alpha blockers easy to under with the help of diagrams

1. ALPHA blockers
Dr. Resu Neha Reddy
2nd year PG
MD Pharmacology
Osmania Medical College

2. HISTORY
 HENRY DALE IN 1913  Adrenaline constricted some blood vessels while
relaxing others
 ALQUIST in 1948 2 types of receptors - excitatory alpha
- Inhibitory beta
 LANGER 1974  2 types of alpha - postsynaptic alpha 1
- presynaptic alpha 2  negative feedback
 BENTLEY 1977 – 2 types of postsynaptic alpha 1
- Prazosin sensitive type - blocked by Prazosin
- Prazosin insensitive type – not blocked by Prazosin
ADRENO
RECEPTORS
ANTAGONISTS

3. HISTORY
ALQUIST SIR HENRY DALE

4. ADRENO
RECEPTORS
ANTAGONISTS

5. RECEPTOR G PROTEIN EFFECTS GENE ON CHROMOSOME
α 1 type :
α 1A
α 1B
α 1D
Gq IP3 , DAG
C8
C5
C20
α 2 type :
α 2 A
α 2 B
α 2 C
Gi cAMP
C10
C5
C4
β type :
β1
β2
β3
Gs cAMP
C10
C5
C8

6. ADRENO
RECEPTORS
ANTAGONISTS

7. ALPHA 1 RECEPTORS ADRENO
RECEPTORS
ANTAGONISTS

8.  G-protein coupled receptors coupled with inactivation of adenylyl cyclase
 This results in decreased release of cAMP hence intracellular calcium
 As calcium levels fall, the release of neurotransmitter from nerve terminal by exocytosis is
inhibited
ADRENO
RECEPTORS
ANTAGONISTS

9. PROBES
Sympathetic Receptors
α1
α2A Pre-synaptic
Alpha α Beta β
α2
α1A α1B/1D α2B Post-synaptic
Prostatic
urethra
capsule Eye-radial
m/s
Sphincters
Blood
vessels
Act like
BRAKE to
symp.
system
Blood
vessels
Brain
Heart
JG cells
Bronchus
GIT
Bladder Uterus
Liver
Skeletal muscle
spindle
Blood vessels
Adipose
tissue
Urinary
bladder
β1 β2 β3
ADRENO
RECEPTORS
ANTAGONISTS

10. CLASSIFICATION ALPHA ADRENERGIC BLOCKING DRUGS
NATURAL AND
HYDROGENATED
ERGOT ALKALOIDS
IMIDAZOLE
DERIVATIVES:
SELECTIVE α BLOCKERS :
PHENOXYBENZAMINE
DIBENAMINE
SELECTIVE α1 BLOCKERS : SELECTIVE α2 BLOCKERS :
PRAZOSIN
TERAZOSIN
DOXAZOSIN
ALFUZOSIN
TAMSULOSIN (α1A)
SILODOSIN
INDORAMIN
URAPIDIL
BUNAZOSIN
Β HALOALKYLAMINES :
PHENTOLAMINE
TOLAZOLINE
YOHIMBINE
IDAZOXAN
MIRTAZAPINE
ADRENO
RECEPTORS
ANTAGONISTS
NON SELECTIVE α BLOCKERS (α1 + α2) :

11. ADRENO
RECEPTORS
ANTAGONISTS
 Miosis
 Diarrhoea
 Na+ retention & Blood volume INCREASE- Renin
mediated through β1
 Urine flow INCREASE – BHP

12. PHENOXYBENZAMINE
 Covalent bond – irreversible
 ADME : ORAL – erratic & incomplete
IM & SC very painful
Lipid soluble
Accumulation toxicity
3 – 4 days – until fresh receptor
synthesis
 S/E : Mutagenic in Ames test- peritoneal
sarcomas and lung tumor
 DOSE : Oral- 20-60mg/day
IV - 1mg/kg slow IV infusion over 1hr
ADRENO
RECEPTORS
ANTAGONISTS

13. PHENOXYBENZAMINE
 USES : 1. Pheochromocytoma 1mg/kg slow IV
10mg BD 1-3weeks pre-operative
Alternate day rise in dose until desired effect reached
 40- 120mg BD/TID
Malignant Pheochromocytoma – Metyrosine
2. BHP
3. Raynaud’s disease ( 10mg TDS orally )

14. PHENTOLAMINE
 Imidazole , competitive inhibitor
 α1 = α2
 Increases NA release
 Venodialatation >>> arteriolar
 USES :
1. Dx & management of Pheochromocytoma – short term, pseudo obstruction of
bowel
2. Peripheral vascular disease – Raynaud’s phenomenon, frostbite
3. Prevent dermal necrosis (s.c)
4. Rx of HTN crisis - Clonidine withdrawal , Cheese reaction
ADME : Oral – poor
Administered IV
Immediate onset
Short DOA
T1/2 – 5-7 hrs
ADRENO
RECEPTORS
ANTAGONISTS
TOLAZOLINE :
Similar
Less potent
Better absorbed – GIT
Rarely used now-a-days

15. ADRENO
RECEPTORS
ANTAGONISTS

16. Reversal of response
vasoconstriction to vasodilatation
produced by alpha blocker is called as
Dale’s vasomotor reversal
ADRENO
RECEPTORS
ANTAGONISTS

17. Dale’s vasomotor reversal

19. ADRENO
RECEPTORS
ANTAGONISTS

20. PRAZOSIN
 α1 selective antagonist
 α1 : α2 selectivity ratio 1000:1
 α1A α1B α1D equally blocked
 Decreases BP
 Arteriolar dialatation >> veins
 Tolerance
 Replaced Phenoxybenzamine
 Inhibits phosphodiesterase - increase cAMP  vasodilation
ADRENO
RECEPTORS
ANTAGONISTS

21.  USES : Anti-HTN
BHP (1-5mg orally BD)
Increase urine flow
Favour – Lipid profile
CHF
Raynaud’s phenomenon
ADRENO
RECEPTORS
ANTAGONISTSPRAZOSIN
ADME : Orally – 60% BA
High bound - α1 acid glycoprotein
M : Liver E : Bile
t1/2 : 2-3hrs
DOA : 6-8hrs

22. ADRENO
RECEPTORS
ANTAGONISTS

23. TERAZOSIN & DOXAZOSIN
 Similar to Prazosin action
 α1A = α1B = α1D #
 Quinozoline nucleus  APOPTOTIC activity
 Apoptosis >> α #
 USES : HTN
BHP
TERAZOSIN : Oral, Long acting
BA > 90%
t1/2 : 12hrs
DOSE : 2-5 mg oral OD
DOXAZOSIN : t1/2 : 20hrs
DOA – 36hrs
DOSE : 1mg daily oral to start
increased to 8mg daily
ADRENO
RECEPTORS
ANTAGONISTS

24. ALFUZOSIN
 Quinozoline based α1 selective #
 USES : BHP – extensively used
 C/I : CYP3A4 ihibitors should be avoided  Inhibit Alfuzosin metabolism
 DOSE : 2.5mg TDS orally
10mg OD extended release
ADRENO
RECEPTORS
ANTAGONISTS
ADME : Oral
t1/2 : 3-5hrs
BA : 65%
M : extensively in LIVER

25. TAMSULOSIN
 Benzene sulphonamide α1 #
 α1 – uroselective / predominant in prostrate
 No apoptosis  Non-quinolazone
 Minimal effect on BP
 USES : BHP (along with Finasteride)
 S/E : Retrograde ejaculation
Floppy iris syndrome
 DOSE : 0.2 – 0.4 mg Oral
ADRENO
RECEPTORS
ANTAGONISTS
ADME : Oral
BA : 100%
t1/2 : 5-10hrs
M : CYP
SILADOSIN : Tamsulosin analogue
Longer acting
Orally effective
S/E : Increased Retrograde ejaculation
Increased postural hypotension
DOSE : 4-8 mg OD

26. TAMSULOSIN

27. PHARMACOLOGICAL USES OF α BLOCKERS
1. ESSENTIAL HTN
2. CHF : Prazosin – Vasodialator, Reduce preload
3. BHP
4. Secondary shock : Phenoxybenzamine
5. PVD : Raynaud’s syndrome
Acrocyanosis
Rx : Prazosin / Phenoxybenzamine
ADRENO
RECEPTORS
ANTAGONISTS

28. YOHIMBINE (α2 #)
 Natural alkaloid – BARK of Pausinystalia Yohimbe
 Promotes NA release – central & periphery
 Lipid soluble – cross BBB
ADRENO
RECEPTORS
ANTAGONISTS
USES : Male erectile dysfunction
Diabetic neuropathy
Postural hypotension – NA transport blocking drugs
Reverse Anti-HTN effect of Clonidine
Veterinary medicine – Reverse Xylazine anaesthesia
S/E : Abruptly reverse anti-HTN affect of α2 agonist (Drug interaction)

29. ADRENO
RECEPTORS
ANTAGONISTS
Peripherally & centrally acting adrenergic # drugs
Peripherally acting adrenergic # drugs
# Vesicular NE uptake

30. CHEESE REACTION

31. INTERESTING FACT !!
Dr. Frances Kathleen Oldham Kelsey
kept thalidomide out of u.s.
Received the president’s award for distinguished federal civilian service from President John F Kennedy, 1962

32. ADRENO
RECEPTORS
ANTAGONISTS
Thank You..