Antihypertensive agents week 1 Flashcards
Alpha-methyldopa
function
uses
toxicity
- converted to α methyl norepinephrine (α agonist centrally)
- stimulates central α2 receptors, “fooling” the body’s
neural control mechanism by reducing efferent
sympathetic activity
- old drug with continued use in hypertension of
pregnancy (found safe over the years)
short half-life (4 hours) long biologic action (24 hours)
Clinical Pearl -
(Note: biologic half-life in blood often unrelated to drug
duration of action) it’s what is at the receptor site.
- toxicity – sedation, CNS effects, Coombs test positive hemolytic anemia, SLE-like syndrome, hepatitis
Clonidine, guanbenz, guanfacine
function
uses
toxicity
- central alpha agonist
- α2 stimulation reduces norepinephrine release, which
reduces the increase in HR seen with other agents
Uses: hypertensive urgency (limited situations), ADHD, Tourette syndrome, CNS anxiety in opiate withdrawal
toxicity – dry mouth, sedation, CNS depression, orthostatic hypotension, bradycardia, respiratory depression, loss of appetite, fatigue, nasal congestion, miosis, rapid withdrawal can result in hypertensive crisis
- CNS toxicity reduces its use, third line agent
guanabenz, guanfacine: less CNS toxicity, similar mechanisms of action to clonidine
Guanethidine, guanadrel
function
uses
toxicities
drug interactions
Guanethidine:
● Competitive reuptake inhibitor-acts as NET substrate
● Gradual depletion of norepinephrine (blocked by cocaine, amphetamine, tricyclic anti-depressants, phenothiazine, phenoxybenzamine) – thus significant drug interactions that can prevent drug action. (note that cocaine, amphetamines, and TCAs interact with NET-see excel sheet for details)
● Toxicity – orthostatic hypotension, retrograde ejaculation, diarrhea, hypertensive crisis in pheochromocytoma patients (releases the excess catecholamines from the tissues)
Availability of supplies intermittent –Last line treatment in refractory hypertension
Guanadrel – like guanethidine, currently more available
- Same side effects from pharmacodynamics actions
Resperine
function
uses
toxicities
Reserpine -
● from Rauwolfia serpentina (plant) India origin
● VMAT inhibitor-inhibits concentration of NE into vesicles
● Toxicity: Sedation, nightmares, depression, extrapyramidal effects (stiffness, rigidity)
● Suicide from drug induced depression a major limiting
problem with its clinical use
● Old agent (infrequently used USA) – due to toxicity
Hydralazine
function/mechanism
use
toxicities
How is it metabolized? How are side effects different with differences in metabolism?
What type of drug is often coadministered and why?
Hydralazine
- Mechanism of action through nitric oxide production by vascular endothelium: increase cGMP. Vasodilates arterioles > veins; afterload reduction
- Uses:
- Severe HTN (particularly acute), HF (with organic nitrate). Safe to use during pregnancy. Frequently coadministered with B blockers to prevent reflex tachycardia.
Toxicities:
-compensatory tachycardia (CI in agina, CAD), fluid retention, headache, agina, lupus like syndrome, peripheral neuropathy, fever
Metabolism – acetylation, slow & fast metabolizers.
- Rapid acetylators lower levels and less lupus like syndrome since it is the non-acetylated drug that causes antibody formation and syndrome.
- Slow acetylators greater amount of hydralazine and more lupus like syndrome
Tolerance – diminished effect over time
Minoxidil
mechanism
uses
toxicities
What kind of drugs must be used in conjunction with minoxidil? Why?
What is the active metabolite?
Minoxidil
- Hyperpolarization of smooth muscle – K channel opener causing depolarization to be more difficult (decreases vascular contraction)
- Active metabolite – Minoxidil sulfate
- Increase HR - reaction to ↓ BP-combine with B blocker
- Increase fluid & salt retention, need to use with diuretic
Uses:
Very potent – used in resistant hypertension – 3rd line agent
Toxicities:
-Hypertrichosis – hair growth (used topically to treat male pattern baldness) hair in “wrong” places is a toxicity (face of woman) – hypertrichosis
Sodium Nitroprusside
mechanism
uses
toxicities
mode of administration
Contraindications
What drug is given as antidote for one of the toxicities of this drug?
Sodium Nitroprusside
-Intravenous only – for severe hypertension and heart failure, used in ICU
- Releases nitric oxide-Activates guanylyl cyclase – dilates vasculature
- Very light sensitive – drug administration set wrapped in aluminum foil to block light
- Dilates both arteries & veins – very potent
- Metabolized to thiocyanate or cyanide by rhodanese (mitochondrial enzyme), enzymedeficiency develops with prolonged administration – thiocynate may accumulate and be toxic (hepatic toxic leading to coma)
- Thiosulfate may correct rhodanese depletion (provides thiol needed for formation of thiocyanate
- Duration of action 10 min-short acting
- Hydroxocobalamin antidote to cyanide poisoning and toxicity due to drug
- Metabolic acidosis may result from drug therapy
- CI: Decreased renal function increases toxicity, thiocyanate build up, drug & metabolite cleared by kidney
- Thiocyanate toxicity: disorientation, psychosis, muscle spasm, convulsions
- Thiocynate interferes with iodine & thus results in thyroid dysfunction
- Methemoglobinemia can develop decreasing hemoglobin O2 release
Diazoxide
mechanism
uses
toxicities
mode of administration
What drugs are coadministered and why?
Diazoxide
- IV only. High affinity to albumin so often given as bolus (time to action 5 min)
- Hyperpolarizing agent of cell membrane in vasculature so vessels do not vasoconstrict
- Thiazide like without diuretic activity
Toxicity: hypotension, hyperglycemia (give with insulin), fluid retention – given with diuretic
Fendolapam
mechanism
uses
toxicities
mode of administration, time of action
Fenoldopam
- Agonist of dopamine (D1) receptors
- Dilates arteries and causes natriuresis
- 10 min half-life (short acting), IV agent
Uses:
Hypertensive emergencies. Used for hypertension during and after surgery
Toxicities:
Increase intraocular pressure (don’t use in patients with
glaucoma)
ACE inhibitors
drugs in this class and their polarities, relative length of action
use
toxicities
contraindications
ACE Inhibitors
Mechanism: Inhibit ACE–> decreased ATII–> decreased GFR by preventing constriction of efferent arterioles. Levels of renin increase as a result of loss of feedback inhibition. Inhibition of ACE also prevents inactivation of bradykinin, a potent vasodilator.
Captopril
- Polar
- Short half-life
- Pro - drug
Enalapril
- Prodrug
- Intermediate half-life
- Polar
Lisinopril
- Long half-life
- Polar
- Pro drug
Quinapril/ramipril
- Pro drugs
- Lipophilic (non polar) – more tissue uptake
- Long half-life
Use:
HTN, HF, proteinuria, diabetic nephropathy (decreased intraglomerular pressure slows GBM thickening). Prevents unfavorable heart remodeling as result of HTN
ACE toxicity
Captorpril’s CATCHH: Cough, Angioedema, Teratogen, Hyperkalemia, Hypotension
Hyperkalemia
Azotemia
Hypotension
Cough – due to inhibition of bradykinin breakdown (↑bradykinin an irritant)
Teratogen FA: fetal renal malformations. Notes: Cranial facial abnormalities – 2nd & 3rd trimesters pregnancy
Drug fever
Angioedema – allergic reaction bradykinin, CI in C1 esterase inhibitor deficiency
Increased creatinine (decreases GFR)
Avoid in bilateral renal artery stenosis bc ACE inhibitors will furthere decrease GFR–> renal failure
ARBs (angiotensin receptor blockers)
drugs in this class
mechanism action
use
toxicities
contraindications
What drugs should not be administered with ARBs?
Losartan, candesartan, valsartan
Mechansim: Selectively block binding of ATII to AT1 receptor. Effects similar to ACE inhibitors but ARBs do not increase bradykinin.
Use: Hypertension, HF, proteinuria, diabetic nephropathy with intolerance to ACE inhibitors (eg cough, angioedema)
Toxicity: Hyperkalemia, decreased renal function, hypotension, teratogen
Advantages & Concerns
- less to no cough
- do not combine with ACE – worsens outcome – too low BP
- Angioedema – rare, but possible with ARBS, more likely with those who have angioedema with ACE.
Aliskiren
mechanism action
use
toxicities
contraindications
Mechanism: direct renin inhibitor, blocks conversion of angiotensiongen to angiotensin I
Uses: HTN
Toxicities: hyperkalemia, decreased renal function, hypotension
CI in diabetics taking ACE inhibitors or ARBs
