutenoeus injections
Abatacept – prevents activation of T cell with 2nd co-stimulatory signal
***binds B7/CD80 on APC – preventing interaction with CD28
Rituximab CD20 – monoclonal Ab that binds CD20 on B cells
- 3 major independent mechanisms of action: are (1) ADCC with NK cells (2) complement-mediated
cytotoxicity (CMC), and (3) apoptosis
- The combined effect results in the elimination of B cells (including the cancerous ones) from the body,
allowing a new population of healthy B cells to develop from lymphoid stem cells.
- used for non-Hodgkin lymphoma, CLL (in non-geriatric patients), RA, granulomatosis with polyangiitis,
idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-
positive mucocutaneous ulcers
Tocilizumab – anti-IL-6 receptor
- treatment of RA, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular
juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, cytokine release syndrome, COVID-19
*risk of serious respiratory infections (due to immunosupression)

Tofacitinib – oral Janus kinase antagonist „TOFA-JAK”

- for moderate to severe RA in patients who have had an inadequate response to MTX
Strong indications for transplant reciepients:

*Cyclosporine – inhibits calcineurin form inducing transcription of IL-2 = decreased T cell proliferation
and decreased production of inflammatory cytokines
- indicated to treat and prevent graft-versus-host disease in bone marrow transplantation
> prevent rejection of kidney, heart, and liver transplants

SIDE EFFECTS: *are dose-dependent and can be decreased by administering lower doses of the drug.
> Gingival hyperplasia and hirsutism – 10-30% of ppl
> Nephrotoxicity: 25%–75% of patients, with a reduction in GFR and renal plasma flow;
> HTN in 30% of patients
> Neurotoxicity (tremor and seizures) in 5%–50% of patients
*Risk of lymphoma
*** Cyclosporine as an ophthalmic emulsion (Restasis) is used to increase tear production in patients with
ocular inflammation associated with keratoconjunctivitis sicca

Tacrolimus – binds to FKBP-12 protien - complex inhibits calcineurin = decreased production of IL-2
= decreased proliferation, differentiation, and activation of T cells and less cytokines
> immunosupressant mainly for LIVER transplants
Side effects: Increased risk for infection; increased risk for lymphoma or skin malignancy; hyperglycemia;
nephrotoxicity; neurotoxicity; HTN

***Can be used as ointment – for eczema and atopic dermatitis, if topical corticosteroids and moisturisers
fail in helping; is as effective as a mid-potency steroid. An important advantage of tacrolimus is that, unlike
steroids, it does not cause skin thinning (atrophy), or other steroid related side effects.

Sirolimus = another immunosuppressant in KIDNEY transplant patients (**not nephrotoxic)

- also binds to FKBP-12; but the sirolimus-FKBP complex inhibits mTOR, a regulatory enzyme involved
in cytokine-driven T-cell proliferation > T-cell production and activation and subsequent cytokine creation
is decreased; humoral repsosne also decresed
- Side effects include increased susceptibility to infection, increased risk of lymphoma,
hypertriglyceridemia, and hyperglycemia.
****Of note, unlike some other immunosuppressants, it is not nephrotoxic.

IL-1 – fever, acute inflammation; activtes endothelium to expression more adhesion moelcules (e.g. E and P
selectins, ICAMs); induces chemokine secretion to recruit neutrophils an macrophages
- Also called osteoclast activating factor (increased bone breakdown)

IL-6 – fever and stimualtes produciton and release of actue phase proteins by liver
e.g. Ferritin – sequester iron; Hepcidin – decrease Fe absorption; CRP = opsonin
TNFa – activates endotheliuml WBC recrutiment; vascular leak

Drugs used for Gout

For ACUTE attacks: NSAIDS (Indomethacin #1) and colchicine
- oral prednisone (30-50 mg/d for couple days, then taper down for a week)
- intra-articular injection: triamcinolone acetonide
- 10 mg (small joints); 30 mg (wrist); 40 mg (knee)
***If patient has renal problems (GFR < 30) – corticosteroids first line (not metabolized by kidney)

Colchicine – inhibits tubulin polymerization = impedes chemotaxis of neutrophils

*only used if patient cannot take NSAIDS or glucocorticoids
* Colchicine must be administered within 36 hours of onset of attack to be effective
* Adverse effects: N/V, abdominal pain, diarrhea, GI hemorrhage, kidney damage, blood dyscrasias
- sometimes the GI side effects are intolerable and treatment is stopped immediately
Probenecid – inhibits reabsorption of urate in PCT (**drink 2L daily – risk of stones); sulfa-drug
***Needs to reach proper therapeutic doses in order to have the beneficial effect
- start of therapy (low dose)– probenecid can actually precipiate gout attack – prevents secretion of urate
- usually patients must go through this initial worsening stage before the theraputic effects are achieved
- Low doses sometimes given w/ pen antibiotics to decrease their secretion and prolong their effects

Lesinurad– inhibits uric acid trasnporter 1 (URAT-1) and OAT4 (organic acid transporter 4)
*only recommended together with either allopurinol/febuxostat when those medications are not enough

Sulfinpyrazone – inhibit uric acid reabsorption

---sometimes is used to reduce PLT aggregation by inhibiting degranulation (= no ADP or TXA2 released)
- trial have found that, Sulfinpyrazone taken in specific daily dose immediately following a patient having
suffered from an MI seem to drastically reduce the incidence of sudden death by as much as 43% and
cardiac mortality by 32% in the 24 months following their heart attack
Allopurinol – metabolized to alloxanthine  Irreversible Xanthine Oxidase inhibitor
(hypoxanthine  xanthine  urate) – less uric acid formaiton = less deposition in joints
Adverse effects:
- Allergic rxns (Drug rash with eosinophilia and systemic symptoms – DRESS); RASH
GI disturbances; ***some ppl experience acute attacks of gout at start
Interactions: enhances effects of some anti-cancer drugs and oral anticoagulants
*** Allopurinol also given during Tumour Lysis syndrome – to prevent uric acid depsotion in kidney
***6-MP metabolized by XO – decrease dose if given to someone on Allopurinol

Febuxostat – non-purine xanthine oxidase inhibitor (binds to molybdenum pterin center = active site)
- Long term treatment of gout
*Side effects = increased risk of death compared to AP, SJS (rash), anaphylaxis, liver enzymes elevation
PEGloticase – recombininat uricase - converts urate  allantoin - more H2O soluble
*3rd line treatment - IV every 2 weeks ; half-life = 10-12 days (big extension due to PEGs)
- PEGylated = attached multiple polyethylene glycol chains – increses T1/2 and decreases immunogencity

Rasburicase –recombinant uricase > non-PEGylated = lower half life (18 hours) ; IV infusion
– prophylaxis and treatment of Tumour lysis syndrome
MAJOR CONTRA:
Recombinant uricases are contra-indicated in patients with G6PDH deficiency (= less NADPH) because
the uricase reaction generates CO2 and H2O2 as byproducts; can induce life-threatening hemolytic anemia

DRUGS FOR HEADACHES:

Prophylaxis – B-blockers are first line – Propanolol and Nadolol; also Pizotifen (5HT2 a/c antaognist)
Prodromal phase: Triptans (5HT1-b/d agonists = Gi = less CAMP = vascontriction) – effective in 80% of
patients; Ergotamines; do not give in patients with CAD (due to risk of vasospasm)
Headache phase – NSAIDS – ibuprofen etc. – for pain management
HEART FAILURE TREATMENT:
in clinical practice, patients without contraindications appear to gain most benefit from combined treatment
with the ‘fantastic four’ (these also decrease mortality) (*Diuretics used as needed – to relieve pulmonary
edema – but do not decrease mortality)
 ARNI = ARB + Neprylisin inhibbitor = („Entresto” = Valsaratan + Sacubitril)
 Beta-blocker (Bisoporolol, Carvedilol, Labetalol)
 Aldosterone antagonist (e.g. spirinolactone, eplerenone)
 SGLT2 inhibitor

Neuropeptide Y (NPY) is a peptide neurotransmitter

• Widely distributed throughout the central and peripheral nervous systems.
• Has multiple physiological functions:
• increasing appetite (one of most potent orexins)
• Energy metabolism - promotes lipid storage in adipose tissue, reducing energy expenditure
• Decreasing stress and anxiety responses - HPA axis
• Packaged in vesicles with NE in sympathetic nerve terminals - released together - vasoconstriction
(makes sense since Gi = less cAMP = more constriction + NE binds a1 = IP3/DAG = Ca2+ )
• All NPY receptors are Gi = less cAMP
• Y1, Y2, Y4, and Y5 receptors, which are expressed on various tissues throughout the body.
• Y1 receptor is primarily involved in regulating appetite
• Y2 receptor is involved in autonomic nervous system functions.
The Y4 and Y5 receptors are predominantly expressed in the gut and are involved in regulating
gastrointestinal functions.
Additional Notes:
> Two organophosphates used in medicine are:
> malathion – against scabies
> metrifonate - antihelminthic agent

> Bethanechol and other M agonists can cause vasodilation by directly activating muscarinic receptors on
the endothelium of blood vessels > Gq > more Ca2+ - activates NO synthase in the endothelial cells – then
NO diffuses into smooth muscle cell underneath – cGMP – inhibits MLCK = vasodilation
- This effect can be blocked by atropine.
- Indirectly acting agents (AChE inhibitors) do not typically cause vasodilation because the endothelial
receptors are not innervated and acetylcholine is not released at this site
- vessels are innervated by sympathetic system !
***Free Acetylcholine mimics bind to M receptors on endothelium
***AchE inhibitors only act in the synapses – and there are no Ach neurons supplying blood vessels
Hypertensive drugs:
ACE inhibitors, ARBs, and diuretics - do not significantly increase heart rate.
- Although dihydropyridine calcium channel blockers do not usually reduce rate markedly (and may increase
it), verapamil and diltiazem (non-dihydro) do inhibit the sinoatrial node and predictably decrease rate.
> Other direct vasodilators regularly increase heart rate, and minoxidil, a very efficacious vasodilator, causes
severe tachycardia that must be controlled with β blockers.

Tranexamic acid (TXA) = lysine analogue – preserves fibrin clots = DO NOT BREAK IT DOWN
- used to treat or prevent excessive blood loss from major trauma, postpartum bleeding, surgery, tooth
removal, nosebleeds, and heavy menstruation.
- taken either orally or by injection into a vein
- antifibrinolytic = 4-5 lysine bind to receptor sites on plasminogen.
- This decreases the conversion of plasminogen to plasmin, preventing fibrin degradation and preserving the
framework of fibrin's matrix structure
- Tranexamic acid also directly inhibits the activity of plasmin with weak potency (IC50 = 87 mM),[6] and it can
block the active-site of urokinase plasminogen activator (uPA)
> Aminocaproic Acid – does same thing – less potent than TXA

Nicotine – Nn and Ng
- Most of body – parasympathetic tone predominates; exception = vessels – sympathetic
> Nicotine poisoning tends to produce symptoms that follow a biphasic pattern.
> The initial symptoms are mainly due to stimulatory effects and include: N/V, excessive salivation, abdominal
pain, pallor, sweating, hypertension, tachycardia, ataxia, muscle tremor, headache, dizziness, muscle fasciculations,
and seizures.
> After the initial stimulatory phase, a later period of depressor effects can occur and may include symptoms of
hypotension and bradycardia, central nervous system depression, coma, muscular weakness and/or paralysis, with
difficulty breathing or respiratory failure
Similar sounding drugs:
Midodrine (α1-agonist = systemic vasoconstriction) – used to increase BP in orthostatic hypotension
- often used in patients with advanced liver disease
- Side efeects: supine HTN, urinary retention

Molsidomine >>> metabolized in liver to active linsidomine = NO donor

- unstable compound that releases nitric oxide (NO) upon decay (dilates arteries and veins)
> prevention & long-term treatment of stable/unstable angina pectoris, with or without left heart failure

Minoxidil (prodrug)  active metabolite = minoxidil sulfate

*** used for HTN and male-pattern hair loss
- Mechanism - opening of arteriolar ATP-sensitive K+ channles = hyperpolarization = decreased smooth muscle
contraction = vasodilation – decreased blood pressure
--- vasodilation also promotes more O2 and nutrient delivery to hair follicles = more growth
--- often causes severe reflex tachycardia that must be controlled with B-blockers
--- can produce hirsutism - excessive growth of dark/coarse hair in a male-like pattern -face, chest and back

Milrinone = PDE-3 INHIBTOR = more CAMP available;

- Heart – more cAMP = increase CO and HR
- Vessels – more cAMP = vasodilation
> Pulmonary vasodilator used in patients who have heart failure (cAMP – inhibition of MLCK)
> Acute decompensated HF with cardiogenic shock
***but only for short term use due to risk of arrytmias !

Diazoxide = thiazide derivative but lacks diuretic properties (open K+ channels and decreases insulin)
> given as IV boluses or as an infusion and has several hours’ duration of action.
> opens K+ channels = hyperpolarizing and relaxing smooth muscle cells – decrease BP
*** opens ATP K+ channels in B cells of pancreas = hyperpolarizaiton = less insulin release
– can be used to treat hypoglycemia caused by INSULINOMAS

Dazoxiben – used for Raynaud’s syndrome (vasospasm of small arteries reduces blood flow to end
arterioles – typically in fingers and less commonly toes „red, white, blue”)
--- Raynaud also treated with = Ca2+ channel blockers (dihydropiridines – more vessel effect)
- TXA2 synthase inhibitor
- Recall: TXA2 mainly made in PLTs – spontaenous degradation in 30 seconds