DRUGS Mode of Action Pharmacokinetics Toxicity

  
METHYLDOPA Lowers blood Enters brain via Sedation– the most common
• Use primarily pressure by aromatic amino acid specially at onset of treatment.
for reducing transporter On long term use:
hypertension peripheral • Half-life: 2 hours • Persistent lassitude & impaired
during vascular • Bioavailability: 25% mental concentration.
pregnancy. resistance • Initial dose: 1g/d • Mental Depression, Nightmares ,
• Cause reduction • Maintenance dose: vertigo.
in renal vascular 1-2g/d • Extrapyramidal symptoms--
resistance • Maximal Parkinsonian signs.
antihypertensive • Hyperprolactinemia--- lactation
effect in 4-6 hours in males & females.
and persist up to 24 • Postural hypotension; only in
hours. volume depleted patients
• Positive Coombs test in 10-20 %
cases treated for longer than12
months.
 DRUGS Mode of Action Pharmacokinetics Toxicity

CLONIDINE • Reduces sympathetic • Lipid-soluble and • Sedation –centrally

• 2-imidazoline and increases rapidly enters the brain mediated & dose
derivative parasympathetic tone from the circulation. dependent.
resulting in low BP and • Half-life: 8-12 hours • Xerostomia (dry mouth)
bradycardia • Bioavailability: 95% centrally mediated &
• Reduction of arterial • Initial dose: 0.2 mg/d dose dependent.
blood pressure is • Maintenance dose: 0.2- • Depression--- withdraw
accompanied by 1.2 md/d the drug. C/I in patients
decreased renal • Oral clonidine must be at risk of depression
vascular resistance given twice a day to • Hypertensive crisis on
and maintenance of maintain smooth blood sudden withdrawal.
renal blood flow. pressure control Marked rise in blood
• Reduce blood • Transdermal pressure if drug is
pressure in supine preparation reduces stopped abruptly.
position blood pressure for 7
• Rarely cause postural days.
hypertension.
 
GUANABENZ Centrally active
& antihypertensive drugs
GUANFACINE that share the central
alpha adrenoreceptor
stimulating effects of
clonidine.
Angiotensin-converting Enzyme Inhibitors (ACEI)
Pharmacokinetics:

 active when administered orally

 most of ACEIs are highly polar, eliminated in the urine, without
CNS penetration

fosinopril - metabolized by the liver

enalapril, quinapril - prodrugs  require metabolic conversion
to active metabolites
enalapril, quinapril and lisinopril - given once daily
captopril - administered twice daily
Adverse effects and contraindications of ACEI:
 They are generally well tolerated. Adverse effects include:

First dose hypotension - particularly in those receiving diuretic

therapy; the first dose should preferably be given at bedtime.
Dry cough
- the most frequent (5-30%) symptom; could be reduced by treatment
with sulindac (inhibits prostaglandin biosynthesis)
Urticaria and angioneurotic edema
-  kinin concentrations  urticarial reactions and angioneurotic
edema)
Functional renal failure
- occurs predictably in patients with hemodynamically bilateral renal
artery stenosis, and in patients with renal artery stenosis in the vessel
supplying a single functional kidney (though they protect the diabetic
kidney) - !!! renovascular disease !!!
Fetal injury
- results in oligohydramnios, craniofacial malformations
- contraindication in pregnancy
Therapeutic combination:
- useful
Interactionof ACEIs with diuretics: Converting enzyme inhibitors interrupt by diuretics
increased plasma renin activity (and the consequent activation of angiotensin II and
aldosterone) and enhance the antihypertensive efficacy of diuretics, as well as
reducing thiazide-induced hypokalemia.
- Adverse
- Interaction of ACE inhibitors with potassium-sparing diuretics and potassium
supplements, leading to hyperkalemia especially in patients with renal impairment !!!
NSAID – ↑ renal damage
B) BLOCKERS OF AT1 RECEPTOR
losartan, valosartan, irbesartan

The receptor blockers - competitively inhibit angiotensin II at its AT1

receptor site
Most of the effects of angiotensin II - including vasoconstriction and
aldosterone release - are mediated by the AT1 receptor
AT1-blockers do not block AT2 receptor, which is exposed to high
concentration of angiotensin II during treatment with AT1-blockers
they influence RAS more effective because of selective blockade
angiotensin II synthesis in tissue is not completely dependent only on
renin release, e.g. in heart, but could be promote by serin-protease -
stronger influence on the myocardial remodeling.
 these drugs lower blood pressure as the ACE inhibitors and have the
advantage of much lower incidence of adverse effects resulting from
accumulation of bradykinin (cough, angioneurotic oedema)
 they cause fetal renal toxicity (like that of the ACE inhibitors)
 these drugs reduce aldosterone levels and cause potassium accumulation
(attainment of toxic levels - hazardous in patients with renal impairment).
Ace inhibitors
current status:
• 1st line antihypertensive drug
• Used in relatively young patients
• Most appropriate antihypertensive in patients with:
diabetes
Chronic kidney disease
Left ventricular hypertropy
Angina,post mi,stroke
Gout

Avoid in: pregnancy, bilateral renal artery stenosis, hyperkalemia

Ace inhibitors (2 important ones)

Captopril:
• Sulfhydryl containing peptide
• Not a prodrug
• Half life :2hrs, multiple doses

Enalapril:
• Prodrug-converted to enalaprilate
• Advantages over captopril
#more potent
# longer duration of action – once daily dose
# absorbtion not affected by blood
# rash and loss of taste are less frequent
# slower onset of action, hence first dose for hypertension
less marked
BLOCKERS OF AT1 RECEPTOR

ANGIOTENSIN RECEPTOR-BLOCKING AGENTS=

• Losartan and valsartan were the first marketed blockers of the angiotensin
II type 1 (AT 1 ) receptor. Candesartan, eprosartan, irbesartan, telmisartan,
and olmesartan are also available.
• No effect on bradykinin metabolism
• More selective blockers of angiotensin effects than ACE inhibitors.
• More complete inhibition of angiotensin action compared with ACE inhibitors
because there are enzymes
• other than ACE that are capable of generating angiotensin II.
• Angiotensin receptor blockers provide benefits similar to
those of ACE inhibitors in patients with heart failure and
chronic kidney disease.

• The adverse effects are similar to those described for ACE

inhibitors, including the hazard of use during pregnancy.

• Cough and angioedema can occur but are uncommon.

• Angiotensin receptor blocking drugs are most commonly used

in patients who have had adverse reactions to ACE inhibitors.
Subclass Mechanism of Effects Clinical pharmacokine
action application tics
• Aliskiren inhibits Reduces Hypertension Oral • Toxicity:
enzyme angiotensin I Hyperkalemia,
activity of and II and renal
renin aldosterone impairment •
potential
teratogen